Abstract

This study was designed to examine whether corticocortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Twelve healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1HAND) at an interstimulus interval (ISI) of 8 ms. Left-to-right cc-PAS (first pulse given to left M1HAND) attenuated left-to-right IHI for one hour after cc-PAS. Left-to-right cc-PAS also increased corticospinal excitability in the conditioned right M1HAND. These effects were not seen in an asymptomatic individual with callosal agenesis. Additional experiments showed no changes in left-to-right IHI or corticospinal excitability when left-to-right cc-PAS was given at an ISI of 1 ms or at multiple ISIs in random order. At the behavioral level, left-to-right cc-PAS speeded responses with the left but not right index finger during a simple reaction time task. Right-to-left cc-PAS (first pulse given to right M1HAND) reduced right-to-left IHI without increasing corticospinal excitability in left M1HAND. These results provide a proof of principle that cc-PAS can induce associative plasticity in connections between the targeted cortical areas. The efficacy of cc-PAS to induce lasting changes in excitability depends on the exact timing of the stimulus pairs suggesting an underlying Hebbian mechanism.

Introduction

Suprathreshold 1-Hz repetitive transcranial magnetic stimulation (rTMS) of the primary motor hand area (M1HAND) has been shown to induce a lasting attenuation of interhemispheric inhibition (IHI) from the stimulated to the contralateral M1HAND (Gilio et al. 2003; Pal et al. 2005). This reduction in IHI was paralleled by an increase in corticospinal excitability in the contralateral M1HAND and did not depend on a change in corticospinal excitability in the directly stimulated M1. Behavioral testing revealed that the rTMS increased corticospinal excitability of the contralateral M1HAND, improving sequential finger movements in healthy subjects (Kobayashi et al. 2004) and simple reaction time (RT) with the contralateral hand in stroke patients (Mansur et al. 2005). Here we introduce associative stimulation of the left and right M1HAND as a new interventional protocol to modify the interhemispheric interaction between the 2 motor cortices.

According to the Hebbian rule, synapses increase their efficacy if the synapse consistently assists the postsynaptic target neuron to generate action potentials (Sejnowski 1999). Associative stimulation of pre- and postsynaptic neurons in slice preparations specified this general rule by showing that synapses in which the presynaptic input fired before the postsynaptic axon get stronger, whereas synapses are weakened in the inverse situation (Levy and Steward 1983; Markram et al. 1997; Bi and Poo 1998). This type of plasticity is referred to as spike-timing–dependent plasticity (STDP).

STDP-like plasticity can be induced in the intact human cortex using paired associative stimulation (PAS) (Thickbroom 2007). Conventional PAS protocols consistently pairs electrical stimulation of the median nerve with TMS of the contralateral primary motor or sensory cortex (Stefan et al. 2000; Wolters et al. 2005). During peripheral-cortical PAS (pc-PAS), the peripheral stimulus elicits a highly synchronized thalamocortical input to the primary sensorimotor cortex at a constant interstimulus interval (ISI) before transcranial cortical stimulation. The direction of excitability changes that can be induced with pc-PAS is governed by an Hebbian learning rule (Wolters et al. 2003). Measurements of TMS-evoked motor-evoked potentials (MEPs) revealed that pc-PAS produced long-term depression-like (LTD-like) effects in fast-conducting corticospinal output neurons when median nerve stimulation preceded the TMS pulse by 10 ms. A long-term potentiation-like (LTP-like) enhancement of cortical excitability was induced when PAS was given at an ISI of 25 ms. The changes in MEP amplitude induced by PAS at a regional level are labeled “LTP- or LTD-like” because they share essential features of associative LTP and LTD (Bliss and Collingridge 1993), such as long duration, associativity, input specificity, dependence on N-methyl-D-aspartic acid (NMDA) receptor activation, and interaction with motor learning (Stefan et al. 2000; Stefan et al. 2002; Wolters et al. 2003; Ziemann et al. 2004).

Here we introduce a new PAS technique for inducing associative plasticity at the regional level in the intact human cortex. Instead of pairing a peripheral with a transcranial stimulus, we consistently paired 2 transcranial stimuli which were applied over the left and right M1HAND. Each stimulus pair consisted of a single TMS pulse over the ipsilateral M1HAND followed by a single TMS pulse over the contralateral M1HAND at a constant ISI of 8 ms (Fig. 1). We chose an interval of 8 ms to match the time between the 2 transcranial stimuli to the onset of IHI (Ferbert et al. 1992). Our protocol was designed to specifically target cortical interneurons in the conditioned (contralateral) M1HAND that integrate the transcallosal input to regulate the excitability of corticospinal output neurons. The first stimulus of each pair was given to the ipsilateral M1HAND to induce highly synchronized action potentials in corticocortical, axons linking both M1HAND. We reasoned that the propagation of the volley in transcallosal axons would cause a trans-synaptic excitation of specific interneurons in the contralateral M1HAND. The second suprathreshold TMS stimulus was directly applied over the contralateral M1HAND to concurrently excite intracortical neurons in the conditioned (contralateral) M1HAND. Assuming an Hebbian mechanism, we hypothesized that corticocortical paired associative stimulation (cc-PAS) protocol should induce associative STDP-like plasticity in interneurons of the conditioned (contralateral) M1HAND that receive transcallosal inputs from the ipsilateral homologous M1HAND.

Figure 1.

Experimental design. Left-to-right cc-PAS was given at a rate of 0.05 Hz to the left and right M1HAND. The intervention consisted of 90 pairs of transcranial stimuli. The stimulus over the left M1HAND was always applied 8 ms before the stimulus over the right M1HAND. Cortical excitability of the conditioned M1HAND was probed with TMS in blocks of measurements immediately before (baseline) and after left-to-right cc-PAS (T0) as well as 30 min (T30) and 60 min (T60) after the end of cc-PAS. Surface EMG activity was recorded from the left first dorsal FDI muscle. Within a single block, we measured several aspects of cortical excitability, including the mean MEP amplitude at rest (MEP), SICI, ICF, the CSP, and left-to-right IHI at short ISIs (short IHI). For details, see methods section.

Figure 1.

Experimental design. Left-to-right cc-PAS was given at a rate of 0.05 Hz to the left and right M1HAND. The intervention consisted of 90 pairs of transcranial stimuli. The stimulus over the left M1HAND was always applied 8 ms before the stimulus over the right M1HAND. Cortical excitability of the conditioned M1HAND was probed with TMS in blocks of measurements immediately before (baseline) and after left-to-right cc-PAS (T0) as well as 30 min (T30) and 60 min (T60) after the end of cc-PAS. Surface EMG activity was recorded from the left first dorsal FDI muscle. Within a single block, we measured several aspects of cortical excitability, including the mean MEP amplitude at rest (MEP), SICI, ICF, the CSP, and left-to-right IHI at short ISIs (short IHI). For details, see methods section.

Methods

Participants

Twelve healthy young volunteers (5 women; mean age: 32 years; age range: 24–39 years) participated in the study. Participants were consistent right handers according to the Edinburgh Handedness Inventory (Oldfield 1971). Experimental procedures were approved by the local Ethics Committee and performed according to the ethical standards laid down in the Declaration of Helsinki. All subjects gave their written informed consent before the experiments. Subjects were seated in a comfortable reclining chair during the experiment.

Main Experiment

Experimental Design

The main experiment was designed to assess the conditioning effects of left-to-right cc-PAS on the excitability of the conditioned right M1HAND (Fig. 1). Cortical excitability of the conditioned M1HAND was probed with TMS in blocks of measurements immediately before (baseline) and after left-to-right cc-PAS (T0) as well as 30 and 60 min (T30 and T60) after the end of cc-PAS. Each block of measurements lasted for approximately 15 min. Within a single block, we first determined the cortical motor threshold, and then recorded MEPs evoked by single-pulse and paired-pulse TMS at rest as well as the cortical silent period (CSP). Finally, we measured left-to-right IHI.

Corticocortical PAS

Ninety pairs of stimuli were continuously delivered at a rate of 0.05 Hz for 30 min. Each pair of stimuli consisted of a monophasic transcranial magnetic stimulus given to the left M1HAND followed by another monophasic transcranial magnetic stimulus given to the right homologous M1HAND. During left-to-right cc-PAS, the conditioning stimulus (CS) was always given to left M1HAND 8 ms before transcranial stimulation of the right M1HAND. All participants showed consistent left-to-right IHI at an ISI of 8 ms when using the conditioning-test paradigm introduced by Ferbert et al. (1992).

Left-to-right TMS was given through 2 high power Magstim 200 stimulators connected to specially designed figure-of-8 coils with a small outer diameter of 7 cm per half wing (Magstim Co., Whitland, Dyfed, UK). The coil current during the rising phase of the magnetic field flowed toward the handle. The coil was placed tangentially to the scalp with the handle pointing backwards and laterally at a 45° angle to the sagittal plane inducing a posterior–anterior current in the brain. The optimum scalp position which consistently elicited the largest MEPs with the steepest initial slope in the relaxed first dorsal interosseus (FDI) muscle (referred to as “motor hot spot”) determined for both the right and left M1HAND. The small diameter of the coils allowed for an optimal placement of the coils over the motor hot spots of the right and left M1HAND. The intensity of TMS was individually adjusted to evoke an electromyography (EMG) response of ∼1 mV peak to peak (115–125% of resting motor threshold [RMT]).

Measurements of Cortical Excitability in the Conditioned Right M1HAND

Monophasic transcranial stimuli were applied over the “motor hot spot” of the contralateral left FDI muscle. Except for measurements of IHI, a conventional figure-of-8-shaped coil with a mean loop diameter of 9 cm was used for TMS. Otherwise, TMS procedures were identical to those used for cc-PAS.

The transcranially evoked responses were recorded with surface EMG from both FDI muscles. Ag-AgCl surface electrodes were placed over the belly and tendon of the FDI muscle. The signal was amplified and band pass filtered (32 Hz to 1 KHz) by a Digitimer D-150 amplifier (Digitimer Ltd., Welwyn Garden City, Herts, UK) and stored at a sampling rate of 10 KHz on a personal computer for off-line analysis (Signal Software, Cambridge Electronic Design, Cambridge, UK). Audiovisual feedback of the recorded EMG activity was given to the subjects to help them maintaining full relaxation (at rest) or producing a constant force level (during tonic contraction).

In each block, we first determined the cortical motor threshold at rest and during tonic contraction. RMT was defined as the minimum intensity that evoked a peak-to-peak MEP of 50 μV in at least 5 out of 10 consecutive trials in the relaxed FDI muscle. Active motor threshold (AMT) was defined as the minimum intensity that elicited a reproducible MEP of at least 200 μV in the tonically contracting FDI muscle in at least 5 out of 10 consecutive trials. Participants were asked to produce a force level of 10% of maximal voluntary contraction.

We then assessed cortical excitability of the conditioned right M1HAND with single and paired-pulse TMS. Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were studied using the conditioning-test paradigm introduced by Kujirai et al. (1993). Two monophasic magnetic stimuli were given through the same stimulating coil over the M1HAND and the effect of the first CS on the second test stimulus (TS) was investigated. SICI and ICF were assessed at ISIs of 2 ms and 12 ms, respectively. To avoid any floor or ceiling effect, the intensity of the CS was set at 80% of AMT. The TS was adjusted to an intensity that, when given alone, would evoke an EMG response of approximately 1 mV peak to peak (about 115–125% RMT). Stimulus intensities were kept constant across the blocks of measurements.

Fifteen trials were recorded for each ISI and randomly intermingled with fifteen trials in which MEPs were elicited by the TS alone. The peak-to-peak amplitude of the unconditioned MEP was taken as a measure of corticospinal excitability. Mean amplitude of the conditioned MEP was expressed as percentage of the amplitude of the unconditioned MEP. The relative change in MEP amplitude induced by the CS characterized the strength of SICI and ICF. Trials in which the FDI muscle was not completely relaxed were discarded from analysis.

The transcranially evoked CSP was recorded during tonic voluntary contraction of the left FDI muscle at approximately 30% of maximum force. The duration of CSP reflects the excitability of intracortical circuits mediating long-lasting inhibition (Siebner et al. 1998; Werhahn et al. 1999). The intensity of stimulation was identical to the intensity used for the TS during paired-pulse TMS and corresponded to 115–125% of resting MT. The onset and duration of CSP were determined in each individual rectified trial. The duration of CSP was measured from the onset of the MEP to full recovery of continuous EMG activity.

The conditioning-test protocol as described by Ferbert et al. (1992) was used to evaluate left-to-right IHI of the right M1HAND. Two high power Magstim 200 stimulators were connected to specially designed figure-of-8 coils with a small outer diameter of each half wing (7 cm). We used the same coil orientation and motor hot spot as for cc-PAS conditioning. The CS was applied to the left M1HAND, and the TS was applied to the homologous right M1HAND. The TS was set at an intensity that, when given alone, would evoke an EMG response of ∼1 mV peak-to-peak amplitude. The intensity of the CS was adjusted to induce an inhibition of the test MEP of approximately 40–50% at an ISI of 8 ms. Left-to-right IHI was tested at 3 ISIs (8, 9, and 10 ms) to study the strength of short-latency IHI. IHI measurements were performed in blocks of 50 trials with an intertrial interval of 4 s. In each block, 20 MEPs evoked by the TS alone and 10 conditioned MEPs at each ISI were recorded from the left FDI muscle in a pseudorandom order. The amplitudes of the conditioned MEPs were measured as peak to peak (mV) in each single trial and averaged for each block of measurement. Peak-to-peak amplitudes of the conditioned responses were expressed as a percentage of the unconditioned response evoked by the TS alone.

Statistical Analysis

The conditioning effects of cc-PAS on motor thresholds (resting and active MT), peak-to-peak MEP amplitude of responses to single-pulse TMS, duration of CSP, paired-pulse intracortical excitability (SICI and ICF), and IHI (short ISIs of 8, 9, and 10 ms and long ISIs of 35, 40, and 45 ms, see below control experiment I) were evaluated in separate repeated-measures analyses of variance (ANOVAs). For each dependent variable, we computed a one-way repeated-measures ANOVA with the within-subject factor TIME (4 levels; baseline, T0, T30, and T60). For the evaluation of motor thresholds, the state of the muscle (relaxation vs. contraction) was included as additional factor in the ANOVA. ISI was considered as additional factors in the ANOVAs testing for changes in paired-pulse measurements (i.e., SICI, ICF, and IHI).

The Greenhouse–Geisser method was used if necessary to correct for nonsphericity. Conditional on a significant F-value, post hoc paired-samples t-tests were performed to explore the strength of main effects and the patterns of interaction between experimental factors. A P-value of < 0.05 was considered significant. All data are given as mean ± SEM.

Additional Experiments

A set of additional experiments complemented the main experiment. Experiments were performed on a subgroup of individuals who had participated in the main experiment.

  • 1) In 5 subjects (3 women; mean age: 30 years; age range: 25–39 years), we evaluated the conditioning effects of left-to-right cc-PAS on left-to-right IHI at long ISI of 35, 40, and 45 ms which test a different interneuronal population with respect to short ISI (Daskalakis et al. 2002). Long-latency IHI was measured before (baseline) and 30 min after (T30) the end of left-to-right cc-PAS.

  • 2) In a control experiment on 8 subjects (4 women; mean age: 29 years; age range: 24–39 years), we adjusted the stimulus intensity of the TS after cc-PAS to elicit a test response of same amplitude compared with baseline. Left-to-right IHI was measured before (baseline) and 30 min after (T30) left-to-right cc-PAS.

  • 3) We had the opportunity to study a right-handed healthy woman with congenital agenesis of the corpus callosum. The woman was 43 years old and had never experienced any neuropsychiatric problems. We measured the mean MEP amplitude elicited with single-pulse TMS over the right M1HAND and left-to-right short-latency IHI before (baseline) as well as immediately after (T0) and 30 (T30) min after left-to-right cc-PAS. RMT was 50% of maximal stimulator output in the right M1HAND and 48% in the left M1HAND. Stimulus intensity was set at 62% of maximal stimulator output for TMS of the right M1HAND and 60% for TMS of the left M1HAND.

  • 4) In 5 participants (3 women; mean age: 30 years; age range: 25–39 years), we examined whether left-to-right cc-PAS also modified the excitability of corticospinal output neurons in the left M1HAND. Before (baseline) and 30 min after left-to-right cc-PAS (T30), we first recorded 15 MEPs from the right FDI muscle evoked by single-pulse TMS to the left M1HAND. We then recorded 15 MEPs from the left FDI muscle elicited by single-pulse TMS to the right M1HAND.

  • 5) In 5 subjects (4 women; mean age: 29 years; range: age 24–39 years), we investigated whether the after effects of cc-PAS were specific for an ISI of 8 ms. Subjects participated in 2 experimental sessions. In the first experiment, we applied left-to-right cc-PAS using a constant ISI of 1 ms. Assuming a transcallosal conduction time of approximately 8 ms, we reasoned that the transcallosal volley would arrive in the contralateral M1 too late to coincide with the direct neuronal stimulation induced by the TMS pulse given directly to the contralateral M1. The relative difference between the ISI used in this control experiment (cc-PAS at 1 ms) and the ISI that had been used in the main experiment (cc-PAS at 8 ms) was 7 ms. Such a difference in the ISI produced a reversal of the after effects on corticospinal excitability in the context of pc-PAS (Wolters et al. 2003). Based on these considerations, we expected cc-PAS at 1 ms to elicit no plastic changes or even a reversal of the after effects that were induced with cc-PAS at 8 ms. In the second experiment, left-to-right cc-PAS used multiple ISIs (i.e., ISIs of 8, 18, 68, 78, 88, 98, 108, 118, and 128 ms) which were delivered in random order (10 paired stimuli per ISI). Left-to-right IHI was tested at an ISI of 8 and 35 ms before (baseline) and 30 min (T30) after cc-PAS.

  • 6) In 8 subjects (3 women; mean age: 30 years; age range: 25–39 years), we tested whether right-to-left cc-PAS would produce similar changes in the excitability of left M1HAND as found after left-to-right cc-PAS in the right M1HAND. We measured the mean MEP amplitude elicited with single-pulse TMS over the left M1HAND and right-to-left short-latency IHI before (baseline) and 30 min after (T30) right-to-left PAS. During right-to-left PAS, the first stimulus was always applied to right M1HAND and the second stimulus was given to the homologous left M1HAND. In 4 of 8 participants, this experiment was performed before the main experiment to exclude order effects.

  • 7) In 8 subjects (3 women; mean age: 28 years; range: 25–39 years) we investigated whether left-to-right cc-PAS alters the RT of the right or left FDI muscle during a simple RT task. Participants had to perform as quickly as possible a brisk abduction movement with the right or left index finger in response to a visual go signal. The go signal was a red light which was presented on a PC screen every 5 s. The intertrial interval varied between 3 and 7 s to avoid response anticipation.

RTs of the right and left index finger were assessed in 2 sessions on separate days. The order of sessions was counterbalanced across participants. RTs were measured in blocks (20 trials per block) before (baseline) and 30 min (T30) after left-to-right cc-PAS. Surface EMG was recorded from the FDI muscle of both hands. In a given trial, RT was defined as the time between the appearance of the go signal and the onset of the EMG response in the FDI muscle. Mean RT was calculated for each block of measurement. In each participant, we determined the right-to-left ratio of mean RT before and after cc-PAS. The Wilcoxon test was used to test whether cc-PAS produced a consistent change in the right-to-left ratio of mean RT.

Results

Effects of Left-to-Right cc-PAS on Left-to-Right IHI

Using the conditioning-test paradigm introduced by Ferbert et al. (1992), we found that left-to-right cc-PAS produced a marked attenuation of left-to-right IHI (main effect of TIME: F3,33 = 6.5, P = 0.001). The strength of IHI was attenuated immediately after left-to-right cc-PAS, and was still reduced 30 and 60 min after the end of cc-PAS (Fig. 2b). The long-lasting decrease in IHI was consistently observed at early ISIs of 8, 9, and 10 ms with no interaction between ISI and TIME (P > 0.4).

Figure 2.

Changes in cortical excitability in the conditioned right M1HAND after left-to-right cc-PAS. (a) The upper panel illustrates the mean MEP amplitudes recorded from the left FDI muscle before (white columns) and after cc-PAS (black columns). Each error bar shows the SEM. MEPs were evoked in the left FDI muscle with unconditioned test stimuli over the right M1HAND using a small figure-8-shaped coil. (b) Effect of left-to-right cc-PAS on left-to-right IHI at short ISIs. Mean MEP amplitudes are expressed as percentage of the unconditioned MEP amplitude (elicited by the test pulse alone). Error bars equal the SEM. A single asterisk (*) indicates a significant TIME effect in the corresponding ANOVA. Two asterisks (**) mark a significant change in mean amplitude relative to preintervention baseline as revealed by post hoc t-tests.

Figure 2.

Changes in cortical excitability in the conditioned right M1HAND after left-to-right cc-PAS. (a) The upper panel illustrates the mean MEP amplitudes recorded from the left FDI muscle before (white columns) and after cc-PAS (black columns). Each error bar shows the SEM. MEPs were evoked in the left FDI muscle with unconditioned test stimuli over the right M1HAND using a small figure-8-shaped coil. (b) Effect of left-to-right cc-PAS on left-to-right IHI at short ISIs. Mean MEP amplitudes are expressed as percentage of the unconditioned MEP amplitude (elicited by the test pulse alone). Error bars equal the SEM. A single asterisk (*) indicates a significant TIME effect in the corresponding ANOVA. Two asterisks (**) mark a significant change in mean amplitude relative to preintervention baseline as revealed by post hoc t-tests.

In 5 subjects, an additional experiment showed that left-to-right cc-PAS also attenuated IHI at longer ISIs of 35, 40, and 45 ms (Supplementary Fig. 1; main effect of TIME: F1,4 = 12.8, P = 0.02). The effect size was comparable among late ISIs with no interaction between the factors ISI and TIME (P > 0.9).

Because left-to-right cc-PAS also led to a lasting facilitation of the MEPs evoked by single-pulse TMS over the right M1HAND (see below), 8 subjects participated in a control experiment in which we adjusted the intensity of the test pulse after left-to-right cc-PAS to account for the PAS induced increase in cortical excitability in the conditioned right M1HAND (Supplementary Fig. 2). Left-to-right cc-PAS reduced left-to-right IHI when the intensity of the TS was adjusted after cc-PAS to elicit a motor response that had the same amplitude compared with baseline (main effect of TIME: F1,7 = 9.7, P = 0.01) on the relative strength of IHI. Left-to-right cc-PAS evenly suppressed IHI at all early ISIs with no interaction between ISI and TIME (P > 0.5). Post hoc paired-samples t-tests confirmed a consistent decrease in left-to-right IHI at all ISIs after left-to-right cc-PAS.

Effects of Left-to-Right cc-PAS on Motor Cortical Excitability

Single-pulse TMS with a standard figure-of-8 coil over the right M1HAND revealed a lasting facilitation of mean MEP amplitudes after left-to-right cc-PAS (Table 1). This shows that in addition to the attenuation in left-to-right IHI, left-to-right cc-PAS increased corticospinal excitability in the conditioned right M1HAND (main effect of TIME: F3,21 = 5.9, P = 0.03). Compared with baseline, post hoc t-tests revealed a relative increase in mean MEP amplitude 30 and 60 min after the end of left-to-right cc-PAS (T30: t(1,7) = 2.5, P = 0.04; T60: t(1,7) = 2.4, P = 0.04), but not immediately after cc-PAS (T0: t(1,7) = 1.7, P = 0.1).

Table 1

Parameters of corticospinal excitability before and after left-to-right cc-PAS

Measurement Baseline T 0 T 30 T 60 
RMT (right hemisphere) (% max stimulator output) 52.7 ± 4.7 53.1 ± 5 53.5 ± 4.8 53.3 ± 4.7 
Large 8-shaped coil     
AMT (right hemisphere) (% max stimulator output) 41.5 ± 3.9 41.1 ± 3.6 41.1 ± 4 41.3 ± 3.8 
Large 8-shaped coil     
RMT (right hemisphere) (% max stimulator output) 43 ± 7 42.7 ± 6.9 43.1 ± 6.9 43.1 ± 7 
Small 8-shaped coil     
RMT (left hemisphere) (% max stimulator output) 44.8 ± 8.2 44.7 ± 7.5 44.5 ± 7.8 44 ± 7 
Small 8-shaped coil     
MEP amplitude (mV) 0.75 ± 0.3 0.9 ± 0.3 1.1 ± 0.7 1.1 ± 0.6 
Large 8-shaped coil (n = 8)     
SICI (% of test response) 46 ± 17 51 ± 17 48 ± 16 51 ± 29 
Large 8-shaped coil (n = 8)     
ICF (% of test response) 112 ± 14 109 ± 17 115 ± 27 117 ± 30 
Large 8-shaped coil (n = 8)     
CSP (ms)Large 8-shaped coil (n = 8) 151 ± 20 150 ± 20 153 ± 25 159 ± 28 
Measurement Baseline T 0 T 30 T 60 
RMT (right hemisphere) (% max stimulator output) 52.7 ± 4.7 53.1 ± 5 53.5 ± 4.8 53.3 ± 4.7 
Large 8-shaped coil     
AMT (right hemisphere) (% max stimulator output) 41.5 ± 3.9 41.1 ± 3.6 41.1 ± 4 41.3 ± 3.8 
Large 8-shaped coil     
RMT (right hemisphere) (% max stimulator output) 43 ± 7 42.7 ± 6.9 43.1 ± 6.9 43.1 ± 7 
Small 8-shaped coil     
RMT (left hemisphere) (% max stimulator output) 44.8 ± 8.2 44.7 ± 7.5 44.5 ± 7.8 44 ± 7 
Small 8-shaped coil     
MEP amplitude (mV) 0.75 ± 0.3 0.9 ± 0.3 1.1 ± 0.7 1.1 ± 0.6 
Large 8-shaped coil (n = 8)     
SICI (% of test response) 46 ± 17 51 ± 17 48 ± 16 51 ± 29 
Large 8-shaped coil (n = 8)     
ICF (% of test response) 112 ± 14 109 ± 17 115 ± 27 117 ± 30 
Large 8-shaped coil (n = 8)     
CSP (ms)Large 8-shaped coil (n = 8) 151 ± 20 150 ± 20 153 ± 25 159 ± 28 

Note: Each value corresponds to the mean (±SD).

An increase in MEP amplitude was also found for the unconditioned MEPs that were elicited with the small figure-of-8 coil over the right M1HAND during measurements of IHI (F3,33 = 6.2, P = 0.001). Left-to-right cc-PAS increased mean peak-to-peak amplitudes of the unconditioned MEPs 30 and 60 min after cc-PAS (Fig. 2a). Post hoc t-tests revealed that the TIME effect was caused by a relative increase in MEP amplitude at T30 (t(1,11) = 2.8, P = 0.01) and T60 (t(1,11) = 2.8, P = 0.01) relative to baseline, whereas MEP facilitation at T0 did not reach significance (t(1,11) = 1.8, P = 0.09).

In addition to single-pulse TMS, we applied paired stimuli through the standard figure-of-8 coil to quantify SICI at ISI of 2 ms and ICF at ISI of 12 ms (Kujirai et al. 1993). There were no change in the ratio between unconditioned and conditioned MEP amplitudes during the 4 blocks of measurements, indicating that the relative strength of SICI and ICF was not altered by left-to-right cc-PAS (Table 1, P > 0.8). Left-to-right cc-PAS also had no effect on the duration of the CSP (Table 1).

In an asymptomatic woman with callosal agenesis, we had the opportunity to study the conditioning effects of left-to-right cc-PAS in the absence of callosal connections between both M1HAND. In accordance with a previous study which used the ipsilateral silent period to measure IHI in patients with callosal agenesis (Meyer et al. 1995), paired-pulse TMS showed an absent IHI. In this individual, left-to-right cc-PAS at a constant ISI of 8 ms had no lasting effect on left-to-right IHI and corticospinal excitability in the right contralateral M1HAND. Mean MEP amplitudes of the left FDI muscle were 0.75 ± 0.1 mV before left-to-right cc-PAS, 0.74 ± 0.1 mV immediately after cc-PAS, and 0.76 ± 0.1 mV 30 min after cc-PAS.

In 5 subjects, we examined whether left-to-right cc-PAS at a constant ISI of 8 ms increased corticospinal excitability in left ipsilateral M1HAND (Supplementary Fig. 3). Single-pulse TMS of left M1HAND revealed no changes in MEP amplitude (right FDI muscle: 0.73 ± 0.1 mV at baseline vs. 0.72 ± 0.1 mV at T30). In contrast, single-pulse TMS of the right M1HAND showed a facilitation of mean MEP amplitude in the left FDI muscle 30 min after left-to-right cc-PAS (0.75 ± 0.2 mV at baseline vs. 0.92 ± 0.1 mV at T30, t(1,4) = 5.4, P = 0.005). Two-factorial repeated-measures ANOVA confirmed a differential effect of cc-PAS on mean MEP amplitudes for TMS of left and right M1HAND, showing an interaction between SIDE of TMS and TIME of measurement (F1,4 = 48.3, P = 0.002).

Impact of the Interval between Stimulus Pairs

In 2 additional experiments, we tested whether the conditioning effects of left-to-right cc-PAS depended on the interval between the 2 transcranial stimuli. In one experiment, the ISI between the left and right transcranial stimulus was kept constant during cc-PAS but the ISI was set at 1 ms instead of 8 ms. In another experiment, multiple ISIs were used and pseudorandomly varied during cc-PAS. Both protocols failed to induce any change in MEP amplitude in the conditioned right M1HAND. In contrast to the main experiment, neither the amplitude of the unconditioned MEP nor the strength of short and long IHI showed any changes when measured 30 min after the modified cc-PAS protocol in both experimental sessions (Fig. 3). Accordingly, 2-way repeated-measures ANOVA revealed no effect of ISI, no effect of TIME and no interaction between ISI and TIME.

Figure 3.

No consistent changes of cortical excitability in right M1HAND after left-to-right cc-PAS at irregular ISIs and at constant ISI of 1 ms, in the 5 individuals who underwent both procedures. (a, b) The bar chart illustrates the mean MEP amplitudes recorded from the left FDI muscle before (white column) and 30 min (black column) after cc-PAS. Error bars equal SEM. MEPs were evoked in the left FDI muscle with unconditioned test stimuli over the right M1HAND using a small figure-8-shaped coil. (c, d) Effect of left-to-right cc-PAS on left-to-right IHI at short (8 ms) and long (35 ms) ISI before (diamonds) and 30 min after cc-PAS (squares). Mean MEP amplitudes are expressed as percentage of the unconditioned MEP amplitude elicited by the TS alone. Error bars equal SEM.

Figure 3.

No consistent changes of cortical excitability in right M1HAND after left-to-right cc-PAS at irregular ISIs and at constant ISI of 1 ms, in the 5 individuals who underwent both procedures. (a, b) The bar chart illustrates the mean MEP amplitudes recorded from the left FDI muscle before (white column) and 30 min (black column) after cc-PAS. Error bars equal SEM. MEPs were evoked in the left FDI muscle with unconditioned test stimuli over the right M1HAND using a small figure-8-shaped coil. (c, d) Effect of left-to-right cc-PAS on left-to-right IHI at short (8 ms) and long (35 ms) ISI before (diamonds) and 30 min after cc-PAS (squares). Mean MEP amplitudes are expressed as percentage of the unconditioned MEP amplitude elicited by the TS alone. Error bars equal SEM.

Effects of Right-to-Left cc-PAS on Excitability in the Conditioned Left M1HAND

In 8 participants, the temporal order of paired stimulation of the left and right M1HAND was reversed during cc-PAS (Fig. 4b). The stimulus given to right M1HAND preceded the stimulation of left M1HAND in order to flip the direction of PAS conditioning from left-to-right to right-to-left. Paralleling the attenuation of left-to-right IHI after left-to-right cc-PAS, right-to-left cc-PAS reduced early right-to-left IHI (main effect of TIME: F1,7 = 34.4, P = 0.0006). Post hoc analysis showed that right-to-left cc-PAS attenuated early right-to-left IHI at all ISIs (ISI of 8, 9, and 10 ms). Accordingly, the ANOVA showed no interaction between ISI and TIME (F2,14 = 0.8, P = 0.4).

Figure 4.

Changes in cortical excitability in the conditioned left M1HAND after right-to-left cc-PAS in 8 individuals. (a) The upper panel illustrates the mean MEP amplitudes recorded from the right FDI muscle before (white columns) and after cc-PAS (black columns). Each error bar shows the SEM. Unconditioned MEP amplitudes were unchanged after right-to-left cc-PAS. (b) Decrease in right-to-left IHI at short ISIs 30 min after cc-PAS (T30) compared with baseline. The MEP amplitudes are expressed as percentage of the unconditioned MEP evoked by the test pulse alone. Error bars equal the SEM. The asterisk (*) indicates a significant TIME effect in the corresponding ANOVA.

Figure 4.

Changes in cortical excitability in the conditioned left M1HAND after right-to-left cc-PAS in 8 individuals. (a) The upper panel illustrates the mean MEP amplitudes recorded from the right FDI muscle before (white columns) and after cc-PAS (black columns). Each error bar shows the SEM. Unconditioned MEP amplitudes were unchanged after right-to-left cc-PAS. (b) Decrease in right-to-left IHI at short ISIs 30 min after cc-PAS (T30) compared with baseline. The MEP amplitudes are expressed as percentage of the unconditioned MEP evoked by the test pulse alone. Error bars equal the SEM. The asterisk (*) indicates a significant TIME effect in the corresponding ANOVA.

Although left-to-right cc-PAS enhanced corticospinal excitability in the right M1HAND, the mean amplitude of the unconditioned MEPs in the right FDI muscle was not altered after right-to-left cc-PAS (Fig. 4a). Because all 8 subjects received left-to-right and right-to-left cc-PAS, it was possible to test whether both interventions produced different after effects in the conditioned contralateral hemisphere (conditioning effects on right M1HAND with left-to-right cc-PAS vs. conditioning effects on left M1HAND with right-to-left cc-PAS). Using the unconditioned MEP amplitude as dependent variable, 2-way repeated-measures ANOVA showed an interaction between INTERVENTION and TIME (F1,7 = 9.5, P = 0.01). This interaction was caused by a lack of a change in MEP amplitude in the right FDI muscle after conditioning the left M1HAND with right-to-left cc-PAS, but a consistent MEP facilitation of the MEPs in left FDI muscle after conditioning the right M1HAND with left-to-right cc-PAS.

Behavioral Effect of Left-to-Right cc-PAS

No participants reported any adverse side effect during the experiments. In 8 participants, we measured simple RTs before and after left-to-right cc-PAS. At baseline, responses with the right and left index finger showed similar RTs (RT with right index finger: 192 ± 24 ms vs. RTs with left index finger: 194 ± 18 ms). Left-to-right cc-PAS had an effector specific effect on mean RTs (Fig. 5). Responses with the left index finger were faster 30 min after the end of left-to-right cc-PAS relative to baseline (RTs with left index finger: 182 ± 20 ms), whereas responses with the right index finger remained unchanged (RTs with right index finger: 193 ± 24 ms). The selective decrease in RT with left hand responses was reflected in a consistent decrease in the left-to-right ratio of mean RTs after cc-PAS (Wilcoxon test, P = 0.01).

Figure 5.

Effect of left-to-right cc-PAS on simple RT. The columns illustrate the relative change in RT with the left (black column) and right (gray column) index finger of 8 subjects. Error bars equal SEM. The asterisk (*) marks a significant change in RT (Wilcoxon test).

Figure 5.

Effect of left-to-right cc-PAS on simple RT. The columns illustrate the relative change in RT with the left (black column) and right (gray column) index finger of 8 subjects. Error bars equal SEM. The asterisk (*) marks a significant change in RT (Wilcoxon test).

Discussion

This is the first study that used associative transcranial stimulation of 2 homologous cortical areas to induce lasting changes in interhemispheric connectivity between the stimulated cortices. Ninety stimuli of cc-PAS were sufficient to attenuate the inhibitory influence of the M1HAND on the homologous contralateral M1HAND. The cc-PAS protocol was only effective when stimulation of both M1HAND was consistently paired at an ISI of 8 ms. In addition to its suppressive effects on IHI, left-to-right cc-PAS increased corticospinal excitability in the conditioned right M1HAND and speeded responses with the left index finger in a simple RT task.

The after effects induced by cc-PAS of both M1HAND closely resemble the functional changes that have been previously induced with suprathreshold focal 1-Hz rTMS (Gilio et al. 2003; Plewnia et al. 2003; Schambra et al. 2003; Pal et al. 2005) or subthreshold continuous theta-burst stimulation (Stefan et al. 2008) of one M1HAND. Focal rTMS of a single cortical area is thought to induce plastic changes in the motor system through cooperative excitation of a distinct set of cortical axons in the stimulated M1HAND. In contrast, our cc-PAS protocol was based on “associative” rather than “cooperate” stimulation because its effectivity was determined by paired stimulation of 2 connected cortices at an appropriately timed interval. This principle has already been successfully applied to induce plasticity in the M1HAND by pairing stimulation of a peripheral nerve with transcranial stimulation of contralateral sensorimotor cortex (Stefan et al. 2000; Wolters et al. 2003). Our results show that the principle of “associative stimulation” as a means of inducing cortical plasticity can be extended to transcranial stimulation of 2 connected cortical areas. As such, we provide a proof of principle that bifocal rTMS of 2 connected cortical areas (cc-PAS) can effectively shape the function of distinct corticocortical pathways, opening up new possibilities for the noninvasive neuromodulation of corticocortical connectivity in the intact human brain.

Attenuation of IHI between Left and Right M1HAND

Left-to-right cc-PAS at an ISI of 8 ms reduced left-to-right IHI at short ISIs between 8 and 10 ms. The reduction in IHI was immediately present after cc-PAS and was stable for at least one hour after the end of cc-PAS. Right-to-left cc-PAS at an ISI of 8 ms also consistently attenuated right-to-left IHI. Together, these findings show that cc-PAS at an ISI of 8 ms can influence the strength of interhemispheric interactions between the right and left M1HAND. In this study, we used a well-established conditioning-test paradigm to probe IHI (Ferbert et al. 1992). Because this form of IHI is mediated via transcallosal corticocortical connections (Meyer et al. 1995, 1998; Di Lazzaro et al. 1999; Wahl et al. 2007), we infer that cc-PAS exerts its after effects at a cortical level by modifying transcallosal interhemispheric interactions between both motor cortices. Accordingly, the after effects of cc-PAS on IHI were abolished in a patient with callosal agenesis.

Our findings confirm and extend previous studies which reported a reduction in left-to-right IHI at short ISIs (Gilio et al. 2003; Pal et al. 2005) and long ISIs (Pal et al. 2005) after a suprathreshold 1-Hz rTMS to left M1HAND. Together, these studies show that TMS provides an effective means of manipulating the strength of interhemispheric interactions. An important difference between these previous and the present study is that a prolonged period of stimulation (900 pulses) were given to reduce the strength of IHI with unilateral 1-Hz rTMS. In contrast, the cc-PAS protocol used in the present study only consisted of 90 stimuli pairs given at a very low repetition rate. In analogy to pc-PAS, we hypothesize that an appropriately timed associative mode of bilateral transcranial stimulation might be more efficient in producing after effects on IHI as rTMS, but this needs to be formally tested in future studies. When interpreting the present results, it is important to bear in mind that the interhemispheric interactions between both M1HAND are not exclusively inhibitory in nature. The existence of transcallosal facilitatory interactions between the motor cortices has been demonstrated with direct cortex stimulation in animals models (Chang 1953; Asanuma and Okamoto 1959). Several TMS studies demonstrated that a facilitatory pathway between the right and left M1HAND also exists in humans (Ferbert et al. 1992; Hanajima et al. 2001; Baumer et al. 2006). This implies that the interhemispheric interactions, as probed with bifocal TMS of the right and left M1HAND, reflect the balance between IHI and facilitation. Therefore, the relative decrease in IHI after cc-PAS may be caused by a decrease in the inhibitory influence of the contralateral M1HAND, an increase in the facilitatory influence of the contralateral M1HAND, or both.

Which set of interneurons was potentiated by cc-PAS? The after effects on IHI were not specific for IHI at short ISIs because left-to-right cc-PAS also attenuated IHI at long ISIs. Short-interval and long-interval IHI are mediated by separated populations of cortical neurons (Ferbert et al. 1992; Gilio et al. 2003). This implies that cc-PAS at an ISI of 8 ms modified 2 different sets of cortical neurons mediating IHI.

Left-to-right cc-PAS led to a lasting facilitation of the MEPs evoked by single-pulse TMS over the left M1HAND. We were concerned that this increase in corticospinal excitability in the conditioned right M1HAND might have contributed to the reduction in left-to-right IHI after left-to-right cc-PAS (Ferbert et al. 1992; Daskalakis et al. 2002). However, left-to-right cc-PAS still produced a reduction of left-to-right IHI when stimulus intensity was adjusted over the conditioned left M1HAND to match the MEP amplitudes after cc-PAS to those obtained at baseline. Moreover, the attenuation in left-to-right IHI was already present at the end of left-to-right cc-PAS, whereas the increase in the unconditioned MEP amplitude was only found 30 min after the end of cc-PAS. Finally the strength of right-to-left IHI was effectively suppressed with right-to-left cc-PAS without any change in corticospinal excitability in the left M1HAND. These results provide converging evidence that cc-PAS primarily modified the strength of IHI. Because direct corticocortical interhemispheric projections to large pyramidal cells in layer V have never been demonstrated in animal studies (Chang 1953; Jacobson and Marcus 1970), we hypothesize that cc-PAS changed the strength of IHI by modulating the excitability of a specific subset of intracortical interneurons in the conditioned M1HAND.

Associative Corticocortical Plasticity

By using an ISI of 8 ms, we made sure that the transcallosal volley elicited by the first TMS pulse over the contralateral M1HAND arrived in the conditioned M1HAND approximately at the same time when the second TMS pulse was applied. Therefore, each stimulus pair led to a coincident stimulation of a distinct subset of interneurons in the conditioned M1HAND via a transcallosal and intracortical route.

Associative stimulation of these interneurons produced a long-lasting change in the processing of the transcallosal input, attenuating the inhibitory influence from the contralateral M1HAND on the conditioned M1HAND. Additional measurements of intracortical excitability revealed no consistent effects of left-to-right cc-PAS on distinct intracortical circuits that subserve intracortical paired-pulse inhibition or facilitation (i.e., SICI and ICF) or generate the contralateral CSP, suggesting that the conditioning effects of cc-PAS were specific for transcallosal circuits. Paired-pulse measurements of intracortical excitability were only assessed at a single ISI, therefore, we cannot exclude minor changes in SICI and ICF following cc-PAS at an ISI of 8 ms. However, any effect on SICI or ICF should be relatively subtle compared with the marked attenuation of IHI.

The temporal relationship between TMS to the left and right M1HAND was crucial as the cc-PAS protocol was only effective if the stimuli given to the left and right M1HAND were consistently paired at an ISI of 8 ms. When we gave cc-PAS at multiple ISI in random order, cc-PAS failed to induce any change in IHI. This finding indicates that cc-PAS needs to be given at a constant ISI and suggests that the induction of plasticity critically depended on a constant temporal relationship of the stimulus pairs during cc-PAS.

A constant temporal pairing at a fixed ISI was not sufficient to render cc-PAS an effective protocol. When left-to-right cc-PAS was given at a constant ISI of 1 ms, no change in left-to-right IHI or left hemispheric corticospinal excitability occurred. Because the only difference between the 2 cc-PAS protocols was the interval between stimulus pairs, the discrepancy in the after effects was caused by the difference in ISI. This strongly suggests that the after effects evoked by cc-PAS at an ISI of 8 ms depended on a temporal Hebbian learning rule. The associative nature of the intervention and the long duration of the after effects, as well as the dependence on a temporal Hebbian rule are readily compatible with the hypothesis that cc-PAS at 8 ms induced STPD-like in the conditioned M1HAND.

With cc-PAS at an ISI of 1 ms, the transcallosal inputs arrived in the conditioned M1HAND after the second TMS pulse had elicited action potentials. In the framework of STDP-like plasticity, one might have expected that cc-PAS at an ISI of 1 ms would produce opposite effects as cc-PAS at 8 ms, and thus strengthen IHI. However, cc-PAS at an ISI of 1 ms was just as ineffective in changing IHI as random cc-PAS at multiple ISIs. The failure to produce LTD-like after effects with cc-PAS at 1 ms may be due to a cancellation of corticocortical volleys in the transcallosal pathway. Given the relatively high intensity of stimulation, it is possible that each TMS pulse elicited ortho- and antidromic action potentials in transcallosal fibers. If this were the case, antidromic and orthodromic volleys would collide and cancel each other at ISIs of ∼1 ms, preventing associative plasticity in the M1HAND. Future studies need to assess the after effects of cc-PAS at a range of ISIs to characterize the temporal profile of the Hebbian learning rule in more detail. These studies should include intervals longer than 8 ms to avoid possible collision effects.

Corticospinal Excitability in the Conditioned M1HAND

After left-to-right cc-PAS, motor responses to single-pulse TMS were facilitated in the left FDI muscle 30 and 60 min after the end of cc-PAS, indicating an increase in corticospinal excitability in the right conditioned M1HAND. Although left-to-right and right-to-left cc-PAS attenuated the strength of IHI in the conditioned M1HAND, only left-to-right cc-PAS increased corticospinal excitability in the conditioned (right) M1HAND. This finding indicates an asymmetry of functional interactions between the right and left M1HAND. This asymmetric changeability of corticospinal excitability may be related to manual dexterity because previous studies demonstrated an hemispheric asymmetry in the strength of IHI depending on handedness (Netz et al. 1995; Baumer et al. 2007). In right handers, the magnitude of IHI from the left (dominant) M1HAND to the right (nondominant) M1HAND is stronger that right-to-left IHI. Hence, an attenuation of IHI may be functionally more relevant for left-to-right IHI than for right-to-left IHI. In consequence, only a removal of left-to-right IHI will trigger an increase in corticospinal excitability in right handers. A logical extension of this hypothesis is that removal of right-to-left IHI will only boost corticospinal excitability of the left M1HAND in left handers with a prevalent left-to-right IHI.

Functional Significance of cc-PAS–Induced Plasticity

Left-to-right cc-PAS did not only change the excitability of corticospinal output neurons but also fastened the initiation of a simple movement in the conditioned right M1HAND. RTs with the left index finger were shortened after cc-PAS, whereas responses with the right index finger remained unchanged. Because our subjects were blinded to the direction of cc-PAS a placebo-like effect seems unlikely. A possible interpretation of these behavioral changes is that the attenuation of left-to-right IHI, along with the increase in corticospinal excitability at rest, facilitated the premovement increase in corticospinal excitability (Chen et al. 2001), thereby speeding up responses made with the left nondominant index finger.

Although the RT changes show that the corticospinal output was recruited faster after cc-PAS, this simple motor task did not specifically probe the behavioral consequences of reduced IHI. As cc-PAS enhanced M1HAND excitability, it is likely that the shorter RT with the left index finger represents a rather unspecific effect that might occur with any facilitating intervention to the respective M1HAND. To show a behavioral relevant effect of cc-PAS on interhemispheric motor interactions, more complex motor tasks need to be used which require transcallosal information transfer.

The physiological and behavioral effects of cc-PAS are of interest in the context of an interhemispheric imbalance between homologous cortical areas following stroke (Hummel and Cohen 2006). Accordingly, Mansur et al. (2005) have demonstrated that near-threshold 1-Hz rTMS of the contralesional M1HAND improved simple RT with the contralateral hand in patients with stroke. In addition some patients with chronic stroke show abnormally increased IHI from the M1HAND of the intact hemisphere to the M1HAND of the affected hemisphere that correlates with motor impairment (Murase et al. 2004). Hence, cc-PAS at an ISI of 8 ms may be used to reduce the abnormal interhemispheric inhibitory drive from the healthy to the lesioned M1HAND in patients with chronic stroke.

Funding

Volkswagenstiftung (grant I/79-932) to H.S.

Conflict of Interest: None declared.

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