Antiepileptic Drug of Levetiracetam Decreases Centrotemporal Spike-Associated Activation in Rolandic Epilepsy

Abstract

The objective was to study the modulation effects of levetiracetam on the fMRI activation/deactivation patterns associated with centrotemporal spikes (CTS) in Rolandic epilepsy. Forty patients with Rolandic epilepsy, including levetiracetam-medicated patients (n = 20) and drug-naive patients (n = 20), were studied. Single and sequential hemodynamic response functions-based EEG-fMRI analysis was performed to detect dynamic activation/deactivation associated with CTS. Comparisons of spatiotemporal features of activation/deactivation were performed between the two groups. Both the groups (CTS were detected in 12 cases of levetiracetam-medicated group, and 11 cases of drug-naive group) showed CTS-associated activation in the Rolandic cortex, whereas activation strength, time-to-peak delay, and overall activation were diminished in the levetiracetam-medicated group. Moreover, the drug-naive group showed deactivation in the regions engaged in higher cognition networks compared with the levetiracetam-medicated group. Levetiracetam inhibits CTS-associated activation intensity and alters the temporal pattern of this activation in the epileptogenic regions, and it also affects the brain deactivation related to higher cognition networks. The findings sheds a light on the pharmocological mechanism of levetiracetam therapy on Rolandic epilepsy.

Keywords: EEG-fMRI; Rolandic epilepsy; antiepileptic drugs; centrotemporal spike; sequential HRFs analysis.

FIGURE 1

Flow chart of dynamic EEG-fMRI analysis. First, we marked time of centrotemporal spikes (CTS) onset on EEG by electroencephalographers. Second, we generated sequential HRFs consisting of 15 successive gamma functions of full-width half-maximum of 5.2 s, peak = 5.4 s and spaced 2 s between one another to model the dynamic BOLD changes induced by CTS. Finally, we convolved a boxcar function expressing the timing of CTS with sequential HRFs shifted from 14 s before to 14 s after the CTS (time point -14 to 14 s), to generate a series of regressors that modeled the dynamic activation/deactivation in individual level. Horizontal axis represented start time of the sequential HRFs. Actually, analysis with HRF centered at zero point (time point 0 s) was the conventional EEG-fMRI result with single HRF. The EEG and activation maps are from one of the patients with drug-naive. CTS, centrotemporal spikes; EEG, electroencephalography; HRF, hemodynamic response function; FWHM, full-width half-maximum; GLM, general-liner-model.

FIGURE 2

Spatial patterns of dynamic CTS-associated activation/deactivation in the drug-naive and LEV-medicated patients. The horizontal axis represented start time of the sequential HRFs. One-sample t-test within each group was performed in each time point in sequential hemodynamic response functions (HRF) analysis (time point -10 to 10 s) for drug-naive and levetiracetam (LEV)-medicated patients. Render maps with p = 1 in the left brain show the consecutively altered dynamic BOLD activity pattern. Slices maps with p < 0.01 (voxel-level p < 0.01, and cluster-level p < 0.05 with GRF correction) show significant activation and deactivation regions in each time point. Both the groups presented centrotemporal spikes (CTS)-associated activation in the Rolandic cortex. Viewed from the dynamic activation/deactivation, (A) drug-naive patients show Rolandic cortex activation during period from -2 to +2 s and extra Rolandic cortices deactivation before CTS onset (-6 to -2 s). (B) LEV-medicated patients show left Rolandic cortex activation during period from -4 to 0 s followed by deactivation after +8 s. LEV, levetiracetam.

FIGURE 3

Temporal features of dynamic activation/deactivation associated with CTS in the Rolandic cortex and other brain regions in the drug-naive and LEV-medicated patients. Activation/deactivation changes during CTS from ROIs of the bilateral Rolandic cortex, left Rolandic cortex, posterior cingulate cortex (PCC), bilateral dorsolateral prefrontal cortex (dlPFC), and bilateral intraparietal sulcus (IPS). Mean value and standard error of activation/deactivation intensity time course in drug-naive patients and levetiracetam (LEV)-medicated patients visualize with red and blue lines, respectively. (A) In the bilateral Rolandic cortices (ROI from the drug-naive group), the LEV-medicated group showed earlier time-to-peak (time point -2 s) compared with the drug-naive group (time point 0 s). Moreover, the LEV-medicated group showed lower peak intensity and relatively rapid decline, resulting in lower activation intensity from 0 to +8 s overall (p < 0.05, with no correction). (B) In the left Rolandic cortex (ROI from the LEV-medicated group), there was no significant intensity difference between the two groups (C–E). In the PCC, dlPFC, and IPS, the LEV group showed higher activation intensity compared with the drug-naive group before the CTS onset from -6 to -2 s, -4 to 0 s, -4 to 0 s, respectively. (p < 0.05, with no correction). ^∗p < 0.05, ^∗p < 0.01. LEV, levetiracetam; PCC, posterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; IPS, intraparietal sulcus.

FIGURE 4

Temporal features of dynamic activation/deactivation associated with CTS in the Rolandic cortex in the monotherapy and polytherapy LEV-medicated patients. Activation/deactivation changes during CTS from ROI of left Rolandic cortex (ROI from LEV-medicated group). Mean value and standard error of activation/deactivation intensity time course in monotherapy LEV-medicated patients and polytherapy LEV-medicated patients visualize with red and blue lines, respectively. There was no significant intensity difference between the two groups.