Abstract

Interhemispheric inhibition (IHI) refers to the neurophysiological mechanism in which one hemisphere of the brain inhibits the opposite hemisphere. IHI can be studied by transcranial magnetic stimulation using a conditioning-test paradigm. We investigated IHI from 5 motor related cortical areas in the right hemisphere to the left primary motor cortex (M1). These areas are hand and face representations of M1, dorsal premotor cortex, somatosensory cortex, and dorsolateral prefrontal cortex. Test stimulus was delivered to the left M1 and conditioning stimulus (CS) was delivered to one of 5 motor related cortical areas in the right hemisphere. The time course of IHI, effects of different CS intensities and current directions on IHI were tested. Maximum IHI was found at interstimulus intervals of ∼10 ms (short latency IHI, SIHI) and ∼50 ms (long latency IHI, LIHI) for the motor related areas tested. LIHI could be elicited over a wide range of CS intensities, whereas SIHI required higher CS intensities. We conclude that there are 2 distinct phases of IHI from motor related cortical areas to the opposite M1 through the corpus callosum, and they are mediated by different neuronal populations.

Introduction

Interhemispheric inhibition (IHI) refers to the neurophysiological mechanism in which one hemisphere inhibits the opposite hemisphere. IHI between homologous primary motor cortices (M1) can be studied by transcranial magnetic stimulation (TMS) with a conditioning-test paradigm. It was found that the first conditioning stimulus (CS) inhibits the motor evoked potential (MEP) generated by the second test stimulus (TS) applied over the contralateral M1 at interstimulus interval (ISI) of 6–50 ms (Ferbert et al. 1992; Gerloff et al. 1998). Further studies in patients with cortical or subcortical infarction (Boroojerdi et al. 1996) and studies of ipsilateral silent period in patients with agenesis of the corpus callosum (Meyer et al. 1995, 1998) supported the view that this inhibition is produced via a transcallosal pathway. Direct evidence that IHI involves cortical inhibition was obtained from the recordings of descending corticospinal volleys in patients with implanted epidural electrodes (Di Lazzaro et al. 1999b). Subsequent studies reported that IHI between homologous M1s at ISIs of ∼10 ms (short latency IHI; SIHI) and ∼40 ms (long latency IHI; LIHI) may have different physiological origins (Chen et al. 2003; Kukaswadia et al. 2005). Pharmacological study proposed that LIHI is mediated by postsynaptic gamma-aminobutyric acid type B (GABAB) receptors, whereas the transmitter system mediating SIHI remains inconclusive (Irlbacher et al. 2007).

Recently, it was reported that CS over the dorsal premotor cortex (PMd) also inhibits the MEP generated by TS over the contralateral M1 at certain ISIs and CS intensities (Mochizuki et al. 2004a;b). These studies raised the possibility that IHI is a widely distributed physiological mechanism produced not only by the M1, but also by other motor related cortical areas. The purpose of the present study is to systematically explore IHI from different motor related cortical areas to the contralateral M1. The motor related cortical areas of interest are the hand (M1Hand) and facial representations (M1Face) of M1, PMd, somatosensory cortex (S1), and dorsolateral prefrontal cortex (DLPFC). M1Hand was selected because IHI between homologous M1s is important for the execution of unimanual and coordinated bimanual movements (Duque et al. 2005; Perez et al. 2007). M1Face was selected because it is close to M1Hand on the somatotopic map of M1 and the facial motor system has unique feature (Paradiso et al. 2005). It was reported that facial muscles may be under both voluntary and emotional control and may have bilateral cortical innervation (Lees 1988). PMd and S1 were selected because they are important for the precise timing and execution of unimanual and coordinated bimanual movements (Geffen et al. 1994; Andres et al. 1999). DLPFC was selected because it is important in decision making during voluntary movement (Hadland et al. 2001; Fecteau et al. 2007). We investigated whether different neuronal pathways and populations are involved in the IHI from these 5 motor related cortical areas. The time course, CS intensity recruitment curve and the effect of CS current direction on IHI were studied for each cortical area.

Materials and Methods

Subjects

We studied 12 right-handed healthy subjects (4 women and 8 men, aged 25–47 years, mean age 32.5 ± 7.2 years). Handedness (laterality quotient, 97.5 ± 6.2) was confirmed using the Oldfield Handedness Inventory (Oldfield 1971). All subjects provided written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University Health Network (Toronto) Research Ethics Board.

Electromyogram Recording

Surface electromyograms (EMG) were recorded from the left and right first dorsal interosseous (FDI) muscles with 9 mm diameter Ag–AgCl surface electrodes. The active electrode was placed over the muscle belly, and the reference electrode over the metacarpophalangeal joint of the index finger. The signal was amplified (1000×), band-pass filtered (2 Hz-2.5 kHz, Intronix Technologies Corporation Model 2024F, Bolton, Ontario, Canada), digitized at 5 kHz by an analog-to-digital interface (Micro1401, Cambridge Electronics Design, Cambridge, UK) and stored in a computer for off-line analysis.

Transcranial Magnetic Stimulation

The TS was applied to the left M1 with a regular figure-of-8 shaped coil (outside diameter of each loop was 9.5 cm) connected to a Magstim 200 stimulator (Magstim, Whitland, Dyfed, UK). The handle of the coil pointed backward at 30–45° from the mid-sagittal line. The induced current in the brain was in the anterior-medial direction, approximately perpendicular to the central sulcus. With this current direction (posterior–anterior, PA), pyramidal neurons are activated trans-synaptically and produce early I waves (Kaneko et al. 1996; Di Lazzaro et al. 2001). The optimal position for activation of the right FDI muscle was marked with a pen as the motor hot spot. Next, we determined TS1mV for each subject. TS1mV was defined as the lowest TS intensity needed to generate MEPs of more than 1 mV in at least 5 out of 10 trials in the right FDI muscle when the muscle was completely relaxed. We used TS1mV (50.3 ± 6.2% of maximum stimulator output, n = 12) as the TS intensity for all experiments.

Four Magstim 200 stimulators, 3 Bistim modules (Magstim, Whitland, Dyfed, UK) and a custom made, small figure-of-8 shaped coil (handle perpendicular to the coil plane; outside diameter of each loop 8 cm) were used to apply CS to the right hemisphere. Each pair of Magstim 200 stimulators was connected to a Bistim module, and the 2 Bistim modules were connected to a third Bistim module. The TMS coil was connected to the third Bistim module. This “pyramid” setup allowed us to deliver pulses of up to 4 different stimulus intensities at short intervals and is associated with power attenuation of about 15% (Sanger et al. 2001). We used this setup for all experiments. For Experiment 1 and 3, only one stimulator was discharged. For Experiments 1 and 2, the coil was placed perpendicular to the mid-sagittal line and it induced medially directed current in the brain (Sakai et al. 1997). We referred to this coil direction as M (medial) direction (Fig. 1). We selected this coil direction to avoid overlapping of the 2 coils. CS intensity was CS1mV for Experiments 1 and 3 and was the lowest stimulus intensity to generate MEP > 1 mV in at least 5 out of 10 consecutive trials in left FDI muscle with CS coil placed over M1Hand in the M direction. CS1mV was 55.7 ± 6.3% (n = 12) of maximum stimulator output. Different CS intensities were tested in Experiment 2.

Figure 1.

Stimulation sites for the study. A 3-dimensional structural MRI of one representative subject. CS coil (small figure-of-8 coil) was placed over the right hemisphere to induce medially (M) directed current in the brain (red arrow). The 5 red dots represent the areas stimulated with the CS coil. They are M1Hand (1), M1Face (2), PMd (3), S1 (4), and DLPFC (5). The TS (regular figure-of-8 coil) was applied over the hand representation of the left hemisphere which induced current in PA direction in the brain (yellow arrow).

Figure 1.

Stimulation sites for the study. A 3-dimensional structural MRI of one representative subject. CS coil (small figure-of-8 coil) was placed over the right hemisphere to induce medially (M) directed current in the brain (red arrow). The 5 red dots represent the areas stimulated with the CS coil. They are M1Hand (1), M1Face (2), PMd (3), S1 (4), and DLPFC (5). The TS (regular figure-of-8 coil) was applied over the hand representation of the left hemisphere which induced current in PA direction in the brain (yellow arrow).

Locations of the Conditioning Stimuli

CS was delivered to one of 5 cortical areas in the right hemisphere: M1Hand and M1Face, PMd, S1, and DLPFC (Fig. 1 shows the CS locations in one representative subject). A magnetic resonance imaging (MRI)–guided neuro-navigational system (Brainsight Frameless; Rogue Research Inc., Montreal, Quebec, Canada) was used to verify the location of the CS coil. MRI was conducted on a 3T GE scanner using an 8-channel volume headcoil. Anatomical images were acquired with 3DFSPGR-IR sequence using a 20 cm field of view (256 × 256) for 172 slices in total. The high-resolution structural T1-weighted MRI of the subject was imported to the Brainsight software and was coregistered with the fiducial landmarks for each subject and the center of the TMS coil. The Brainsight system allows visualization of the coil location in relation to the brain in real time to ensure accurate online positioning. M1Hand was defined as the motor hot spot of left FDI muscle and M1Face as the hot spot for the left masseter muscle (Guggisberg et al. 2001; Paradiso et al. 2005). PMd was defined as the area 2.5 cm anterior and 1 cm medial to M1Hand measured from the scalp (Mochizuki et al. 2004a). This area is located on the superior frontal gyrus. S1 was defined as the area posterior to M1Hand on the postcentral gyrus. DLPFC was defined as the area 5 cm anterior to M1Hand measured from the scalp (Herwig et al. 2001). This area is located on the middle frontal gyrus. In addition, we checked the locations for PMd and DLPFC with respect to the individual MRI. We slightly adjusted the CS coil to make sure that the stimulating coil was on the gyrus of the individual. Following the IHI study, we coregistered the MRI of each subject to the standard Talairach atlas (Analysis of Functional Neuroimaging software, National Institutes of Health, Medical College of Wisconsin, Milwaukee, WI) to identify the coordinates for each location of CS coil. The ranges of Talairach's coordinates in all subjects are (23-45R, 7-23P, 44-60S) for M1Hand, (47-57R, 6-17P, 38-52S) for M1Face, (19-36R, 5A-5P, 45-60S) for PMd, (26-44R, 24-37P, 50-58S) for S1, and (30-46R, 9-22A, 39-51S) for DLPFC (R, right; P, posterior; A, anterior; S, superior).

Data Analysis and Statistical Analysis

MEP amplitudes were measured peak-to-peak. The MEP amplitude evoked by paired-pulse (CS–TS) stimulation was expressed as a percentage of the mean MEP amplitude of TS alone. Values below 100% indicate inhibition and values above 100% indicate facilitation. Unless otherwise stated, values are reported as mean ± standard deviation.

Repeated measures ANOVA was used for statistical analysis. The Greenhouse–Geisser correction was used to correct for nonsphericity. Post hoc test was used when ANOVA showed significant main effects. SPSS (10.0) software (SPSS Inc., Chicago, IL) was used for statistical analysis. The significance level was set at P < 0.05. Statistical analysis for each experiment is described in greater detail below.

Experiment 1: The Time Courses of IHI

The time courses of IHI from all 5 CS locations were investigated in all 12 subjects. Thirteen ISIs (4, 6, 8, 10, 12, 16, 20, 30, 40, 50, 60, 80, and 100 ms) were investigated because a previous study reported peak IHI at ISIs of ∼10 and ∼40 ms for M1–M1 interaction (Chen et al. 2003). CS intensity was CS1mV and TS intensity was TS1mV. Ten trials for each ISI and twenty trials for TS alone (total of 150 trials) were delivered in random order for each subject. Different CS locations were tested in separate runs in counterbalanced order. A 2-way repeated measures ANOVA was used to examine the effects of ISI and CS location (within-subject factors) on IHI. Separate one-way repeated measures ANOVA with ISI as the within-subject factor was conducted for each CS location to examine the time courses of IHI at different cortical areas tested. The MEPs for each ISI were compared with those from TS alone using the paired t-tests with Bonferroni correction for multiple comparisons to determine at which ISIs and CS locations there were significant IHIs.

We performed 5 control experiments to confirm the IHI found in the main experiment. The first control experiment is to clarify at which level (cortical or subcortical) IHI is produced. We compared the effect of the TS as TMS versus transcranial electrical stimulation (TES) in 4 subjects (one woman, aged 34.0 ± 7.0 years). TES was performed using a Digitimer D180A high-voltage stimulator (Digitimer, Welwyn Garden City, UK, maximum output 1500 V) with the time constant set at 100 μs (Chen and Garg 2000). Cup electrodes with conducting gel were used. Anode was placed over the motor hot spot (determined by TMS) and cathode was placed over the vertex. TS1mV for TES was then determined (similar to TMS). TMS was used as CS at an intensity of CS1mV. ISIs of 10 and 50 ms were tested because peak IHIs were found at these ISIs in the main experiment. Because the latency of MEPs generated by TES is about 2 ms shorter than those generated by TMS, the ISIs for CS–TES combination were adjusted to 12 and 52 ms (Rothwell 1997). Six conditions were tested: CS–TES (ISIs 12 and 52 ms), CS–TMS (ISIs 10 and 50 ms), TES alone and TMS alone. TS intensities were TS1mV for both TMS and TES. Because TES caused pain in most subjects, we only recorded 5 trials for each condition. Thirty trials for each CS location were delivered in random order. Data for different CS locations was collected in separate run in counterbalanced order. A 3-way repeated measures ANOVA (stimulus type, ISI and CS location were the within-subject factors) was conducted. Post hoc paired t-tests with Bonferroni correction for multiple comparisons were used to examine whether MEPs generated by TES and TMS were different.

The second control experiment examined the contribution of spinal activities to SIHI and LIHI found in the main experiment. We examined whether H-reflex amplitude was changed by the CS in 5 subjects (one woman, aged 33.4 ± 9.2 years). H-reflex was recorded in right flexor carpi radialis (FCR) muscle with active electrode placed over the muscle belly and reference electrode placed about 2 cm away. Electrical stimulation delivered by a Digitimer DS7A constant current stimulator (Digitimer, pulse width 1 ms) connected to a bar electrode placed over the median nerve at the elbow was used as TS to evoke H-reflex. The TS intensity was adjusted to generate H-reflexes of ∼0.5 mV in amplitude. We measured the latencies of H-reflex and TMS induced MEP in the FCR muscle for each subject. The latency of H-reflex was about 3 ms longer than that of MEP. ISIs of 10 and 50 ms were tested and they were adjusted with the individual difference of latencies in H-reflex and MEP (e.g., 7 and 47 ms were used for the subject who showed latency difference of 3 ms). The stimulation configuration included 3 states: one for TS alone and 2 for the adjusted ISIs. Ten trials for each state (30 trials in total) were delivered in random order. M1Forearm (motor hot spot for left FCR muscle), M1Face, PMd, S1, and DLPFC were selected for the CS locations. The CS intensity was set to generate ∼1 mV MEP in the left FCR muscle when CS was placed over M1Forearm. Data for different CS locations was collected in separate run in counterbalanced order. A 2-way repeated measures ANOVA with ISI and CS location as the within-subject factors was conducted to examine whether forearm H-reflex was inhibited at different ISIs and CS locations.

The third control experiment was performed in 6 subjects (one woman, aged 31.2 ± 7.1 years) to test for nonspecific effects of TMS such as click sound by applying the CS outside the motor related cortical areas of interest. The CS coil was placed on the inion. The test conditions were otherwise the same as that used in the main experiment. One-way repeated measures ANOVA with ISI as the within-subject factor was conducted to examine the time course.

The fourth control experiment was performed in 5 subjects (one woman, aged 33.4 ± 9.2 years) to test for the effects of sensory feedback caused by TMS which may potentially contaminate the LIHI. We used electrical stimulation on the ulnar nerve at the left wrist instead of TMS as the CS to mimic the muscle twitch of the FDI muscle caused by TMS. Electrical stimulation was delivered by a Digitimer DS7A constant current stimulator with pulse width of 200 μs connected to a bar electrode with conducting gel. The intensity was adjusted to generate ∼1 mV compound muscle action potential in the left FDI muscle. Nine ISIs (10, 15, 20, 25, 30, 35, 40, 50, 60 ms) were studied. Because MEP latency from TMS is about 20 ms, these selected ISIs are corresponded to the ISIs of ∼30–80 ms used in the main experiment where LIHI was found. TS was the same as that used in the main experiment. Ten trials for each ISI and TS alone (100 trials in total) were delivered in random order. One-way repeated measures ANOVA with ISI as the main factor was conducted to examine the time course of this effect.

The fifth control experiment was performed in 6 subjects (one woman, aged 31.2 ± 7.1 years) to exclude the possibility that IHI was caused by stimulation of sensory afferents in the scalp. We replaced the TMS with electrical stimulation over the scalp as the CS. The electrical stimulation was delivered by a Digitimer DS7A constant current stimulator with the pulse width at 200 μs (Okabe et al. 2003) connected to cup electrodes with conducting gel. Anode was placed on one of 5 CS locations and cathode was placed on the vertex. The intensity was set at 2 times sensory threshold. At this intensity, the skin and scalp muscles are stimulated but there is no effective stimulation of the brain because of high resistance of the skull. ISIs of 10 and 50 ms were tested. Ten trials for each ISI and TS alone (30 trials in total) were delivered in random order. Data for different CS locations was collected in separate runs in counterbalanced order. One-way repeated measures ANOVA was conducted at ISIs of 10 and 50 ms (CS location was the within-subject factor).

Experiment 2: The Effects of CS Intensities on IHI

Ten subjects (4 women, aged 32.1 ± 7.7 years) participated. Active motor threshold (AMT) for the left FDI muscle was determined with the CS coil held in the M direction. AMT was defined as the minimum stimulator output that induced MEPs of > 200 μV in at least 5 out of 10 consecutive trials during voluntary contractions of 20% maximum. Subjects were provided with visual feedback to maintain constant background EMG activity. The EMG signal passed through a leaky integrator and the EMG level was displayed to the subject on an oscilloscope. The CS intensities were calculated as fractions of the AMT. ISIs of 10 and 50 ms and 8 CS intensities, from 0.6 to 2.0 AMT in increment of 0.2 AMT, were tested. Four Magstim 200 stimulators were used to deliver CS. The first run consisted of 4 randomly selected CS intensities at ISIs of 10 and 50 ms and TS alone (9 conditions). Ten trials for each condition were delivered in random order. The second run used the same configuration but tested the 4 CS intensities not previously tested. Data for different CS locations was collected in separate runs in counterbalanced order. A 3-way repeated measures ANOVA was used to examine the effects of ISI, CS intensity, and CS location (within-subject factors) on IHI. Additionally, separate 2-way ANOVA with CS intensity and CS location as the within-subject factors was conducted for ISIs of 10 and 50 ms. Paired t-tests with Bonferroni correction for multiple comparisons were used to examine at which CS intensities and locations IHI was significant. Post hoc paired t-tests were conducted to examine whether one CS location was different from others at each ISI. The effects of CS intensity and CS location on the MEP amplitude generated by CS were also tested with the 2-way repeated measures ANOVA. The relationships of IHI and CS generated MEP amplitude for each individual were examined by Pearson's correlation coefficient. ANOVA was used to examine whether the slopes of the regression lines between IHI and CS induced MEP amplitude were different at various CS locations. Post hoc paired t-tests with Bonferroni correction for multiple comparisons were conducted to examine whether the slope of the regression line for M1Hand was different from other CS locations.

Because the current spreads into M1Hand from other CS locations may potentially contaminate the IHI found in the main experiment, we performed a control experiment in 5 subjects (2 women, aged 35.0 ± 9.3 years) to investigate this possibility. M1Hand, M1Face, PMd, and 2 mid points were selected as CS locations. We named the mid point between M1Hand and M1Face as MP1, and that between M1Hand and PMd as MP2. CS intensity was set at 2.0 AMT, which was the highest used in the main experiment. TS was same as that used in the main experiment. ISIs of 10 and 50 ms were tested. We tested 3 states: ISIs of 10 and 50 ms, and TS alone. Ten trials for each state were delivered in random order. Data for different CS locations was collected in separate runs in counterbalanced order. A 2-way repeated measures ANOVA with ISI and CS location as the within-subject factors was used for statistical analysis. Post hoc paired t-tests with Bonferroni correction for multiple comparisons were used to examine whether the IHI at one CS location is different from each other.

Experiment 3: The Effects of CS Current Directions on IHI

We investigated 4 different CS current directions in 8 subjects (2 women, aged 32.3 ± 8.1 years). We selected M (Fig. 1), lateral (L), anterior (A), and posterior (P) directions for the CS current induced in the brain. In some subjects, CS and TS coils overlapped when CS coil was in A or P direction. In these cases, we moved the TS coil slightly away from the motor hot spot and adjusted the TS intensity to generate 1 mV MEP. ISIs of 10 and 50 ms were tested. CS1mV (1 mV MEP for M direction) was used as the CS intensity in all 4 current directions. Ten trials for each ISI and TS alone (total of 30 trials) were delivered in random order. Different CS current directions and locations were studied in separate runs in counterbalanced order. A 3-way repeated measures ANOVA (ISI, CS location and current direction were the within-subject factors) and separate 2-way repeated measures ANOVA (at ISI of 10 and 50 ms) were performed.

Results

Experiment 1: Time Courses of IHI

CS1mV produced MEP amplitudes of 1.22 ± 0.38 mV (n = 12) in the left FDI muscle when CS was applied to M1Hand. The MEP amplitudes generated by TS alone are listed in Table 1. They did not vary with different CS locations. Figure 2 shows the time courses of IHI with the CS coil placed over different cortical areas. ANOVA showed a significant effect of ISI but no significant effect of CS location on IHI (Table 2). There was also a significant CS location × ISI interaction (Table 2), indicating that the significant effects of ISI were different depending on the CS location. Further separate ANOVA showed that significant IHI occurred at each CS location tested (Table 3). Figure 2 showed that the significant interaction is due to peak IHI occurring at both short ISIs of ∼10 ms (SIHI) and longer ISIs of ∼50 ms (LIHI) for M1Hand, M1Face and PMd but only LIHI was evident for stimulation of S1 and DLPFC. In addition, LIHI occurred at slightly longer ISIs for PMd, S1 and DLPFC (∼30 ms) than M1Hand and M1Face (∼20 ms). Multiple comparisons with paired t-test (Table 4) confirmed that significant IHI was found at ISIs of 8, 10, 12, 20, 30, 40, 50 ms for M1Hand, at ISIs of 8, 10, 16, 20, 30, 40, 50, 60 ms for M1Face, at ISIs of 6, 8, 10, 40, 50, 60 ms for PMd. Only LIHI could be found for S1 (significant ISIs were 30, 40, 50 ms) and DLPFC (significant ISIs were 30, 40, 50, 60 ms).

Table 1

MEP amplitude (mV) elicited by TS alone at different CS locations in 3 main experiments

 Experiment 1 (n = 12) Experiment 2 (n = 10) Experiment 3 (n = 8) 
M1Hand 1.25 ± 0.34 1.37 ± 0.47 1.34 ± 0.26 
M1Face 1.34 ± 0.46 1.44 ± 0.48 1.34 ± 0.41 
PMd 1.38 ± 0.31 1.34 ± 0.48 1.29 ± 0.31 
S1 1.31 ± 0.47 1.37 ± 0.42 1.26 ± 0.33 
DLPFC 1.32 ± 0.46 1.48 ± 0.40 1.26 ± 0.30 
 Experiment 1 (n = 12) Experiment 2 (n = 10) Experiment 3 (n = 8) 
M1Hand 1.25 ± 0.34 1.37 ± 0.47 1.34 ± 0.26 
M1Face 1.34 ± 0.46 1.44 ± 0.48 1.34 ± 0.41 
PMd 1.38 ± 0.31 1.34 ± 0.48 1.29 ± 0.31 
S1 1.31 ± 0.47 1.37 ± 0.42 1.26 ± 0.33 
DLPFC 1.32 ± 0.46 1.48 ± 0.40 1.26 ± 0.30 
Table 2

Experiment 1: 2-way repeated measures ANOVA with factors of “ISI” and “CS location” on IHI

 df F value P value 
ISI 13 14.52 <0.001 
CS location 1.31 n.s. 
ISI × CS location 52 1.56 0.009 
 df F value P value 
ISI 13 14.52 <0.001 
CS location 1.31 n.s. 
ISI × CS location 52 1.56 0.009 

Note: n.s. = not significant.

Table 3

Experiment 1: separate one-way repeated measures ANOVA for different “CS location” with factor of “ISI” on IHI

 df F value P value 
M1Hand 13 6.82 <0.001 
M1Face 13 5.43 <0.001 
PMd 13 5.10 <0.001 
S1 13 3.66 <0.001 
DLPFC 13 2.76 0.002 
 df F value P value 
M1Hand 13 6.82 <0.001 
M1Face 13 5.43 <0.001 
PMd 13 5.10 <0.001 
S1 13 3.66 <0.001 
DLPFC 13 2.76 0.002 
Table 4

Experiment 1: Paired t-tests with Bonferroni correction comparing conditioned MEP with different ISIs to MEP induced by TS alone at 5 CS locations

ISI (ms) df M1Hand M1Face PMd S1 DLPFC 
  t Value P value t Value P value t Value P value t Value P value t Value P value 
11 −1.16 n.s. 2.18 n.s. −0.80 n.s. −0.39 n.s. 0.07 n.s. 
11 2.18 n.s. 2.33 n.s. 4.82 0.007 0.52 n.s. 0.69 n.s. 
11 3.93 0.031 4.41 0.013 5.42 0.003 1.50 n.s. 1.37 n.s. 
10 11 4.76 0.008 3.87 0.034 5.80 0.001 2.37 n.s. 1.74 n.s. 
12 11 3.81 0.038 0.34 n.s. 3.02 n.s. 1.62 n.s. 1.44 n.s. 
16 11 0.33 n.s. 3.72 0.044 −0.75 n.s. 0.26 n.s. 1.97 n.s. 
20 11 5.78 0.001 5.03 0.006 −0.04 n.s. 1.13 n.s. 0.50 n.s. 
30 11 4.82 0.007 5.15 0.005 0.55 n.s. 4.83 0.007 3.68 0.047 
40 11 7.18 <0.001 4.41 0.004 4.73 0.008 5.56 0.003 4.50 0.012 
50 11 5.39 0.003 5.35 0.003 5.35 0.003 5.42 0.003 5.58 0.003 
60 11 2.55 n.s. 4.22 0.018 5.81 0.001 2.99 n.s. 6.46 0.001 
80 11 −0.22 n.s. 2.97 n.s. 0.62 n.s. 1.87 n.s. 0.33 n.s. 
100 11 −0.89 n.s. 0.82 n.s. 0.68 n.s. −0.42 n.s. 0.69 n.s. 
ISI (ms) df M1Hand M1Face PMd S1 DLPFC 
  t Value P value t Value P value t Value P value t Value P value t Value P value 
11 −1.16 n.s. 2.18 n.s. −0.80 n.s. −0.39 n.s. 0.07 n.s. 
11 2.18 n.s. 2.33 n.s. 4.82 0.007 0.52 n.s. 0.69 n.s. 
11 3.93 0.031 4.41 0.013 5.42 0.003 1.50 n.s. 1.37 n.s. 
10 11 4.76 0.008 3.87 0.034 5.80 0.001 2.37 n.s. 1.74 n.s. 
12 11 3.81 0.038 0.34 n.s. 3.02 n.s. 1.62 n.s. 1.44 n.s. 
16 11 0.33 n.s. 3.72 0.044 −0.75 n.s. 0.26 n.s. 1.97 n.s. 
20 11 5.78 0.001 5.03 0.006 −0.04 n.s. 1.13 n.s. 0.50 n.s. 
30 11 4.82 0.007 5.15 0.005 0.55 n.s. 4.83 0.007 3.68 0.047 
40 11 7.18 <0.001 4.41 0.004 4.73 0.008 5.56 0.003 4.50 0.012 
50 11 5.39 0.003 5.35 0.003 5.35 0.003 5.42 0.003 5.58 0.003 
60 11 2.55 n.s. 4.22 0.018 5.81 0.001 2.99 n.s. 6.46 0.001 
80 11 −0.22 n.s. 2.97 n.s. 0.62 n.s. 1.87 n.s. 0.33 n.s. 
100 11 −0.89 n.s. 0.82 n.s. 0.68 n.s. −0.42 n.s. 0.69 n.s. 

Note: n.s. = not significant. P values were listed with Bonferroni correction. Bold faced values indicate the significant interactions.

Figure 2.

The time courses of IHI. Time courses of IHI (n = 12) from 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) to the left motor cortex. The abscissa indicates the ISI. The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. The dashed lines indicate the MEP amplitude generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. There are 2 phases of IHI with maximum inhibition at ISIs of ∼10 and ∼50 ms for M1Hand, M1Face, and PMd. For S1 and DFPFC, the early phase of IHI is absent and only the late phase is evident. *P < 0.05, **P < 0.01, ***P < 0.001, compared with TS alone.

Figure 2.

The time courses of IHI. Time courses of IHI (n = 12) from 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) to the left motor cortex. The abscissa indicates the ISI. The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. The dashed lines indicate the MEP amplitude generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. There are 2 phases of IHI with maximum inhibition at ISIs of ∼10 and ∼50 ms for M1Hand, M1Face, and PMd. For S1 and DFPFC, the early phase of IHI is absent and only the late phase is evident. *P < 0.05, **P < 0.01, ***P < 0.001, compared with TS alone.

To confirm our findings were due to IHI, we performed 5 control experiments. Figure 3 shows the results of the first control experiment. It was found that CS inhibited the MEP induced by TMS at both ISIs of 10 and 50 ms, similar to the main experiment. On the other hand, the MEP induced by TES was not inhibited by the CS at any location at either ISI (except for slight inhibition by M1Hand stimulation at 10 ms). ANOVA confirmed that TS type (TES or TMS) has a significant effect on IHI (F1,12 = 12.71, P = 0.038). The effect of CS location (F4,12 = 3.55, P = 0.039) and ISI (F1,12 = 1335.02, P < 0.001) were also significant. Post hoc tests showed that TMS as TS produced significantly greater SIHI (ISI 10 ms) than TES as TS for CS locations of M1Hand, M1Face and PMd. For S1 and DLPFC, there was no significant SIHI for TS as either TMS or TES (Fig. 3A). For LIHI (ISI 50 ms), TMS as TS produced significantly greater inhibition than TES as TS for all CS locations tested (Fig. 3B). Fig. 4 shows the results of the second control experiment. Forearm H-reflex amplitudes were not changed by the CS. ANOVA confirmed that neither the main effects of CS location (F4,32 = 0.19, P = 0.938), ISI (F2,32 = 0.81, P = 0.479) nor the interaction (F4,32 = 0.39, P = 0.916) between them were significant.

Figure 3.

Comparison between TES and TMS as the TS for IHI. Data from 4 subjects. The abscissa indicates the 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) where CS was applied. The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. ISIs of 10 ms (A) and 50 ms (B) were tested. The filled circles represent MEP generated by TES as the TS. The open circles represent MEP generated by TMS as the TS. The dashed lines indicate the MEP amplitude generated by TS alone (100%). *P < 0.05, comparing TES as TS and TMS as TS.

Figure 3.

Comparison between TES and TMS as the TS for IHI. Data from 4 subjects. The abscissa indicates the 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) where CS was applied. The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. ISIs of 10 ms (A) and 50 ms (B) were tested. The filled circles represent MEP generated by TES as the TS. The open circles represent MEP generated by TMS as the TS. The dashed lines indicate the MEP amplitude generated by TS alone (100%). *P < 0.05, comparing TES as TS and TMS as TS.

Figure 4.

Effects of CS on forearm H-reflex. Data from 5 subjects. The abscissa indicates the 5 different cortical areas (M1Forearm, M1Face, PMd, S1, and DLPFC) where CS was applied. The ordinate indicates the amplitude of conditioned H-reflex expressed as a percentage of the H-reflex amplitude induced by TS alone. The filled columns represent ISI of 10 ms and the open columns represent ISI of 50 ms. The dashed line indicates the H-reflex amplitude generated by TS alone (100%).

Figure 4.

Effects of CS on forearm H-reflex. Data from 5 subjects. The abscissa indicates the 5 different cortical areas (M1Forearm, M1Face, PMd, S1, and DLPFC) where CS was applied. The ordinate indicates the amplitude of conditioned H-reflex expressed as a percentage of the H-reflex amplitude induced by TS alone. The filled columns represent ISI of 10 ms and the open columns represent ISI of 50 ms. The dashed line indicates the H-reflex amplitude generated by TS alone (100%).

Figure 5A shows the results of the third control experiment. When the CS was placed on the inion no significant IHI was found at any ISI tested (F13,65 = 0.45, P = 0.945). Figure 5B shows the results of the fourth control experiment. When electrical stimulation was used to mimic the muscle twitch in the left FDI muscle caused by TMS, no significant IHI was found at any ISI tested (F9,36 = 0.41, P = 0.920). Figure 5C shows the results of the fifth control experiment. When electrical stimulation on the scalp was used as CS, no significant IHI was found at either ISIs of 10 (F5,25 = 0.60, P = 0.698) or 50 ms (F5,25 = 0.94, P = 0.472).

Figure 5.

IHI induced by magnetic stimulation over the inion, electrical stimulations of the ulnar nerve or scalp. (A) Time course of IHI with CS placed over the inion (n = 6). The abscissa indicates the ISI. (B) Time course of IHI induced by electrical stimulation of the ulnar nerve at left wrist (n = 5). TS was applied to left M1. The abscissa indicates the ISI. (C) IHI induced by electrical stimulation of the scalp (n = 6). The abscissa indicates the CS location. Filled circles indicate the data from ISI of 10 ms, open circles indicate those from ISI of 50 ms. The ordinates in (A), (B), and (C) indicate the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. The dashed lines indicate the MEP generated by TS alone (100%). No IHI can be found with CS was placed over inion, ulnar nerve stimulation or with scalp electrical stimulation delivered as CS.

Figure 5.

IHI induced by magnetic stimulation over the inion, electrical stimulations of the ulnar nerve or scalp. (A) Time course of IHI with CS placed over the inion (n = 6). The abscissa indicates the ISI. (B) Time course of IHI induced by electrical stimulation of the ulnar nerve at left wrist (n = 5). TS was applied to left M1. The abscissa indicates the ISI. (C) IHI induced by electrical stimulation of the scalp (n = 6). The abscissa indicates the CS location. Filled circles indicate the data from ISI of 10 ms, open circles indicate those from ISI of 50 ms. The ordinates in (A), (B), and (C) indicate the amplitude of conditioned MEP expressed as a percentage of the MEP amplitude from TS alone. The dashed lines indicate the MEP generated by TS alone (100%). No IHI can be found with CS was placed over inion, ulnar nerve stimulation or with scalp electrical stimulation delivered as CS.

Experiment 2: CS Intensity Recruitment Curves for IHI

MEP amplitude generated by TS alone was similar for different CS locations (Table 1). AMT in the left FDI muscle was 35.3 ± 4.6% (n = 10) of maximum stimulator output. Figure 6 shows how IHI changed with different CS intensities. ANOVA showed that all 3 factors of ISI, CS intensity and CS location had significant effects on IHI (Table 5). Additionally, the interactions between ISI and CS intensity and between ISI and CS location were also significant (Table 5), indicating that CS intensity and location had different effects on SIHI and LIHI. To clarify these interactions, we performed the separate 2-way ANOVA for ISIs of 10 and 50 ms. The results (Table 6) showed that inhibition increased with higher CS intensity for both SIHI and LIHI. The effect of CS location was also significant for both phases of IHI. However, the interaction between CS intensity and location was significant for SIHI but not for LIHI, indicating that for SIHI the effect of CS intensity depended on the CS location whereas for LIHI different CS intensities had similar effects at all CS locations (Table 6). Multiple comparisons with paired t-test (Table 7) showed that SIHI (ISI 10 ms) was significant at CS intensities of 1.6, 1.8, 2.0 AMT for M1Hand, M1Face, and PMd. Only at CS intensity of 2.0 AMT was SIHI significant for S1, and no significant SIHI was found for DLPFC. On the other hand, significant LIHI (ISI 50 ms) could be found over a wide range of CS intensities. LIHI was significant at CS intensity from 1.2 to 2.0 AMT for M1Hand and DLPFC, from 1.4 to 2.0 AMT for M1Face, PMd, and S1. Additionally, it was found that SIHI from DLPFC stimulation was significantly less than SIHI from stimulation of other cortical areas tested (P < 0.05 for all comparison). SIHI from S1 was significantly less than SIHI from M1Hand (P < 0.05).

Table 5

Experiment 2: 3-way repeated measures ANOVA with factors of “ISI,” “CS intensity,” and “CS location” on IHI

 df F value P value 
ISI 9.17 0.014 
CS intensity 28.55 <0.001 
CS location 5.77 0.001 
ISI × CS intensity 5.00 <0.001 
ISI × CS location 6.63 <0.001 
CS intensity × CS location 32 1.33 n.s. 
ISI × CS intensity × CS location 32 1.11 n.s. 
 df F value P value 
ISI 9.17 0.014 
CS intensity 28.55 <0.001 
CS location 5.77 0.001 
ISI × CS intensity 5.00 <0.001 
ISI × CS location 6.63 <0.001 
CS intensity × CS location 32 1.33 n.s. 
ISI × CS intensity × CS location 32 1.11 n.s. 

Note: n.s. = not significant.

Table 6

Experiment 2: separate 2-way repeated measures ANOVA for ISI of 10 and 50 ms with factors of “CS intensity” and “CS location” on IHI

 ISI 10 ms ISI 50 ms 
 df F value P value df F value P value 
CS intensity 14.36 <0.001 27.46 <0.001 
CS location 9.20 <0.001 2.80 0.040 
CS intensity × CS location 32 1.79 0.007 32 0.60 n.s. 
 ISI 10 ms ISI 50 ms 
 df F value P value df F value P value 
CS intensity 14.36 <0.001 27.46 <0.001 
CS location 9.20 <0.001 2.80 0.040 
CS intensity × CS location 32 1.79 0.007 32 0.60 n.s. 

Note: n.s. = not significant.

Table 7

Experiment 2: Paired t-tests for Bonferroni correction comparing conditioned MEP with different CS intensities to MEP induced by TS alone at 5 CS locations

CS intensity (AMT) df M1Hand M1Face PMd S1 DLPFC 
t Value P value t Value P value t Value P value t Value P value t Value P value 
ISI = 10 ms 
    0.6 0.83 n.s. −0.57 n.s. −0.17 n.s. 0.71 n.s. −1.85 n.s. 
    0.8 −0.39 n.s. −0.27 n.s. −1.63 n.s. −0.79 n.s. 0.26 n.s. 
    1.0 0.39 n.s. 0.95 n.s. 0.27 n.s. −0.81 n.s. −0.18 n.s. 
    1.2 1.43 n.s. −0.13 n.s. 0.05 n.s. 0.64 n.s. −1.60 n.s. 
    1.4 2.25 n.s. 0.93 n.s. 3.01 n.s. 0.44 n.s. −1.24 n.s. 
    1.6 4.19 0.018 3.62 0.044 4.13 0.021 1.29 n.s. −2.30 n.s. 
    1.8 5.99 0.002 4.68 0.010 4.43 0.013 2.93 n.s. 0.91 n.s. 
    2.0 5.51 0.003 6.23 0.002 5.95 0.002 6.23 0.002 1.15 n.s. 
ISI = 50 ms 
    0.6 0.75 n.s. −2.23 n.s. −1.37 n.s. −1.13 n.s. −1.47 n.s. 
    0.8 0.29 n.s. 0.52 n.s. −0.60 n.s. −0.91 n.s. −0.18 n.s. 
    1.0 3.21 n.s. 1.34 n.s. 0.12 n.s. 1.76 n.s. 2.90 n.s. 
    1.2 4.87 0.007 2.26 n.s. 1.37 n.s. 2.74 n.s. 3.76 0.032 
    1.4 8.33 <0.001 6.65 <0.001 3.69 0.040 6.42 <0.001 6.74 <0.001 
    1.6 7.00 <0.001 6.47 <0.001 7.32 <0.001 6.36 <0.001 6.51 <0.001 
    1.8 16.18 <0.001 6.38 <0.001 6.43 <0.001 7.59 <0.001 8.34 <0.001 
    2.0 13.37 <0.001 6.81 <0.001 6.36 <0.001 6.75 <0.001 6.66 <0.001 
CS intensity (AMT) df M1Hand M1Face PMd S1 DLPFC 
t Value P value t Value P value t Value P value t Value P value t Value P value 
ISI = 10 ms 
    0.6 0.83 n.s. −0.57 n.s. −0.17 n.s. 0.71 n.s. −1.85 n.s. 
    0.8 −0.39 n.s. −0.27 n.s. −1.63 n.s. −0.79 n.s. 0.26 n.s. 
    1.0 0.39 n.s. 0.95 n.s. 0.27 n.s. −0.81 n.s. −0.18 n.s. 
    1.2 1.43 n.s. −0.13 n.s. 0.05 n.s. 0.64 n.s. −1.60 n.s. 
    1.4 2.25 n.s. 0.93 n.s. 3.01 n.s. 0.44 n.s. −1.24 n.s. 
    1.6 4.19 0.018 3.62 0.044 4.13 0.021 1.29 n.s. −2.30 n.s. 
    1.8 5.99 0.002 4.68 0.010 4.43 0.013 2.93 n.s. 0.91 n.s. 
    2.0 5.51 0.003 6.23 0.002 5.95 0.002 6.23 0.002 1.15 n.s. 
ISI = 50 ms 
    0.6 0.75 n.s. −2.23 n.s. −1.37 n.s. −1.13 n.s. −1.47 n.s. 
    0.8 0.29 n.s. 0.52 n.s. −0.60 n.s. −0.91 n.s. −0.18 n.s. 
    1.0 3.21 n.s. 1.34 n.s. 0.12 n.s. 1.76 n.s. 2.90 n.s. 
    1.2 4.87 0.007 2.26 n.s. 1.37 n.s. 2.74 n.s. 3.76 0.032 
    1.4 8.33 <0.001 6.65 <0.001 3.69 0.040 6.42 <0.001 6.74 <0.001 
    1.6 7.00 <0.001 6.47 <0.001 7.32 <0.001 6.36 <0.001 6.51 <0.001 
    1.8 16.18 <0.001 6.38 <0.001 6.43 <0.001 7.59 <0.001 8.34 <0.001 
    2.0 13.37 <0.001 6.81 <0.001 6.36 <0.001 6.75 <0.001 6.66 <0.001 

Note: n.s. = not significant. P values were listed with Bonferroni correction. Bold faced values indicate the significant interactions.

Figure 6.

CS recruitment curves for IHI. CS recruitment curves for IHI (n = 10) from 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) at ISIs of 10 (left side) and 50 ms (right side). The abscissa indicates the CS intensity (expressed as a fraction of AMT). The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP from TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. IHI at ISI of 50 ms occurred at lower CS intensities than that at 10 ms for all brain areas tested. *P < 0.05, **P < 0.01, ***P < 0.001, comparing to TS alone.

Figure 6.

CS recruitment curves for IHI. CS recruitment curves for IHI (n = 10) from 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) at ISIs of 10 (left side) and 50 ms (right side). The abscissa indicates the CS intensity (expressed as a fraction of AMT). The ordinate indicates the amplitude of conditioned MEP expressed as a percentage of the MEP from TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. IHI at ISI of 50 ms occurred at lower CS intensities than that at 10 ms for all brain areas tested. *P < 0.05, **P < 0.01, ***P < 0.001, comparing to TS alone.

We analyzed the MEP amplitude in the left FDI muscle generated by the CS (Fig. 7). MEP amplitude increased with higher CS intensities (effect of CS intensity: F7,252 = 52.78, P < 0.001). Moreover, M1Hand stimulation resulted in high MEP amplitude than other CS locations (effect of CS location: F4,252 = 26.16, P < 0.001). The interaction between CS intensity and location was also significant (F28,252 = 21.99, P < 0.001). Additionally, no MEP was recorded when CS was placed over DLPFC.

Figure 7.

MEP recruitment curve for the left FDI muscle. Mean MEP amplitude (n = 10) in the left FDI muscle generated by CS. CS was placed over one of 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC). The abscissa indicates the CS intensity (expressed as a fraction of AMT) and ordinate indicates the MEP amplitude in the left FDI muscle.

Figure 7.

MEP recruitment curve for the left FDI muscle. Mean MEP amplitude (n = 10) in the left FDI muscle generated by CS. CS was placed over one of 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC). The abscissa indicates the CS intensity (expressed as a fraction of AMT) and ordinate indicates the MEP amplitude in the left FDI muscle.

We further analyzed the relationship between IHI and the CS generated MEP amplitude (Fig. 8). Data from DLPFC stimulation was not included because no MEP can be recorded (Fig. 7). ANOVA and post hoc tests showed that the slope of the regression line for IHI vs. MEP amplitude induced by CS for M1Hand was different from those for other CS locations for both ISIs of 10 and 50 ms (Table 8). Thus, for the same MEP amplitude induced by CS, stimulation of M1Face, PMd, and S1 resulted in greater SIHI and LIHI than M1Hand (Fig. 8). The R2 value was also higher for M1Hand compared with the other stimulation sites (Table 8) indicating that the MEP amplitude accounted for a bigger percentage of the variance of IHI for M1Hand than other stimulation sites.

Table 8

Experiment 2: ANOVA and post hoc testing for the slopes of individual IHI versus MEP amplitude induced by CS regression lines for different CS locations

ANOVA ISI 10 ms ISI 50 ms 
df = 3; F = 8.76; P < 0.001 df = 3; F = 6.19; P < 0.001 
Post hoc R2 Slope P value R2 Slope P value 
M1Hand 0.54 ± 0.26 −17.0 ± 2.2 — 0.51 ± 0.26 −21.4 ± 7.2 — 
M1Face 0.27 ± 0.17 −48.1 ± 6.1 0.006 0.24 ± 0.18 −53.5 ± 14.3 0.028 
PMd 0.27 ± 0.22 −84.3 ± 17.6 0.025 0.35 ± 0.19 −92.0 ± 15.6 0.016 
S1 0.18 ± 0.15 −72.5 ± 6.8 <0.001 0.21 ± 0.19 −92.7 ± 16.1 0.013 
ANOVA ISI 10 ms ISI 50 ms 
df = 3; F = 8.76; P < 0.001 df = 3; F = 6.19; P < 0.001 
Post hoc R2 Slope P value R2 Slope P value 
M1Hand 0.54 ± 0.26 −17.0 ± 2.2 — 0.51 ± 0.26 −21.4 ± 7.2 — 
M1Face 0.27 ± 0.17 −48.1 ± 6.1 0.006 0.24 ± 0.18 −53.5 ± 14.3 0.028 
PMd 0.27 ± 0.22 −84.3 ± 17.6 0.025 0.35 ± 0.19 −92.0 ± 15.6 0.016 
S1 0.18 ± 0.15 −72.5 ± 6.8 <0.001 0.21 ± 0.19 −92.7 ± 16.1 0.013 

Note: — = not applicable.

Figure 8.

Relationship between IHI and MEP amplitude generated by CS at different locations. Data from 10 subjects. Data from ISI of 10 ms is shown in (A) and data from ISI of 50 ms in (B). The abscissa indicates the MEP amplitude in the left FDI muscle generated by the CS. The ordinate indicates the conditioned MEP amplitude expressed as a percentage of MEP amplitude generated by TS alone. Data from stimulation of the M1Hand (red), M1Face (blue), PMd (green), and S1 (yellow) was compared. The relationship between IHI and MEP in the left FDI was different for M1Hand compared with other CS locations.

Figure 8.

Relationship between IHI and MEP amplitude generated by CS at different locations. Data from 10 subjects. Data from ISI of 10 ms is shown in (A) and data from ISI of 50 ms in (B). The abscissa indicates the MEP amplitude in the left FDI muscle generated by the CS. The ordinate indicates the conditioned MEP amplitude expressed as a percentage of MEP amplitude generated by TS alone. Data from stimulation of the M1Hand (red), M1Face (blue), PMd (green), and S1 (yellow) was compared. The relationship between IHI and MEP in the left FDI was different for M1Hand compared with other CS locations.

Figure 9 shows the results of the control experiment where IHI from M1Hand, M1Face and PMd was compared with 2 mid points between them. ANOVA showed that CS location has a significant effect on IHI (F4,16 = 8.05, P < 0.001). The effect of ISI (F1,16 = 0.60, P = 0.481) and the interaction between CS location and ISI (F4,16 = 0.21, P = 0.927) were not significant. Post hoc tests showed that SIHI (Fig. 9A) at MP2 was significantly weaker than that at M1Hand (P < 0.01) and PMd (P < 0.05). Same results (P < 0.05 for both comparison) were obtained for LIHI (Fig. 9B). However, neither SIHI nor LIHI at MP1 was significantly different from those at M1Hand or M1Face.

Figure 9.

Effects of CS location on IHI. Data from 5 subjects. CS was placed over one of 5 different cortical areas: M1Hand, M1Face, PMd, and MP1 (mid point between M1Hand and M1Face), MP2 (mid point between M1Hand and PMd) at ISIs of 10 (A) and 50 ms (B). The abscissa indicates the CS location. The ordinate indicates conditioned MEP expressed as a percentage of MEP amplitude generated by TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. *P < 0.05, **P < 0.01, comparing 2 different CS locations.

Figure 9.

Effects of CS location on IHI. Data from 5 subjects. CS was placed over one of 5 different cortical areas: M1Hand, M1Face, PMd, and MP1 (mid point between M1Hand and M1Face), MP2 (mid point between M1Hand and PMd) at ISIs of 10 (A) and 50 ms (B). The abscissa indicates the CS location. The ordinate indicates conditioned MEP expressed as a percentage of MEP amplitude generated by TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. *P < 0.05, **P < 0.01, comparing 2 different CS locations.

Experiment 3: Effect of CS Current Direction on IHI

CS1mV produced MEP amplitude of 1.33 ± 0.46 mV (n = 8) in the left FDI when CS was applied to M1Hand in M direction. MEP size generated by TS alone did not change with different CS locations or directions (Table 1). Figure 10 shows the effects of CS current direction on SIHI (ISI 10 ms) and LIHI (ISI 50 ms). Three-way ANOVA showed that the effects of ISI and CS location on IHI were significant, but the factor of CS current direction was not (Table 9). In addition, the interaction between ISI and CS location was also significant, suggesting that CS location had different effects on SIHI and LIHI (Table 9). Separate 2-way ANOVA showed that for SIHI, the effect of CS location was significant, but the effect of CS current direction and the interaction between 2 effects were not (Table 10). This result suggests that SIHI varies with different CS locations but all current directions have similar effect at a certain CS location. For LIHI (Table 10), 2-way ANOVA showed no significant main effect of CS current direction and CS location, indicating that various current directions at different CS locations produce similar degree of inhibition.

Table 9

Experiment 3: 3-way repeated measures ANOVA with factors of “ISI”, “CS current direction” and “CS location” on IHI

 df F value P value 
ISI 11.50 0.012 
CS current direction 1.82 n.s. 
CS location 3.45 0.021 
ISI × CS current direction 0.31 n.s. 
ISI × CS location 4.38 0.007 
CS current direction × CS location 12 0.82 n.s. 
ISI × CS current direction × CS location 12 0.56 n.s. 
 df F value P value 
ISI 11.50 0.012 
CS current direction 1.82 n.s. 
CS location 3.45 0.021 
ISI × CS current direction 0.31 n.s. 
ISI × CS location 4.38 0.007 
CS current direction × CS location 12 0.82 n.s. 
ISI × CS current direction × CS location 12 0.56 n.s. 

Note: n.s. = not significant.

Table 10

Experiment 3: separate 2-way repeated measures ANOVA for ISI of 10 and 50 ms with factors of “CS current direction” and “CS location”

 ISI 10 ms ISI 50 ms 
 df F value P value df F value P value 
CS current direction 0.93 n.s. 2.22 n.s. 
CS location 4.93 0.004 2.38 n.s. 
CS current direction × CS location 12 0.65 n.s. 12 0.84 n.s. 
 ISI 10 ms ISI 50 ms 
 df F value P value df F value P value 
CS current direction 0.93 n.s. 2.22 n.s. 
CS location 4.93 0.004 2.38 n.s. 
CS current direction × CS location 12 0.65 n.s. 12 0.84 n.s. 

Note: n.s. = not significant.

Figure 10.

Effects of CS current direction on IHI. CS was placed over one of 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) at ISIs of 10 (A) and 50 ms (B). The abscissa indicates the CS location. The ordinate indicates conditioned MEP expressed as a percentage of MEP amplitude generated by TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. M, L, A, P indicate medially, laterally, anteriorly, posteriorly directed induced currents in the brain, respectively.

Figure 10.

Effects of CS current direction on IHI. CS was placed over one of 5 different cortical areas (M1Hand, M1Face, PMd, S1, and DLPFC) at ISIs of 10 (A) and 50 ms (B). The abscissa indicates the CS location. The ordinate indicates conditioned MEP expressed as a percentage of MEP amplitude generated by TS alone. The dashed lines indicate the MEP generated by TS alone (100%). Values below 100% represent inhibition and values above 100% represent facilitation. M, L, A, P indicate medially, laterally, anteriorly, posteriorly directed induced currents in the brain, respectively.

Discussion

We examined the IHI from 5 motor related cortical areas to the contralateral M1. The main findings are 1) There are 2 distinct phases of IHIs that occur at ISIs of ∼10 (SIHI) and ∼50 ms (LIHI) for the motor related cortical areas tested. 2) LIHI can be elicited over a wide range of CS intensities, whereas SIHI requires higher CS intensities or is even absent from some cortical areas.

Two Distinct Phases of IHI

Our findings showed that SIHI and LIHI represent distinct phases of IHI. This is because the detailed time course showed that 2 phases could be separated (Fig. 2), the locations where SIHI and LIHI could be elicited are different (Figs 2, 6, 10), LIHI could be elicited by lower intensity stimuli (Fig. 6) than SIHI. Our result for SIHI occurs at ISIs of ∼10 ms is consistent with previous studies of SIHI from M1 (Ferbert et al. 1992; Chen et al. 2003) or PMd (Mochizuki et al. 2004a) to the contralateral M1. The most robust finding of the present study is that IHI, especially the LIHI (ISI 50 ms), can be produced by widely distributed motor related cortical areas. LIHI has been previously demonstrated for M1Hand (Chen et al. 2003) but not for any other motor related cortical areas.

Site of IHI

TMS activates interneurons which connect to the corticospinal neurons, whereas TES discharges the axon of the corticospinal neurons directly (Edgley et al. 1997; Di Lazzaro et al. 1999a). The first control experiment showed that CS from different motor related cortical areas inhibited the MEP generated by TMS but not that by TES, suggesting that both SIHI and LIHI are due to cortical inhibition. TES studies for IHI originating outside the M1hand have not been previously reported. It should be noted that M1Hand stimulation at ISI of 10 ms slightly inhibited the response to TES (Fig. 3). It is possible that subcortical activities also contribute to SIHI between homologous M1s, and is consistent with a previous study (Gerloff et al. 1998). We performed the second control experiment to further address this question. It is widely held that H-reflex measures the excitability of α-motoneuron pool (Knikou 2008). The present results that the CS at any location did not change H-reflex amplitude confirmed that spinal inhibitory mechanisms do not substantially contribute to SIHI/LIHI. We performed the third control experiment by delivering TMS to inion, a brain area outside the 5 motor related cortical areas of interest. The distance from the TMS coil to the ear is similar to the other stimulation sites used in the main experiment. Because no inhibition was found at any ISI, it is unlikely that the acoustic effects or other nonspecific effects caused by the discharge of the coil could account for the IHI found in the main experiment (Loo et al. 2000). Thus, IHI only occurs with stimulation of specific motor related cortical areas. The fourth control experiment used electrical stimulation on ulnar nerve to examine the effect of sensory feedback on LIHI. Because the conduction time for the possible sensory feedback to the contralateral M1 is about 20 ms and is longer than the ISIs for SIHI, sensory feedback cannot account for SIHI. For LIHI, we found no inhibition in a detailed time course suggesting that sensory feedback caused by TMS cannot account for IHI found in the main experiment. The fifth control experiment was performed as replacing the TMS by an electrical stimulation at the 5 main CS locations. Electrical stimulation caused comparable cutaneous and muscle stimulation on the scalp as TMS (Okabe et al. 2003). However, no IHI was found at any CS location. The results confirmed that IHI is not caused by activation of local sensory afferents. Taken together, the time course of the IHI and the results of the control experiments suggest that there is a widely distributed IHI system connecting motor related cortical areas to the contralateral M1.

Possible Spread of Stimulation to the Motor Cortex from Other Motor Related Cortical Areas

The study of CS intensity recruitment curve (Fig. 6) showed that SIHI and LIHI increase with higher CS intensities. At high CS intensities, a large area might be stimulated with the possibility of stimulating current spreading to the M1. However, this mechanism is unlikely to explain our results entirely based on 4 lines of evidence. First, we performed a control experiment comparing IHI from 3 cortical areas of interest (M1Hand, M1Face, and PMd) to that from 2 mid points (MP1 and MP2) between these areas. Because the distances from MP1 and MP2 to M1Hand were shorter than that from M1Face or PMd, SIHI and LIHI should be more prominent at MP1 or MP2 than M1Face and PMd if the current spread to M1hand was the main reason of IHI. However, SIHI and LIHI at MP2 were weaker than those at M1Hand and PMd. SIHI and LIHI at MP1 was similar to M1Face or M1Hand. This may be because MP1 is located at other body representations of the M1 such as the proximal arm area. These cortical areas may also have inhibitory fibers projecting to the contralateral M1Hand. Second, for CS locations other than M1Hand, the CS generated rather small MEPs at intensities lower than 2.0 AMT and no MEP at intensities of 1.4 AMT or lower (Fig. 7). Because IHI requires suprathreshold CS, it is unlikely that the small current spread to M1 would result in notable IHI from ipsilateral M1Hand stimulation (Ferbert et al. 1992; Mochizuki et al. 2004a). However, we cannot completely exclude the possibility that inhibitory fibers projecting to contralateral M1 have lower threshold than the corticospinal system and may be activated without producing any MEP. Third, the current spreading to M1Hand should produce the same time course as M1Hand stimulation. However, SIHI was absent in S1 and DLPFC (Fig. 2). The different time courses for different CS locations are confirmed by the significant ISI × CS location interactions for Experiment 1 (Table 2), 2 (Table 5), and 3 (Table 9). Fourth, the relationship between SIHI/LIHI and CS generated MEP in the contralateral FDI muscle is different for M1Hand compared with other CS locations (Table 8 and Fig. 8). If IHI at other CS locations was entirely due to spreading current to M1, similar regression lines should be obtained. For the same MEP amplitude generated by the CS, stimulation of the M1Face, PMd, and S1 produced greater IHI than M1Hand stimulation. However, current spreading into M1 might contribute to IHI at high CS intensities such as 2.0 AMT.

Possible Pathways Mediating SIHI and LIHI

We found SIHI to the contralateral M1 from M1Hand, M1Face, and PMd, but no SIHI from S1 and DLPFC. It was suggested that the fibers mediating SIHI between homologous M1s pass through the posterior body and isthmus of the corpus callosum which is somatotopically organized (Meyer et al. 1998; Wahl et al. 2007). Given that SIHI from PMd to contralateral M1Hand had similar latency as SIHI for homologous M1s (∼10 ms) and conduction time from PMd to ipsilateral M1 takes at least 4 ms (Civardi et al. 2001), SIHI from PMd to M1Hand may be mediated by direct transcallosal fibers. Indeed, an MRI tractography study showed that the transcallosal fibers from PMd are located in the middle of the body of the corpus callosum, immediately anterior to M1–M1 fibers, and these 2 groups of fibers overlap (Zarei et al. 2006). Fibers mediating SIHI from PMd to M1Hand may pass through this area of the corpus callosum. The SIHI from M1Face to M1Hand may be conducted along a similar pathway. Conversely, transcallosal connections from the prefrontal cortex are located in the genu and anterior part of the corpus callosum and they do not overlap with M1-M1 connections (Zarei et al. 2006), which may explain why DLPFC stimulation did not produce SIHI. Additionally, callosal projections from S1 to contralateral M1 overlap with M1–M1 connections. Transcallosal fibers from S1 may have higher threshold than M1Hand because S1 stimulation produced SIHI only when CS was increased to 2.0 AMT (Fig. 6).

Our findings suggest that neurons that mediate LIHI have lower firing threshold than those mediate SIHI. Additionally, this low threshold system (LIHI) is widely distributed in motor related cortical areas of the brain as LIHI was found at all 5 CS locations tested. It has been suggested that LIHI from M1Hand may be mediated by similar neuronal population as long interval intracortical inhibition (Kukaswadia et al. 2005; Irlbacher et al. 2007). The pathway for LIHI from other motor related areas to the contralateral M1 may be complex. Several possible pathways may be involved. First is a pathway that passes through the transcallosal fibers between homologous M1s via relay in the ipsilateral M1. It was reported that ipsilateral M1 can be facilitated by the CS delivered to PMd (Civardi et al. 2001) and posterior parietal cortex (Koch et al. 2007) at certain ISIs and CS intensities. It is possible that there are facilitatory pathways from other motor related cortical areas to the ipsilateral M1 and they are activated by CS. LIHI was then mediated by inhibitory connections between homologous M1s. Experiment 1 showed that the LIHI emerges at slightly longer ISIs for PMd, S1, and DLPFC than M1Hand and M1Face (Fig. 2) suggesting that a common circuit (probably the transcallosal connections between homologous M1s) may account for LIHI from different areas. It may be speculated that the latency to activate the common circuit is longer for PMd, S1, and DLPFC than M1 itself, depending on their distances to the common circuit and their different functions in motor control. Second, a pathway through the corpus callosum to the contralateral homologous cortical area (correspondence to the CS location) and then to the targeted M1 is also possible. Indeed, a recent study using near-infrared spectroscopy explored the inhibitory connection between homologous PMds (Mochizuki et al. 2007), suggesting the existence of transcallosal fibers between homologous cortical areas other than M1–M1 connection. Third, similar to the LIHI between homologous M1s, slow but direct transcallosal pathways from the motor related cortical areas to the contralateral M1 may be involved. It is of great interest to determine which pathways mediate this widely distributed IHI system. Recently, a study assessed transcallosal fibers with fractional anisotropy and investigated their functions with IHI between M1hand areas (Wahl et al. 2007). Future studies may correlate the degree of IHI from different cortical regions to the contralateral M1 with fractional anisotropy of the fibers involved.

The Effect of CS Current Directions on SIHI and LIHI

ANOVA showed that different CS current directions have similar effects on IHI. This is consistent to a previous study showing no current directional preference for IHI between homologous M1s (Chen et al. 2003). However, we cannot entirely exclude the possibility that the fibers mediating IHI have different orientations in different cortical areas because 2 factors potentially have influenced the result. First, the effective latencies of IHI may be different among various current directions and we only tested one ISI for SIHI and LIHI. This may be a significant factor for SIHI. Second, IHI at various current directions may have different thresholds and we used the same stimulus intensities for different directions. Studies with different stimulus intensities and ISIs may examine this further.

Inhibitory and Facilitatory Interhemispheric Interactions

We found a widely distributed inhibitory system from motor related cortical areas to the contralateral M1. It was reported that facilitatory interactions can be activated between homologous M1s at short ISIs and certain CS and TS conditions (Hanajima et al. 2001). Similar facilitatory interaction was also found between PMd and contralateral M1 (Baumer et al. 2006). These studies indicated that transcallosal connections may be complex. Inhibitory and facilitatory transcallosal fibers may have different threshold or directional preference. It was reported that SIHI between homologous M1s decreased at the premovement stage (Murase et al. 2004) and during force generation (Perez and Cohen 2008) ipsilateral to the target M1. It would be of interest to determine how IHI from different cortical areas to the contralateral M1 modulates with voluntary activity. In addition, it was reported that SIHI was weaker in well trained musician than in normal subject (Ridding et al. 2000), suggesting that the balance between inhibition and facilitation in the widely distributed IHI system may be altered with training.

Possible Difference between Dominant and Nondominant Sides

We investigated the SIHI/LIHI from the motor related cortical areas in the nondominant hemisphere to the dominant M1. There is a differential modulation of M1-M1 IHI between left and right hand movements (Duque et al. 2007). Additionally, left PMd has greater effects on movement selection in both left and right hands (Rushworth et al. 2003). Right DLPFC but not the left plays a crucial role in decision making (Fecteau et al. 2007). Therefore, SIHI/LIHI from the dominant to nondominant side may be different from the present findings.

Potential Implications

IHI plays an important role in unimanual and coordinated bimanual movements, including assistance in bilateral movements and suppression of unwanted motor activity in the opposite limbs during unilateral movements (Duque et al. 2005). During the execution of voluntary contraction, the IHI targeting the M1 ipsilateral to the moving limb has been shown to increase (Ferbert et al. 1992), suggesting that inhibitory drive to the targeted M1 minimizes mirror activity (Leocani et al. 2000; Duque et al. 2005). Our finding that SIHI/LIHI is widely distributed among motor related cortical areas suggests that this inhibitory drive may contribute to unimanual and coordinated bimanual movements at different stages of motor control, including the decision making (DLPFC), movement selection (S1 and PMd) and execution (M1, PMd, S1). Studies investigating IHI from various motor related cortical areas in neurological disorders such as Parkinson's disease (Li et al. 2007) or stroke (Murase et al. 2004) may provide further understanding of their pathophysiology.

The present study investigated IHI produced by different motor related cortical areas with 3 variables: ISI, CS intensity, and CS current direction. We conclude that there are 2 distinct phases of IHI from motor related cortical areas to the opposite M1, and that they are mediated by different neuronal populations.

Funding

Canadian Institutes of Health Research Operating Grant to R.C. (MOP 62917); and Canadian Institutes of Health Research Fellowship Award in the Area of Dystonia to Z.N. (DFF 88348).

Conflict of Interest: None declared.

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