Cortical and subcortical contributions to absence seizure onset examined with EEG/fMRI

Abstract

In patients with idiopathic generalized epilepsies (IGEs), bursts of generalized spike and wave discharges (GSWDs) lasting > or =2 seconds are considered absence seizures. The location of the absence seizures generators in IGEs is thought to involve interplay between various components of thalamocortical circuits; we have recently postulated that medication resistance may, in part, be related to the location of the GSWD generators [Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Epilepsy Behav. 2010;17:525-30]. In the present study we hypothesized that patients with medication-refractory IGE (R-IGE) and continued absence seizures may have GSWD generators in locations other than the thalamus, as typically seen in patients with IGE. Hence, the objective of this study was to determine the location of the GSWD generators in patients with R-IGE using EEG/fMRI. Eighty-three patients with IGE received concurrent EEG/fMRI at 4 T. Nine of them (aged 15-55) experienced absence seizures during EEG/fMRI and were included; all were diagnosed with R-IGE. Subjects participated in up to three 20-minute EEG/fMRI sessions (400 volumes, TR=3 seconds) performed at 4 T. After removal of fMRI and ballistocardiographic artifacts, 36 absence seizures were identified. Statistical parametric maps were generated for each of these sessions correlating seizures to BOLD response. Timing differences between brain regions were tested using statistical parametric maps generated by modeling seizures with onset times shifted relative to the GSWD onsets. Although thalamic BOLD responses peaked approximately 6 seconds after the onset of absence seizures, other areas including the prefrontal and dorsolateral cortices showed brief and nonsustained peaks occurring approximately 2 seconds prior to the maximum of the thalamic peak. Temporal lobe peaks occurred at the same time as the thalamic peak, with a cerebellar peak occurring approximately 1 second later. Confirmatory analysis averaging cross-correlation between cortical and thalamic regions of interest across seizures corroborated these findings. Finally, Granger causality analysis showed effective connectivity directed from frontal lobe to thalamus, supporting the notion of earlier frontal than thalamic involvement. The results of this study support our original hypothesis and indicate that in the patients with R-IGE studied, absence seizures may be initiated by widespread cortical (frontal and parietal) areas and sustained in subcortical (thalamic) regions, suggesting that the examined patients have cortical onset epilepsy with propagation to thalamus.

Figure 1

Anatomical ROIs for which group activation timecourses were calculated.

Figure 2

Representative activation pattern for subject #2 (Table 1) for time shifts of 0 and −2 seconds relative to EEG seizure onset. BOLD signal increases are shown in red and decreases are shown in blue with a T-score threshold of 2 and −2 respectively. Slice locations are provided in the sagittal brain view in the upper left.

Figure 3

Group activation timecourse, shown from −4 sec. to +1 sec. in 1 second increments, for 6 axial brain slices. Timings indicate the shift of the BOLD HRF onset relative to the onset of seizure activity according to EEG. There is a progression of activation patterns, from −3 sec. to the time of the EEG onset, peaking in succession in parietal/frontal regions followed by temporal/limbic regions and the thalami. Activations shown are at p < 0.05, family-wise error corrected. Slice z coordinates, indicated on the sagittal view, are in MNI space.

Figure 4

Group activation timecourses, represented as the bootstrapped mean of positive T scores in select anatomic regions of interest (ROI) vs. the time shift of the modeled BOLD response relative to the seizure onset on EEG. Error bars represent the extents of mean T bootstrap distributions. The ROI is indicated for each subplot. The shaded bar highlights zero time shift, where the BOLD onset is considered to coincide with seizure onset. Note that frontal/parietal activity peaks the earliest; 2–3 seconds prior to seizure onset. The limbic lobe peaks between 0 and −1 seconds while the temporal lobe and thalamus peak at the time of seizure onset. The cerebellar response tends to lag the beginning of seizure activity by 0 to 1 seconds.

Figure 5

Distributions of time shifts maximizing cross-correlation between five cortical regions and the thalamus among all observed seizures. Frontal, parietal, and temporal regions were found to have significant mean time shifts. Negative shifts reflect the cortical region preceding the thalamus. Means are indicated in the figure along with the standard error of the mean. P values are for a test of the null hypothesis of zero mean.

Figure 6

Distributions of net Granger causal link between each of five cortical regions and the thalamus among all observed seizures. Only the frontal region was found to have significant mean effective connectivity directed to the thalamus. Positive values reflect net connectivity directed from the cortical region to the thalamus. Means are indicated in the figure along with the standard error of the mean. P values are for a test of the null hypothesis of zero mean.