Monitoring cortical excitability during repetitive transcranial magnetic stimulation in children with ADHD: a single-blind, sham-controlled TMS-EEG study

Background: Repetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children. Objective: TMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available. Methods: In a single-blind sham-controlled study, twenty-five school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition. Results: TMS-evoked N100 amplitude decreased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation. Conclusion: The TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition

Dipole moment of N100 during, pre and post rTMS.

<p>(<b>A</b>) The momentum of the dipole component shown in the dipole model on the right (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050073#pone-0050073-g004" target="_blank">Figure 4C</a>) is presented for the N100 time interval: before rTMS is shown in black, after 1 Hz-rTMS in red and after sham stimulation in blue. The TMS artifact (black box) has been cut out. (<b>B</b>) Momentum of the dipole component shown in the dipole model on the right (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050073#pone-0050073-g004" target="_blank">Figure 4C</a>) during 1 Hz-rTMS. The TMS artifact (black box) has been cut out. The lines illustrate representative trial blocks at the beginning, in the middle and at the end of 1 Hz-rTMS (trials 1–100, 501–600 and 801–900). (<b>C</b>) Source model (cf. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050073#pone-0050073-g003" target="_blank">Figure 3</a>).</p

TMS-evoked N100 amplitude reduction after 1 Hz-rTMS.

<p>(<b>A</b>) Comparison of N100 before rTMS (black) with after 1 Hz-rTMS (red) and after sham stimulation (blue): N100 amplitude was only reduced after 1 Hz-rTMS. TMS artifact (black box) has been cut out. (<b>B</b>) N100 amplitude was reduced after 1 Hz-rTMS but not after sham stimulation irrespective of ORDER (blue: first 1 Hz-rTMS, second sham stimulation; red: first sham stimulation, second 1 Hz-rTMS; vertical bars show 0.95 confidence intervals). (<b>C</b>) Voltage and current source density (CSD) maps (blue for negativity, red for positivity) show TMS-evoked N100 localization above the stimulated left primary motor cortex and an intensity reduction after 1 Hz-rTMS.</p

N100 amplitude decrease during 1 Hz-rTMS.

<p>(<b>A</b>) N100 amplitude reduction during 1 Hz-rTMS (group mean values). The TMS artifact (black box) has been cut out. Each curve represents an average of 100 trials (1–100, 101–200, …, 801–900). Electrodes C3, CP3’ and CP5’ were pooled. <i>Left</i>: TMS-evoked N100 amplitude continuously decreased during the stimuli 1–500. <i>Right</i>: N100 amplitude reached a plateau and was not further reduced by continued stimulation (pulses 500–900). (<b>B</b>) Single patient example. (<b>C</b>) TMS-evoked N100 amplitude was reduced during 1 Hz-rTMS regardless of the order of 1 Hz-rTMS vs. sham stimulation (blue: first 1 Hz-rTMS, second sham stimulation; red: first sham stimulation, second 1 Hz-rTMS; vertical bars show 0.95 confidence intervals). (<b>D</b>) Voltage and current source density (CSD) maps (blue areas indicate negativity, red areas positivity) show an N100 maximum above the stimulated left left central area and an intensity reduction during 1 Hz-rTMS. <i>Left</i>: N100 during stimuli 1–100. <i>Right</i>: N100 during stimuli 801–900.</p

Sample characteristics.

<p>(RMT = resting motor threshold; rTMS = repetitive transcranial magnetic stimulation).</p

Source model of TMS-evoked N100.

<p>(<b>A</b>) The RAP-MUSIC (recursively applied and projected multiple signal classification) revealed a single source component located near the stimulated hand area of the primary motor cortex with an orientation approximately perpendicular to the precentral gyrus. (<b>B</b>) The first two principal components explained over 99% of the signal during the N100 time interval. The TMS artifact (black box) has been cut out. (<b>C</b>) The dipole moment of the single source component showed a maximum in the N100 interval. The TMS artifact (black box) has been cut out.</p

Comparison of TMS-evoked N100 amplitudes between trial blocks throughout the 1 Hz-rTMS session (Newman Keuls post hoc tests).

<p>Comparison of TMS-evoked N100 amplitudes between trial blocks throughout the 1 Hz-rTMS session (Newman Keuls post hoc tests).</p