Preconditioning Stimulus Intensity Alters Paired-Pulse TMS Evoked Potentials

Abstract

Motor cortex (M1) paired-pulse TMS (ppTMS) probes excitatory and inhibitory intracortical dynamics by measurement of motor-evoked potentials (MEPs). However, MEPs reflect cortical and spinal excitabilities and therefore cannot isolate cortical function. Concurrent TMS-EEG has the ability to measure cortical function, while limiting peripheral confounds; TMS stimulates M1, whilst EEG acts as the readout: the TMS-evoked potential (TEP). Whilst varying preconditioning stimulus intensity influences intracortical inhibition measured by MEPs, the effects on TEPs is undefined. TMS was delivered to the left M1 using single-pulse and three, ppTMS paradigms, each using a different preconditioning stimulus: 70%, 80% or 90% of resting motor threshold. Corticospinal inhibition was present in all three ppTMS conditions. ppTMS TEP peaks were reduced predominantly under the ppTMS 70 protocol but less so for ppTMS 80 and not at all for ppTMS 90. There was a significant negative correlation between MEPs and N45 TEP peak for ppTMS 70 reaching statistical trends for ppTMS 80 and 90. Whilst ppTMS MEPs show inhibition across a range of preconditioning stimulus intensities, ppTMS TEPs do not. TEPs after M1 ppTMS vary as a function of preconditioning stimulus intensity: smaller preconditioning stimulus intensities result in better discriminability between conditioned and unconditioned TEPs. We recommend that preconditioning stimulus intensity should be minimized when using ppTMS to probe intracortical inhibition.

Keywords: EEG; TEPs; TMS; TMS-EEG; cortical inhibition; paired-pulse TMS; short-interval intracortical inhibition.

Figure 1

Corticospinal and cortical inhibition measured during ppTMS protocols. (A): Corticospinal excitability measured by MEP amplitudes after spTMS and each of the ppTMS conditions. (B): Average TEP waveform from four electrodes around the site of stimulation (C1, C3, CP1 and CP3). Shaded areas around the TEP waveform represent standard error of the mean. Black bars under each plot represent statistically significant (p < 0.05) time points, calculated from Wilcoxon signed-rank tests, after FDR correction. (C): Scalp plots showing the TEP distribution across our six timepoints of interest, for each condition. (D): TEP peaks at six time-points (15 ms, 30 ms, 45 ms, 60 ms, 100 ms and 180 ms) are extracted for each subject and plotted for each stimulation condition. (E): Percentage change of individual TEP peaks during ppTMS conditions with respect to spTMS TEPs. Due to differences in polarity between conditions, values were squared first and then represented as a fraction of the spTMS TEP peak. Values below the dashed line depict suppression; those above depict facilitation. Asterisks represent statistically significant differences (* = p < 0.05, ** = p < 0.01).

Figure 2

Spearman rank correlations between MEP and TEP peaks for single pulse, ppTMS 70, 80, 90. Each plot (A–F) shows Spearman rank correlations between the MEP amplitude and TEP peak amplitude (N15, P30, N45, P60, N100 and P180), for spTMS and each ppTMS condition. Above each plot is the distribution of each peak per condition. Time-frequency characteristics of ppTMS TEPs. Bold text in the figure represents interactions reaching statistical significance at a level of 0.05.

Figure 3

TEP-related spectral perturbation (TRSP) and intertrial coherence (ITC) of spTMS and ppTMS 70, 80, 90 conditions for the C3 electrode. Top row (A) shows the 5-48 Hz TRSP with warmer colors depicting greater power and cooler colors depicting lower power. Bottom row (B) shows ITC, where values vary from 0 to 1 (1 represents perfect coherence between trials, whereas 0 represented no coherence between trials). Monte Carlo permutation tests with cluster correction are performed and shown adjacent to TRSP/ITC plots. Threshold for statistical significance is set to 0.05. Each ppTMS condition is paired with the spTMS (Left M1 TEP) condition to facilitate visualization.