Cortical Excitability, Synaptic Plasticity, and Cognition in Benign Epilepsy With Centrotemporal Spikes: A Pilot TMS-EMG-EEG Study

Abstract

Purpose: Children with benign epilepsy with centrotemporal spikes have rare seizures emerging from the motor cortex, which they outgrow in adolescence, and additionally may have language deficits of unclear etiology. We piloted the use of transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG, TMS-EEG) to test the hypotheses that net cortical excitability decreases with age and that use-dependent plasticity predicts learning.

Methods: We assessed language and motor learning in 14 right-handed children with benign epilepsy with centrotemporal spikes. We quantified two TMS metrics of left motor cortex excitability: the resting motor threshold (measure of neuronal membrane excitability) and amplitude of the N100-evoked potential (an EEG measure of GABAergic tone). To test plasticity, we applied 1 Hz repetitive TMS to the motor cortex to induce long-term depression-like changes in EMG- and EEG-evoked potentials.

Results: Children with benign epilepsy with centrotemporal spikes tolerate TMS; no seizures were provoked. Resting motor threshold decreases with age but is elevated above maximal stimulator output for half the group. N100 amplitude decreases with age after controlling for resting motor threshold. Motor cortex plasticity correlates significantly with language learning and at a trend level with motor learning.

Conclusions: Transcranial magnetic stimulation is safe and feasible for children with benign epilepsy with centrotemporal spikes, and TMS-EEG provides more reliable outcome measures than TMS-EMG in this group because many children have unmeasurably high resting motor thresholds. Net cortical excitability decreases with age, and motor cortex plasticity predicts not only motor learning but also language learning, suggesting a mechanism by which motor cortex seizures may interact with language development.

Figure 1. Summary of TMS-EMG-EEG Methodology:

EQUIPMENT: (A) Subjects received TMS to the left motor cortex using a 70mm butterfly coil. (B) A 257-lead EGI cap was placed and paste was applied to the 48 electrodes illustrated in gray (standard 10–20 montage plus additional central coverage); the TMS-EEG Evoked Potential (TEP) of interest (the N100 amplitude) was measured at the C3 electrode (black circle). (C) Motor evoked potentials (MEPs) were recorded from the right abductor pollicis brevis. EXPERIMENTAL PROCEDURE: Before repetitive TMS (rTMS), a resting motor threshold (rMT) was established. Subjects then received 70–100 single pulses of TMS to the left motor cortex. Resulting (D) N100 TEPs and (E) MEPs were grand averaged across all trials and the amplitude of this averaged waveform was calculated (baseline-to-peak for TEPs; peak-to-peak for MEPs). Baseline excitability was quantified by the rMT and pre-rTMS N100 TEP amplitude. Next, rTMS was administered to the left motor cortex. After rTMS administration, subjects again received 70–100 single pulses of TMS, and mean (F) N100 TEP and (G) MEP amplitudes were derived. Cortical plasticity was measured by calculating the ratio of post-rTMS to pre-rTMS TEP and MEP amplitudes.

Figure 2. N100 TEP Amplitude Decreases with Age:

N100 amplitude decreases as a function of age after controlling for whether rMT was elicitable (<100% MSO) or supramaximal (>100% MSO). N100 TEP amplitude increases as a function of stimulation intensity within a given individual. rMT is used to normalize stimulation intensity across individuals, but this cannot be done for those with supramaximal rMTs. Consequently, subjects with supramaximal rMTs (triangles) have smaller N100 amplitudes than those with elicitable rMTs (circles). Age becomes a significant predictor of N100 TEP amplitude after stratifying by rMT.

Figure 3. N100 TEP Plasticity Depends on Baseline Excitability:

There is a strong relationship between baseline excitability and TEP plasticity. Children with smaller initial N100 TEP amplitudes experience a decrease in N100 amplitude after 1 Hz rTMS (circles below x-axis) while those with larger initial N100 TEP amplitudes have an increase in N100 amplitude after 1 Hz rTMS (circles above x-axis).

Figure 4. MEP Plasticity Correlates with Motor Learning:

MEP plasticity, a change from baseline amplitude, is represented here as movement away from the x-axis. MEP amplitude increases with rTMS (values above the x-axis) for most children and this change correlates with greater improvements in motor speed.

Figure 5. TEP Plasticity Correlates with Language Learning:

TEP plasticity, a change from baseline amplitude, is represented here as movement away from the x-axis. A decrease in N100 TEP amplitude after rTMS (values below x-axis) correlates with worse language learning scores while an increase in N100 TEP amplitude correlates with better scores. The trend line is fitted to all 9 points. However, it is notable that medicated (diamonds) and unmedicated (circles) children cluster differently with regard to these measurements.