Spatiotemporal changes in regularity of gamma oscillations contribute to focal ictogenesis

Abstract

In focal ictogenesis, gamma oscillations (30-70 Hz) recorded by electroencephalography (EEG) are related to the epileptiform synchronization of interneurons that links the seizure onset zone (SOZ) to the surrounding epileptogenic zone. We hypothesized that the synchronization of interneurons could be detected as changes in the regularity of gamma oscillation rhythmicity. We used multiscale entropy (MSE) analysis, which can quantify the regularity of EEG rhythmicity, to investigate how the regularity of gamma oscillations changes over the course of a seizure event. We analyzed intracranial EEG data from 13 pediatric patients with focal cortical dysplasia. The MSE analysis revealed the following characteristic changes of MSE score (gamma oscillations): (1) during the interictal periods, the lowest MSE score (the most regular gamma oscillations) was always found in the SOZ; (2) during the preictal periods, the SOZ became more similar to the epileptogenic zone as the MSE score increased in the SOZ (gamma oscillations became less regular in the SOZ); and (3) during the ictal periods, a decreasing MSE score (highly regular gamma oscillations) propagated over the epileptogenic zone. These spatiotemporal changes in regularity of gamma oscillations constitute an important demonstration that focal ictogenesis is caused by dynamic changes in interneuron synchronization.

Figure 1

Comparison of multiscale entropy (MSE) score in the gamma band among interictal (inter), preictal (pre), and ictal periods for each patient (Pt). The results are plotted as the mean ± standard deviation (error bar). n represents the number of electrodes analyzed for each patient. Significant differences were evaluated with a Steel-Dwass test. P-values < 0.05 were considered significant and are denoted by an asterisk (*).

Figure 2

Topographic maps of multiscale entropy (MSE) scores in four representative patients (Pt 1, 7, 9, and 12). The leftmost column shows the location of the seizure onset zone (SOZ; red circles) and the resection area (RA; outlined in yellow). The other 3 columns (from left to right) represent interictal, preictal, and ictal MSE-score maps. Color-coded MSE scores are topographically superimposed onto an intraoperative photograph of each individual patient’s brain surface and grid.

Figure 3

Differences in multiscale entropy (MSE) scores among the three areas for each period. The error bars indicate mean ± standard deviation. MSE scores were compared with Steel-Dwass tests. P-values < 0.01 were considered significant and are denoted by an asterisk (*). Inter, interictal; Pre, preictal; SOZ, seizure onset zone; RA-SOZ, resection area outside the SOZ; Outside RA, outside resection area.

Figure 4

Schematic representation of the spatiotemporal dynamics of the multiscale entropy (MSE) score in gamma oscillations during the transitions leading to an ictal period. Our results suggest that (1) during interictal periods, inhibitory interneuron synchronization (low MSE score) is maintained at high levels in the seizure onset zone (SOZ), while the desynchronizing (high MSE score) effect that acts to prevent seizures is maintained in the surrounding zones; (2) the preictal periods begin with the collapse of the balance between interneuron inhibition and excitation (increasing MSE score in the SOZ), which leads epileptic activity to assimilate the SOZ into the epileptogenic zone; and (3) In ictal periods, hypersynchronization (decreasing MSE score) via excitatory interneuron networks propagates over the epileptogenic zone to precipitate the seizure.

Figure 5

Multiscale entropy (MSE) curve with mean values and standard error of sample entropy (SampEn) over time scale factor τ = 1 to 20 among three periods for each area. n represents the number of electrodes analyzed for each area. SOZ, seizure onset zone; RA-SOZ, resection area outside the SOZ; Outside RA, outside resection area. In τ = 3 to 7 corresponding to the gamma frequency (28.6–66.7 Hz), the MSE curves in the SOZ apparently differentiated among three periods, and the MSE curves in the RA-SOZ apparently differentiated between ictal period and the other two periods.