The Effect of Lamotrigine and Levetiracetam on TMS-Evoked EEG Responses Depends on Stimulation Intensity

Abstract

The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) has uncovered underlying mechanisms of two anti-epileptic medications: levetiracetam and lamotrigine. Despite their different mechanism of action, both drugs modulated TMS-evoked EEG potentials (TEPs) in a similar way. Since both medications increase resting motor threshold (RMT), the current aim was to examine the similarities and differences in post-drug TEPs, depending on whether stimulation intensity was adjusted to take account of post-drug RMT increase. The experiment followed a placebo controlled, double blind, crossover design, involving a single dose of either lamotrigine or levetiracetam. When a drug-induced increase of RMT occurred, post-drug measurements involved two blocks of stimulations, using unadjusted and adjusted stimulation intensity. A cluster based permutation analysis of differences in TEP amplitude between adjusted and unadjusted stimulation intensity showed that lamotrigine induced a stronger modulation of the N45 TEP component compared to levetiracetam. Results highlight the impact of adjusting stimulation intensity.

Keywords: AED; electroencephalography; epilepsy; pharmaco-TMS-EEG; transcranial magnetic stimulation.

Figure 1

Left part of (A) shows RMT-values given as % of Maximum Stimulator Output (MSO) pre (blue = RMT1) and post (red = RMT2) the intake of levetiracetam (LEV), lamotrigine (LTG), and placebo (PBO). The right part shows individual RMT values (expressed as % MSO) before and after the intake of each drug condition. (B) TEPs recorded pre (blue) and post-RMT1 (red; unadjusted intensity) intake of levetiracetam (LEV, left) and lamotrigine (LTG, right). Levetiracetam and lamotrigine increased the N45 over the left hemisphere and decreases the P180 component over channels contralateral to the stimulated left M1. Adapted from Premoli et al. (2016). (C) TEPs recorded pre (blue) and post-RMT2 (red; adjusted intensity) intake of levetiracetam (LEV, left) and lamotrigine (LTG, right). Levetiracetam increased the N45 and decreased the P70, while lamotrigine suppressed the P180. Effects are observed over the stimulated left hemisphere. Black asterisks underneath represent significant drug-induced changes in TEPs. Shades indicate ± 1 SEM. T-statistic maps of the TEP amplitude post-drug vs. pre-drug differences are shown for each comparison. Blue represents increase in negativity or reduced positivity. Each TEP plot shows the grand-average across significant channels which are indicated by black dots in the t-statistic maps.

Figure 2

(A) TEPs measured post drug conditions with unadjusted (Post-drug with RMT1, blue) and adjusted (Post-drug with RMT2, red) intensity. Levetiracetam (left) increased the N100 potential over the left hemisphere, while lamotrigine increased P25 and N45 peaks on channels contralateral to the stimulated left M1. T-statistic maps of the TEP differences are shown. Blue represents increase in negativity (i.e., N100 and N45) and red increased positivity (i.e., P25) (B) Difference between Post-drug with RMT2 and Post-drug with RMT1 for levetiracetam (blue) and lamotrigine (red) which showed a significant difference corresponding with the N45 potential latency over contralateral sites as indicated in the t-statistic map. Black bars underneath each curve represent significant changes. Shades indicate ± 1 SEM. Each plot shows the grand-average across significant channels which are indicated by black dots in the t-statistic maps.