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Logo of jphysiolThe Journal of Physiology SiteMembershipSubmissionJ Physiol
J Physiol. Sep 15, 2008; 586(Pt 18): 4489–4500.
Published online Jul 31, 2008. doi:  10.1113/jphysiol.2008.156596
PMCID: PMC2614023

Theta burst stimulation induces after-effects on contralateral primary motor cortex excitability in humans

Abstract

Interhemispheric interactions between the primary motor cortices (M1) have been described with a variety of TMS methods. Here we give a detailed description of the interhemispheric interactions of a period of theta burst simulation (TBS), a rapid method of producing long lasting after-effects on the excitability of the stimulated M1. A total of 18 right handed healthy subjects participated. In most experiments, continuous and intermittent TBS (cTBS and iTBS) were delivered over the right M1 using a coil orientated to induce antero-posterior followed by postero-anterior (AP–PA) currents in the brain. The intensity of stimulation was 80% of active motor threshold (AMT), and a total of 600 pulses were applied. The effects on the amplitude of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated in the left and right M1 before and at three different times after TBS. We also tested long-interval intracortical inhibition (LICI) in right M1 and interhemispheric inhibition (IHI) from right to left M1. Finally, to explore the effect of different polarities of cTBS over dominant and non-dominant hemisphere we delivered AP–PA and postero-anterior followed by antero-posterior (PA–AP) cTBS over either right or left M1 and tested MEPs in both hemispheres. In the stimulated hemisphere, cTBS reduced MEPs and SICI whereas iTBS increased MEPs and SICI. In the non-stimulated hemisphere cTBS increased MEPs and reduced SICI, while iTBS reduced MEPs and increased SICI. There were no effects on ICF, LICI or IHI. Although both AP–PA cTBS and PA–AP cTBS reduced MEPs in the stimulated M1, the former increased MEPs from non-stimulated M1 whereas the latter did not. There was no difference in the effect of cTBS on the dominant or non-dominant hemisphere.

Interhemispheric interactions between the left and right primary motor cortex (M1) are thought to occur mainly through transcallosal fibres that run in the midbody of the corpus callosum (CC) (Rouiller et al. 1994; Zarei et al. 2006). One way to explore the interhemispheric projections in the human motor system is through application of TMS. Three different TMS protocols are available: interhemispheric inhibition (IHI), interhemispheric facilitation (IHF) and ipsilateral silent period (iSP). IHI consists of a paired pulse TMS protocol with a conditioning pulse delivered over M1 that inhibits the size of the MEP evoked by a test pulse given over the contralateral M1 (cM1) 10 and 40 ms later (Ferbert et al. 1992; Gerloff et al. 1998; Chen et al. 2003). IHF consist of a similar protocol of IHI with the test pulse following the conditioning pulse at 4 ms (Hanajima et al. 2001). Finally, iSP is the interruption of ongoing voluntary electromyographic (EMG) activity by TMS of the ipsilateral M1 (Ferbert et al. 1992). IHI and iSP are reduced or absent in patients without a corpus callosum (Meyer et al. 1995, 1998) and therefore are thought to be mediated mainly by activation of transcallosal projections to cM1 (Ferbert et al. 1992; Ziemann et al. 1999; Hanajima et al. 2001; Daskalakis et al. 2002; Chen et al. 2003; Avanzino et al. 2007).

A different approach to test interhemispheric interactions in humans is through application of repetitive transcranial magnetic stimulation (rTMS). rTMS induces lasting changes in cortical excitability at the site of stimulation as well as in remote sites that are functionally connected with the target area (network effect) (Hallett, 2000; Siebner & Rothwell, 2003; Pascual-Leone et al. 2005; Ridding & Rothwell, 2007). At first sight the literature on the effects of 1 Hz rTMS on the contralateral M1 seems confusing: although 1 Hz rTMS regularly depresses excitability of the stimulated hemisphere, in some studies it facilitates contralateral M1 whereas in others it suppresses it (Wassermann et al. 1998; Gilio et al. 2003; Schambra et al. 2003; Gorsler et al. 2003; Plewnia et al. 2003; Pal et al. 2005; Heide et al. 2006). One possible explanation for this relates to the different intensities of stimulation used in each study (Wassermann et al. 1998; Gorsel et al. 2003; Gilio et al. 2003; Schambra et al. 2003; Plewnia et al. 2003; Pal et al. 2005; Heide et al. 2006). A second possible explanation could be whether the rTMS was applied over the dominant or non-dominant hemisphere (Wassermann et al. 1998; Gorsel et al. 2003; Gilio et al. 2003; Schambra et al. 2003; Plewnia et al. 2003; Pal et al. 2005; Heide et al. 2006).

Theta Burst Simulation (TBS) is a new rTMS protocol characterized by high frequency and low intensity (80% AMT) stimulation (Huang & Rothwell, 2004, 2005, 2007, 2008). When applied in a continuous form (cTBS) it depresses cortical excitability, whereas when given in an intermittent form (iTBS), excitability is increased (Huang et al. 2004, 2005, 2007, 2008). There have been two recent studies of the effects of TBS on the non-stimulated M1: Ishikawa et al. (2007) found that cTBS reduced MEPs in both target and contralateral M1; in contrast Stefan et al. (2008) reported that cTBS reduced MEPs in the target M1 but increased them in the non-stimulated M1. The explanation for this difference is unclear. It may be because subtly different intensities of stimulation were used (80% AMT and 70% RMT, respectively) or to other uncontrolled factors.

The aim of the present study was to explore in more detail the effects of cTBS and iTBS on the stimulated and non-stimulated M1. In addition to MEP amplitude we tested SICI, ICF, LICI and IHI. We also explored the effect of different polarities of cTBS and compared its effects on dominant (left) and non-dominant (right) hemispheres. These baseline data can then be used in future studies to inform the use of interventional neurostimulation approaches to treat different types of neurological diseases such as stroke, neuropathic pain and movement disorders.

Methods

Subjects

The study group comprised 18 right handed normal subjects (11 male and 7 female; mean age ±s.d.: 31 ± 5; age range 26–45). None of the subjects were taking drugs acting on the central nervous system. All subjects gave their written informed consent, and the study was approved by the local ethical committee and conformed with the Declaration of Helsinki.

Stimulation techniques

A ‘conditioning–test’ protocol was used in the present experiments (Fig. 1A and B).

Figure 1
Experimental protocols in the first (experiments 1, 2, 3 and 4) (A) and second (experiments 5 and 6) set of experiments (B) showing the time course considered before and after conditioning cTBS and iTBS

Conditioning-rTMS

Conditioning-rTMS was delivered through a high-frequency magnetic stimulator (Magstim Super Rapid; The Magstim Company Ltd, Whitland, UK) connected to a figure-of-eight coil with mean loop diameter of 9 cm. The magnetic stimulus had a biphasic waveform with a pulse width of ~300 μs. During the first phase of the stimulus, the current in the centre of the coil flowed toward the handle. The coil was held tangentially to the scalp with the handle pointing antero-medially from the midline at 45 deg (AP coil orientation) inducing antero-posterior followed by postero-anterior (AP–PA) currents in the brain (Kammer et al. 2001) because this coil orientation is thought to be the most effective for biphasic TMS (Kammer et al. 2001; Di Lazzaro et al. 2001; Di Lazzaro et al. 2005; Gilio et al. 2003; Gorsler et al. 2003; Talelli et al. 2007; Suppa et al. 2008; Zafar et al. 2008). The coil was placed over the optimum scalp position (hot spot) to elicit motor responses (MEPs) in the contralateral first dorsal interosseus (FDI) muscle. Coil positioning was visually controlled during the experimental session through marks on the subject's scalp.

Motor threshold was calculated at rest (RMT) and considered as the lowest intensity able to evoke a MEP of more than 50 μV in at least 5 out of 10 consecutive trials in the FDI muscle. Active motor threshold (AMT) was calculated as the lowest intensity able to evoke a MEP of 200 μV during a 10% maximum voluntary contraction of the FDI muscle.

Conditioning TMS consisted of two different theta burst stimulation protocols (cTBS and iTBS) delivered in all subjects in different sessions randomly assigned with an interval between each session of at least 7 days. Both cTBS and iTBS consisted of bursts of three pulses delivered at 50 Hz (20 ms between each pulse) repeated at 5 Hz (200 ms between each burst) with a total of 600 pulses at intensity of 80% of AMT. In the cTBS protocol the stimulation consisted of one train of 40 s. The iTBS protocol consisted of 20 trains of 2 s repeated every 10 s (intertrain pause of 8 s) for a total of 190 s (Huang et al. 2005).

Test TMS

Test TMS techniques were delivered through monophasic Magstim 200 stimulators connected by a Y-cable to a 9 cm diameter figure-of-eight coil. The magnetic stimulus delivered by Magstim 200 had a nearly monophasic pulse configuration with a rise time of ~100 μs, decaying back to zero over ~0.8 ms; the coil current during the rising phase of the magnetic field flowed toward the handle.

The coil was placed tangentially to the scalp of the right and left hemispheres and with the handle pointing back and away from the midline at 45 deg (PA coil orientation) inducing postero-anterior (PA) monophasic current in the brain.

In all experimental sessions the different TMS protocols used (single and paired pulses) were delivered in a randomized order.

Experimental design

Experiment 1: effect of conditioning cTBS and iTBS on MEPLeft FDI, SICIRight FDI and ICFRight FDI

In experiment 1 we tested in 15 subjects the right and left M1 cortical excitability before and after conditioning cTBS and iTBS over right M1. On the right M1 we delivered 15 single pulse TMS with an interpulse interval of 4 s to test MEPs amplitude from left FDI (MEPLeft FDI). TMS stimulation intensity was set at the value able to evoke MEPLeft FDI of 1 mV amplitude before conditioning cTBS and iTBS. On the left M1 (cM1) we delivered 30 paired pulse TMS with interval (ISI) between the two pulses of 3 ms and 10 ms (Kujirai et al. 1993) and interval between paired pulses of 4 s to explore from right FDI short interval intracortical inhibition and facilitation (SICIRight FDI and ICFRight FDI). The intensity of conditioning TMS in the paired pulse protocol was set at 80% of AMT (as tested before conditioning cTBS and iTBS). In order to reduce variability, the intensity of the test TMS pulse was adjusted to evoke MEPs from the right FDI (Test MEPRight FDI) with an amplitude of about 1 mV (Ziemann et al. 1996; Ilic et al. 2002) before and after conditioning cTBS and iTBS.

Experiment 2: effect of conditioning cTBS and iTBS on MEPRight FDI

In experiment 2 we tested in 10 subjects the left M1 (cM1) cortical excitability before and after conditioning cTBS and iTBS over right M1 delivering 15 single pulse TMS with an interpulse interval of 4 s on the left M1 and testing MEPs amplitude from the right FDI (MEPRight FDI) before and after cTBS and iTBS. TMS stimulation intensity was fixed before conditioning cTBS and iTBS at a level able to evoke MEPRight FDI of 1 mV amplitude.

Experiment 3: effect of conditioning cTBS and iTBS on LICI 100Right FDI and LICI 150Right FDI

In experiment 3 we tested in eight subjects left M1 (cM1) cortical excitability with LICI before and after conditioning cTBS and iTBS over right M1. LICI consists of a conditioning stimulus which inhibits MEPs evoked by a test stimulus delivered over M1 in the same hemisphere at ISI of 100 (LICI 100Right FDI) and 150 ms (LICI 150Right FDI) (Valls-Sole et al. 1992). We tested LICI 100Right FDI and LICI 150Right FDI on the left M1 delivering 30 paired pulses at interstimulus intervals of 100 and 150 ms and with an interval between each TMS paired pulse stimulation of 4 s. The intensity of test and conditioning pulses in LICI was continuously monitored to evoke with the test pulse, MEPs from the right FDI (Test MEPRight FDI) of 1 mV amplitude.

Experiment 4: effect of conditioning cTBS and iTBS on IHI 10Right FDI and IHI 40Right FDI

In experiment 4 we tested IHI in eight subjects before and after conditioning cTBS and iTBS over right M1. IHI consists of a conditioning stimulus delivered over M1 which inhibits MEPs evoked by a test stimulus applied on cM1 at 10 ms (IHI 10Right FDI) or 40 ms later (IHI 40Right FDI) (Ferbert et al. 1992; Chen et al. 2003; Pal et al. 2005). We tested IHI 10Right FDI and IHI 40Right FDI with conditioning stimulus delivered on the right and the test stimulus on the left M1 (cM1) through two monophasic Magstim 200 stimulators independently connected to two 7 cm diameter figure-of-eight coils (Chen et al. 2003; Pal et al. 2005). We delivered 30 paired pulses at ISI of 10 and 40 ms with an interval between each TMS paired pulse stimulation of 4 s. The intensity of test and conditioning TMS pulses was continuously monitored to evoke with both TMS pulses MEPs from the right (Test MEPRight FDI) and the left FDI (Test MEPLeft FDI) of 1 mV amplitude.

Experiment 5: effect of conditioning cTBS on MEPRight FDI, SICILeft FDI and ICFLeft FDI

In experiment 5 we measured in five subjects MEPs in the right FDI (MEPRight FDI) evoked by 15 single pulse TMS on the left M1 with an interpulse interval of 4 s, before and after AP–PA cTBS over right M1. TMS stimulation intensity was fixed before conditioning cTBS at the value able to evoke MEPRight FDI of 1 mV amplitude. We also tested MEP amplitudes evoked by paired pulse TMS at 3 and 10 ms ISI (Kujirai et al. 1993) from the left FDI (SICILeft FDI and ICFLeft FDI) before and after AP–PA cTBS over right M1. The intensity of the conditioning TMS pulse was fixed to 80% of AMT as tested before conditioning cTBS. The intensity of the test TMS pulse was continuously monitored after conditioning cTBS to steadily evoke MEPs from the left FDI (Test MEPLeft FDI) of 1 mV amplitude.

Experiment 6: effect of conditioning AP–PA and PA–AP cTBS over left and right M1 on MEPLeft FDI and MEPRight FDI

In experiment 6 we tested the effect of AP–PA and PA–AP cTBS over right and left M1 exploring in five subjects MEPs amplitude from left and right FDI (MEPLeft FDI and MEPRight FDI) evoked by single pulse TMS over right and left M1. TMS stimulation intensity was fixed at the value able to evoke MEPLeft FDI and MEPRight FDI of 1 mV amplitude before conditioning cTBS.

The degree of left hemispheric dominance was evaluated using the laterality quotient (LQ) score of the Edinburgh Handedness Inventory (Oldfield, 1971).

Time course of the after-effects of conditioning TBS

We explored in all the experiments the time course of the after-effects of conditioning cTBS and iTBS.

In the cTBS sessions all the TMS parameters were tested before (T0) and after cTBS at T1 (immediately after the end of conditioning cTBS), at T2 (after 15 min) and at T3 (after 30 min).

In the iTBS sessions all the TMS parameters were tested before (T0) and after iTBS at T1 (5 min after the end of conditioning iTBS), at T2 (after 20 min) and at T3 (after 35 min). The time course was set according to time-related observations described in previous studies (Huang et al. 2005, 2007, 2008; Di Lazzaro et al. 2005) (Fig. 1A and B).

Recording techniques and measurements

The electromyographic (EMG) activity was recorded through pairs of surface electrodes (Ag–AgCl) placed over the right and the left FDI muscle, using a belly tendon montage. EMG signals were recorded, amplified and filtered with a Digitimer D 360 (Digitimer Ltd, Welwyn Garden City, UK) (bandwidth 5 Hz to 1 kHz), acquired at a sampling rate of 5 kHz through a 1401 plus AD laboratory interface (Cambridge Electronic Design, Cambridge, UK) and stored on a personal computer for off-line analysis (Signal software; Cambridge Electronic Design). Experiments were performed with subjects fully relaxed and with their eyes open. The level of baseline EMG activity before, during and after conditioning cTBS and iTBS was controlled by visual feedback through an oscilloscope screen and auditory feedback through a loudspeaker. Trials with background EMG activity were rejected. The amplitude of MEPs was measured peak to peak (mV) and then averaged.

Statistical analysis

All data collected in the experimental sessions were analysed as absolute values (mV) by repeated measures ANOVA.

Experiment 1: effect of conditioning cTBS and iTBS on MEPLeft FDI, SICIRight FDI and ICFRight FDI

The effect of conditioning cTBS and iTBS on the amplitude of MEPLeft FDI, SICIRight FDI and ICFRight FDI was analysed with a three-way repeated-measures ANOVA with ‘Intervention’ (cTBS versus iTBS), ‘Time’ (T0versus T1, T2 and T3) and ‘ISI’ (MEPLeft FDIversus SICIRight FDIversus ICFRight FDI) as main factors of analysis.

Correlation study: MEPLeft FDI and SICIRight FDI

Pearson's correlation test was used to examine the possible correlation between the after-effects of cTBS and iTBS on MEPLeft FDI and SICIRight FDI in each subject involved in experiment 1 at T2 (the after-effects are expected to be maximal at this time interval).

Experiment 2: effect of conditioning cTBS and iTBS on MEPRight FDI

The effect of conditioning cTBS and iTBS on the amplitude of MEPs evoked by single pulse TMS over left M1 (MEPRight FDI) was analysed with a two-way repeated-measures ANOVA with ‘Intervention’ (cTBS versus iTBS) and ‘Time’ (T0versus T1, T2 and T3) as main factors of analysis.

Experiment 3: effect of conditioning cTBS and iTBS on LICI 100Right FDI and LICI 150Right FDI

The effect of conditioning cTBS and iTBS on the amplitude of MEPs evoked by LICI 100Right FDI and LICI 150Right FDI over left M1 was analysed with a two-way repeated-measures ANOVA with ‘Time’ (T0versus T1, T2 and T3) and ‘ISI’ (Test versus LICI 100Right FDI versus LICI 150Right FDI) as main factors of analysis.

Experiment 4: effect of conditioning cTBS and iTBS on IHI 10Right FDI and IHI 40Right FDI

The effect of conditioning cTBS and iTBS on the amplitude of MEPs evoked by IHI 10Right FDI and IHI 40Right FDI were both analysed with a two-way repeated-measures ANOVA with ‘Time’ (T0versus T1, T2 and T3) and ‘ISI’ (Test versus IHI 10Right FDI versus IHI 40Right FDI) as main factors of analysis.

Experiment 5: effect of conditioning cTBS on MEPRight FDI, SICILeft FDI and ICFLeft FDI

The effect of conditioning cTBS on the amplitude of MEPs evoked by single pulse TMS over left M1 (MEPRight FDI) was analysed with a one-way repeated-measures ANOVA with ‘Time’ (T0versus T1, T2 and T3) as main factors of analysis.

The effect of conditioning cTBS on the amplitude of MEPs evoked by paired pulse at 3 and 10 ms ISI over right M1 (SICILeft FDI and ICFLeft FDI) was analysed with a two-way repeated-measures ANOVA with ‘Time’ (T0versus T1, T2 and T3) and ‘ISI’ (TestLeft FDI versus SICILeft FDI versus ICFLeft FDI) as main factors of analysis.

Experiment 6: effect of conditioning AP–PA and PA–AP cTBS over left and right M1 on MEPLeft FDI and MEPRight FDI

The effect of conditioning AP–PA and PA–AP cTBS over left and right M1 on the amplitude of MEPLeft FDI and MEPRight FDI was analysed with a four-way repeated-measures ANOVA with ‘Target M1’ (right versus left), ‘Current polarity’ (PA–AP versus AP–PA), ‘Time’ (T0versus T1, T2 and T3) and ‘MEPs' (MEPLeft FDI versus MEPRight FDI) as main factors of analysis.

To verify in all the experiments (experiments 1–4) if the amplitude of Test MEPRight FDI in SICIRight FDI, ICFRight FDI, LICI 100Right FDI and LICI 150Right FDI, IHI 10Right FDI and IHI 40Right FDI protocols and Test MEPLeft FDI in SICILeft FDI protocol was constantly at 1 mV, we performed a three-way ANOVA with ‘Intervention’ (cTBS versus iTBS), ‘Time’ (T0versus T1, T2 and T3) and ‘Condition’ (Test MEPRight FDI in SICIRight FDI and ICFRight FDI protocol versus Test MEPRight FDI in LICI 100Right FDI and LICI 150Right FDI protocol versus Test MEPRight FDI in IHI 10Right FDI and IHI 40Right FDI protocol versus Test MEPLeft FDI in SICILeft FDI protocol) as main factors of analysis.

Bonferroni's correction was used for all post hoc analysis. The Greenhouse–Geisser correction was used when necessary to correct for non-sphericity. A P-value < 0.05 was considered significant for all statistical analysis.

Results

None of the subjects experienced any adverse effects. In sum, ANOVA showed that cTBS reduced MEPs on target M1 but increased MEP in cM1. Conversely, iTBS increased MEPs on target M1 but reduced MEPs on cM1. cTBS reduced whereas iTBS increased SICI on cM1. The study of the time course showed that the after-effects on cortical excitability induced by both cTBS and iTBS on target M1 and cM1 were maximal at T2 (15–30 min in cTBS protocol; 20–35 min in iTBS protocol). Considering each subject enrolled in experiment 1, no significant correlation was seen between changes in MEP amplitude tested with single pulse TMS over target M1, and changes in MEPs tested by SICI over cM1 at T2 after both cTBS and iTBS. Both cTBS and iTBS left cM1 ICF and LICI 100–150 unchanged. cTBS and iTBS also did not modify IHI 10 and 40. cTBS reduced SICI and left ICF unchanged also in target M1. Finally although both AP–PA cTBS and PA–AP cTBS reduced MEPs over target M1, the former increased significantly MEPs amplitude elicited over cM1 whereas the latter did not, considering either the dominant or the non-dominant hemisphere as a target of cTBS.

Experiment 1

Effect of conditioning cTBS and iTBS on MEPLeft FDI

Three-way ANOVA showed a significant main effect of factor ‘ISI’ (F2.1,29.6= 17.35; P < 0.01), a significant two-way interaction of factor ‘Intervention’ by ‘ISI’(F3,42= 6.85; P < 0.01) and a significant three-way interaction of ‘Intervention’, ‘Time’ and ‘ISI’ (F9,126= 6.05; P < 0.01).

One-way ANOVA showed that cTBS significantly reduced MEPLeft FDI amplitude as shown by a significant effect of factor ‘Time’ (F3,42= 7.02; P < 0.01). Post hoc analysis showed that the after-effects were present at T1 (P < 0.01) and T2 (P < 0.01) (Fig. 2A).

Figure 2
Cortical excitability tested before and after conditioning cTBS over right M1

One-way ANOVA showed that iTBS significantly increased MEPLeft FDI amplitude as shown by a significant effect of factor ‘Time’ (F3,42= 4.7; P < 0.01). Post hoc analysis showed that the after-effects were present at T2 (P = 0.03) and T3 (P = 0.02) (Fig. 2D).

Effect of conditioning cTBS and iTBS on SICIRight FDI and ICFRight FDI

In the cTBS experiment two-way ANOVA showed a significant effect of factor ‘ISI’ (F2,28= 17.84; P < 0.01) and significant two-way interaction of factor ‘ISI’ and factor ‘Time’ (F6,84= 2.42; P < 0.01). Post hoc one-way ANOVA showed a significant effect of factor ‘Time’ (F3,42= 5.5; P < 0.01) on SICI but not on ICF showing that cTBS reduced SICI at T1 (P = 0.02), T2 (P = 0.02) and T3 (P = 0.01) but left ICF unchanged (Fig. 2B). SICI was significantly present before (T0) (P < 0.01) and after the end of cTBS at T3 (P = 0.02) but not at T1 and T2. ICF was significantly present at T0 (P = 0.03) (Fig. 2B).

In the iTBS experiment two-way ANOVA showed significant effect of factor ‘Time’ (F3,42= 2.86; P < 0.05) and ‘ISI’ (F2,28= 26.19; P < 0.01). Post hoc one-way ANOVA showed a significant effect of factor ‘Time’ (F3,42= 5.0; P < 0.01) on SICI but not on ICF showing that iTBS increased SICI at T2 (P = 0.02) but left ICF unchanged (Fig. 2E). SICI was significantly present at T0 (P = 0.01), at T1 (P < 0.01), T2 (P < 0.01) and at T3 (P = 0.02). ICF was significantly present at T0 (P = 0.01) (Fig. 2E).

Correlation study: MEPLeft FDI and SICIRight FDI

Pearson's correlation test showed that after cTBS and iTBS a correlation between MEPLeft FDI and SICIRight FDI at T2 in each subject enrolled in the main experiment was slightly present even if not significant (cTBS: r =−0.30; P = 0.27; iTBS: r =−0.38; P = 0.16).

Experiment 2: effect of conditioning cTBS and iTBS on MEPRight FDI

Two-way ANOVA showed main effect of factor ‘Intervention’ (F1,9= 63.3; P < 0.01) and a significant two-way interaction of ‘Intervention’ and ‘Time’ (F3,27= 16.9; P < 0.01).

Post hoc analysis showed that cTBS significantly increased MEPs amplitude as shown by a significant effect of factor ‘Time’ (F3,27= 5.1; P < 0.01) and the after-effects were present at T2 (P = 0.02) (Fig. 2C). On the other hand iTBS significantly reduced MEPs amplitude as shown by a significant effect of factor ‘Time’ (F3,27= 16.5; P < 0.01) and the after-effects were present at T1 (P = 0.01), T2 (P < 0.01) and T3 (P < 0.01) (Fig. 2F).

Experiment 3: effect of conditioning cTBS and iTBS on LICI 100Right FDI and LICI 150Right FDI

In the cTBS experiment two-way ANOVA showed a main effect of factor ‘ISI’ (F2,14= 11.36; P = 0.01). Post hoc analysis showed that both LICI 100Right FDI and LICI 150Right FDI reduced Test MEPRight FDI at T0 (P = 0.02 and P = 0.03). cTBS left both LICI 100Right FDI and LICI 150Right FDI unchanged (Fig. 3A).

Figure 3
Effect of cTBS and iTBS applied over the right M1 on LICI and IHI in left M1

In the iTBS experiment two-way ANOVA showed main effect of factor ‘ISI’ (F2,14= 66.6; P < 0.01). Post hoc analysis showed that both LICI 100Right FDI and LICI 150Right FDI reduced Test MEPRight FDI amplitude at T0 (P < 0.01 and P < 0.01). iTBS left both LICI 100Right FDI and LICI 150Right FDI unchanged (Fig. 3B).

Experiment 4: effect of conditioning cTBS and iTBS on IHI 10Right FDI and IHI 40Right FDI

In the cTBS experiment two-way ANOVA showed main effect of factor ‘ISI’ (F2,14= 13,15; P < 0.01). Post hoc analysis showed that both IHI 10Right FDI and IHI 40Right FDI inhibited Test MEPRight FDI amplitude at T0 (P < 0.01 and P = 0.01). cTBS left both IHI 10Right FDI and IHI 40Right FDI unchanged (Fig. 3C).

In the iTBS experiment two-way ANOVA showed main effect of factor ‘ISI’ (F2,14= 37.69; P < 0.01). Post hoc analysis showed that both IHI 10Right FDI and IHI 40Right FDI inhibited Test MEPRight FDI amplitude at T0 (P < 0.01 and P < 0.01) and iTBS left both IHI 10Right FDI and IHI 40Right FDI unchanged (Fig. 3D).

Experiment 5: effect of conditioning cTBS on MEPRight FDI, SICILeft FDI and ICFLeft FDI

One-way ANOVA showed that cTBS significantly increased MEPRight FDI as shown by a significant effect of factor ‘Time’ (F3,12= 5.84; P = 0.01). Post hoc analysis showed that the after-effects were present at T2 (P < 0.01) (Fig. 4A).

Figure 4
MEPs evoked by single pulse TMS over left M1 (MEPRight FDI) (A) and MEPs evoked by test pulse, paired pulse at 3 ms (SICI) and 10 ms (ICF) TMS over right M1 before and after AP–PA cTBS over right M1 (B)

Two-way ANOVA showed significant effect of factor ‘ISI’ (F2,8= 12.66; P < 0.01). Post hoc one-way ANOVA showed a significant effect of factor ‘Time’ (F3,12= 8.19; P < 0.01) on SICI but not on ICF showing that cTBS reduced SICI at T1 (P < 0.05), T2 (P < 0.01) and T3 (P < 0.01) but left ICF unchanged. SICI was significantly present at T0 (P < 0.01), T1 (P < 0.01), and T3 (P = 0.01) but not at T2 (P = 0.11). ICF was significantly present at T0 (P = 0.02), T1 (P < 0.01), T2 (P = 0.05) and T3 (P < 0.01) (Fig. 4B).

Experiment 6: effect of conditioning AP–PA and PA–AP cTBS over left and right M1 on MEPLeft FDI and MEPRight FDI

Four-way ANOVA showed main effect of factor ‘Current polarity’ (F1,4= 26.68; P < 0.01), factor ‘MEPs' (F1,4= 94.43; P < 0.01) and a significant three way interaction of factors ‘Current polarity’, ‘Time’ and ‘MEPs' (F3,12= 11.38; P < 0.01). Post hoc one-way ANOVA showed that AP–PA cTBS over either dominant or non-dominant hemisphere of five right handed subjects (mean LQ ±s.d.: 80.5 ± 12.1) increased MEPs in cM1 (AP–PA cTBS over dominant hemisphere: F3,12= 12.55; P < 0.01; AP–PA cTBS over non-dominant hemisphere: F3,12= 3.97; P = 0.03) (Fig. 5A and B). Conversely, PA–AP cTBS did not significantly modify MEPs in cM1 (PA–AP cTBS over dominant hemisphere: F3,12= 0.46; P = 0.72; PA–AP cTBS over non-dominant hemisphere: F3,12= 0.37; P = 0.78) (Fig. 5C and D).

Figure 5
MEPs evoked by test pulse delivered over right and left M1 (MEPLeft FDI and MEPRight FDI) before and after conditioning AP–PA (A and B) and PA–AP (C and D) cTBS over left (upper panel) and right (lower panel) M1

Discussion

Due to the large number of variables that we examined in these experiments, it was not possible to study all of them simultaneously in a single experimental session. Instead, we examined a small number of them in a series of six parallel experiments conducted on subsets of our 18 healthy subjects. Although the experiments were conducted separately, we discuss them below as a single whole.

The present results confirm that cTBS and iTBS have after-effects on the excitability of MEPs and SICI evoked in the stimulated M1 (Huang et al. 2005). They also confirm that both procedures have effects on excitability of MEPs in the non-stimulated hemisphere (see also Ishikawa et al. 2007; Stefan et al. 2008). The novel findings are that (1) there are effects also on SICI in the non-stimulated hemisphere but no changes in ICF, LICI or IHI, (2) MEPs elicited from the dominant and non-dominant hemispheres react in the same way to cTBS, and (3) different polarities of cTBS have different effects on MEPs from the non-stimulated hemisphere.

Effects on the stimulated hemisphere

One important feature of the present experiments was that we used the opposite orientation of TBS to that originally applied by Huang et al. (2005). Thus, the induced current in the brain was AP–PA rather than PA–AP. The reason for this was that with a biphasic stimulator, AP–PA is a more efficient way of stimulating M1 than other orientations. Talelli et al. (2007) recently compared the efficiency of cTBS/iTBS with opposite coil orientations. They noted that the effects of cTBS were more powerful after this AP–PA stimulation, whereas the effect of iTBS was variable. This was not the case in a more recent report from Zafar et al. (2008) but this may have been because they used a different coil type. Alternatively it may be that since the TBS protocol is very brief, it is more susceptible to individual differences than longer lasting methods. In the present larger group of subjects, the effects of iTBS were quite reproducible so that we used AP–PA stimulation for both forms of TBS. The after-effects of TBS in the stimulated hemisphere were very similar to those reported previously, with MEPs and SICI decreasing after cTBS and MEPs increasing after iTBS. However we did not observe any changes in ICF with the reverse current flow direction whereas Huang et al. (2005) noted a small decrease after cTBS. Indeed, Talelli et al. (2007) also reported no effect on ICF after cTBS with AP–PA stimulation. They speculated that this was because ICF depended on interaction of I3 inputs to corticospinal neurones in M1. Since AP–PA biphasic stimulation tends to recruit I3 inputs less effectively than PA–AP stimulation, it is less likely to change ICF.

Effects on the non-stimulated hemisphere

The MEPs in the non-stimulated hemisphere were affected in the opposite way to those in the stimulated hemisphere, confirming that long lasting after-effects in one area of cortex are likely to have an impact on function in distant connected areas of brain. There have been only two previous reports of the after-effects of TBS on the excitability of MEPs in the non-stimulated M1, but both of them used PA–AP cTBS rather than the AP–PA orientation that we used in the majority of our experiments. In fact, when we used this orientation of cTBS (experiment 6) we found no significant effects on the non-stimulated M1, which is in contrast to the findings of Stefan et al. (2008) who found that MEPs were facilitated and Ishikawa et al. (2007) who thought they were suppressed. As noted by Stefan et al. (2008), it is unclear why these results differed. In the present study we used 80% of AMT similar to that used by Ishikawa et al. (2007) and we found that the direction of the after-effects are similar to that used by Stefan et al. (2008). The difference in the direction of the after-effects observed in the two studies (Ishikawa et al. 2007; Stefan et al. 2008) therefore is unlikely be due to the different intensity of stimulation used. Possible further mechanisms include differences in magnetic stimulator, handedness and laterality quotients (LQ), prior activity of the muscle under testing (e.g. Gentner et al. 2008), or to the different ethnic origin of subjects studied. Indeed, as noted in the Introduction, similar divergent effects have been seen after 1 Hz rTMS. Perhaps the best conclusion is that ‘although all these studies suggest that conditioning one M1 may influence excitability of the contralateral M1, the direction of these contralateral changes may depend on variables that have yet to be identified’ (Stefan et al. 2008).

cTBS and iTBS affected SICI as well as MEPs in the non-stimulated M1, but in contrast to the results in the stimulated hemisphere where cTBS/iTBS influenced MEPs and SICI in the same direction, in the non-stimulated hemisphere, the effects on SICI were opposite to those on MEPs. Thus, although cTBS increased MEPs, it reduced SICI; similarly although iTBS reduced MEPs, it increased SICI. It is possible that the changes in the MEP in the non-stimulated hemisphere were secondary to the changes in SICI; alternatively, separate pathways may mediate the effects on MEP and SICI. It should be noted that these effects on SICI are unlikely to be the result of the concurrent changes in excitability of MEPs in the non-stimulated hemisphere since the amplitude of the test MEP was adjusted to compensate for this. Additionally, there was no effect on the AMT so that the intensity of the conditioning intensity remained fixed at 80% AMT.

There was no effect of cTBS/iTBS on LICI in the non-stimulated M1, nor on the amount of IHI from the stimulated M1 onto the non-stimulated M1. Although previous observations showed that suprathreshold TMS may interact with IHI and LICI circuits in cM1 (Daskalakis et al. 2002; Gilio et al. 2003; Chen et al. 2003, 2004; Pal et al. 2005; Kukaswadia et al. 2005), we suggest that the low intensity of stimulation in cTBS and iTBS protocols might be insufficient to affect the high threshold LICI and IHI circuits (Chen et al. 2003, 2004; Kukaswadia et al. 2005), or even to influence their tonic levels of activity.

Orientation and dominance effects

We also explored the effect of different polarities of cTBS (AP–PA and PA–AP) over the dominant and non-dominant hemisphere and found that both AP–PA and PA–AP cTBS reduced MEPs in the stimulated M1 but that the former increased MEPs in non-stimulated M1 whereas the latter did not. There was no difference in the results whether or not the dominant or non-dominant hemisphere received cTBS. We suggest that the effect of orientation may result from some of the differences seen in its effects on the stimulated hemisphere where ICF is reduced by cTBS (PA–AP) (Huang et al. 2005) but not by cTBS (AP–PA). If the effects on the non-stimulated M1 are due to long-term changes in the ongoing activity in interhemispheric pathways from the stimulated M1, then these changes in the stimulated hemisphere could be highly relevant. We also found that both orientations of cTBS induced similar after-effects whether or not the dominant or non-dominant hemisphere was stimulated. This contrasts with the evidence for subtle differences in cortical excitability as tested by single or paired pulse TMS over dominant and non-dominant hemispheres (Civardi et al. 2000; De Gennaro et al. 2004; Ilic et al. 2004; Duque et al. 2007). Whether this represents a true difference between hemispheric influences on short and long-term responses to TMS is unclear since the number of subjects studied in the present experiments was relatively small. However, it does suggest that the difference, if it exists, is small and therefore will have little influence on the data obtained in future studies.

Mechanism of the interhemispheric transfer of TBS effects

Both forms of TBS (iTBS/cTBS) were delivered with very low intensity stimulation (80% AMT). For a single stimulus, this is below the threshold for generating corticospinal output from the site of stimulation (Hanajima et al. 2007), so that it seems likely that during TBS, stimulation-evoked activity was local to M1. If so, then the after-effects on non-stimulated M1 must be due to lasting changes in the ongoing activity in interhemispheric connections. Thus, for cTBS to increase excitability of MEP generating circuits in the non-stimulated M1, there would have to be a net reduction in the amount of ongoing inhibition (or increase in facilitation) from the stimulated M1. Moreover, for cTBS to reduce the excitability of circuits involved in SICI would require an increase in the net facilitation (or reduced inhibition) from the stimulated M1. What pathways might mediate these effects is unknown. They could involve transcallosal connections or connections via subcortical structures. Further studies would be required to answer this. Nevertheless, the idea is consistent with current views of the importance of ongoing interactions between the hemispheres (Reis et al. 2008), and have, for example, been found to be abnormal in some patients after stroke (Werhahn et al. 2002, 2003; Murase et al. 2004).

Acknowledgments

We thank Mr Richard Symonds and Mr Peter Owbridge for technical support. E.O. was supported by a grant from the Regione Autonoma della Sardegna (Master and Back Program). N.Z. was supported by a DFG fund (graduiertenkolleg 632; neuroplasticity, from molecules to systems). The work was funded by the Medical Research Council, UK.

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