The aim of this study was to evaluate the origins of absence seizures in patients with IGEs using combined EEG/fMRI and to test the hypothesis that in patients with R-IGEs the origin of absence seizures is frontal/cortical. The results of time-shifted GLM analyses, confirmed additionally and separately by cross-correlation and Granger causality analyses, appear to support our hypothesis and suggest that the examined R-IGE patients who experienced absence seizures during the EEG/fMRI procedure have broad cortical (e.g., frontal and parietal) rather than thalamic seizure onset. Although this finding may be surprising, the credence of our results is supported by congruent findings from confirmatory analyses including Granger causality that showed causal directionality from the cortical regions to thalami and findings from previously published animal and human studies.
There are two main and contradictory theories in support of the GSWD generators in human brain. Originally in 1947 Jasper and Droogleever-Fortuyn proposed the idea of a deep “pacemaker” as a source of petit mal
). An invasive study by Williams led Penfield and Jasper to propose the centrencephalic
theory, which posits the thalamus and the upper brain stem as the origin of GSWD in generalized epilepsies (39
). Other invasive studies did not confirm these findings (41
). In fact, the study by Niedermeyer et al. indicated that patients with similar phenotypes suggestive of generalized epilepsy might have had different sources of the GSWD leading to different responses to antiepileptic drugs; at least two of his patients with a typical IGE phenotype proved to have frontal lobe epilepsy; one of them became seizure-free after surgical intervention (41
). Therefore, Niedermeyer proposed the more global, cortical theory
of generalized absence seizure onset postulating that typical generalized seizures are triggered by localized, (e.g., frontal) cortical foci (43
). Finally, Pierre Gloor based on feline experiments attempted to reconcile the above theories by proposing the corticoreticular
theory whereby both, functional cortex and functional thalami are necessary for the development of GSWD (45
). It is possible that all these theories are correct and the results of a study depend on patient/subject selection.
Rodent models of generalized epilepsies provide mixed and at times conflicting results regarding seizure and/or GSWD onset. Some studies suggested Na+
- and/or Ca++
-channel mutations in thalamic neurons as the etiology of absence epilepsy (49
). In contrast, studies of ethosuximide in the genetic rat model of absence epilepsy showed that this AED diminished the firing rate of nucleus reticularis thalami by 90% when administered systemically, but the response was much slower and of lower magnitude when it was administered directly into the thalamus suggesting that the thalamus might not be the only source of GSWD and that the participation of the cortical structures in the generation of GSWD remains likely (51
). Another study in WAG/Rji rats potentially contradicted the thalamic theory of GSWD onset – lidocaine injected into the somatosensory cortex led to a decrease in GSWD supporting the notion that the somatosensory (i.e., fronto-parietal) cortex may play an important role for the occurrence of GSWD (52
). Finally, a recent EEG/fMRI study of WAG/Rij rats showed BOLD signal changes in both, cortical and thalamic structures in response to absence seizures (53
Although the animal studies indicate that the thalamus and its connections are essential for the production of GSWD and their characteristic morphology, the major differences between these models and human generalized epilepsy are that these models are “man-made” and that the discharges in these models are much faster than in human IGEs therefore making these models similar to but not exactly like human epilepsy (43
). While the thalamus, with its connections to all areas of the cortex and its baseline rhythmic firing of bursts of action potentials appears to be an important, if not the most important part of the network underlying GSWD generation, evidence suggests that there may be cortical sources contributing to the etiology of IGEs (54
). This notion is consistent with the early human epilepsy literature focusing on cortical onset as the main source of generalized epileptic seizures (41
). Certainly, our findings in patients with R-IGEs are in agreement with the cortical theory
of generalized absence seizure onset (43
). While we observed BOLD signal changes in both thalami and symmetrically in widespread cortical areas, the cortical BOLD signal increases preceded thalamic changes suggesting that the cortical areas are initiating and the thalami sustaining the GSWD.
The frontal involvement in generalized epilepsies is further supported by abnormal neuroimaging and neurocognitive results in IGE patients that are similar to abnormalities identified in frontal lobe epilepsies. For example, the issue of frontal lobe dysfunction in patients with frontal lobe epilepsy and JME was previously examined using neuropsychological testing and PET (56
). These studies found frontal lobe dysfunction in patients with JME to be similar to the abnormalities seen in patients with frontal lobe epilepsy. Furthermore, MRI studies at 1.5T confirmed that up to 40% of patients with JME have minor structural abnormalities (62
), but neither these nor other studies have addressed the issue of whether the functional and structural abnormalities are more prevalent in patients with medication-resistant vs. medication-responsive IGEs. These structural/anatomical studies confirmed though the previous autopsy findings of a few small series of patients with IGE and/or JME that have shown cortical and subcortical dystopic neurons and microdysgenesis in some of these patients (65
). In contrast to the above studies, cross-sectional MRS evaluation of thalamic structures in patients with IGEs revealed reduction in NAA/Cr ratio in comparison to healthy controls, that was dependent on the duration of epilepsy (67
). This is again suggestive of thalamic neuronal dysfunction and a possibility of thalamic participation in the etiology of generalized seizures but it does not exclude the possibility of seizure onset in frontal lobes with later thalamic involvement and possible damage (67
). In search of an explanation for these discrepancies one study examined EEGs of patients with JME, and found that patients with VPA-resistant JME have SWD asymmetries in 40% vs
. 5% with VPA-responsive JME (11
). Another study showed that patients with AED-resistant (VPA ± other AEDs) JME have higher frequency of all types of seizures (myoclonic + generalized + absence) than patients with AED-responsive (VPA ± other AEDs) JME (62.5% vs
. 23.3%) and that the presence of psychiatric problems pointing toward possible frontal lobe dysfunction is higher in AED-resistant JME patients (58.3% vs
. 19%) suggesting again that some patients with otherwise typical IGEs may have frontal abnormalities that may be the cause of their epilepsy (61
). The above issues, especially the possibility of focal cortical abnormalities causing an IGE-like syndrome associated with asymmetric SWD remain controversial (1
). The availability of high-field/high-resolution MRI, EEG/fMRI and modern data analysis methods makes addressing some of these questions possible.
Although EEG/fMRI is a fairly new neuroimaging technique, it has been already extensively used in the studies of generalized epilepsies (17
). In one of the early EEG/fMRI studies of patients with various types of IGEs (childhood and juvenile absence, JME, and generalized seizures only), 15/25 patients showed GSWD and BOLD signal response (69
). BOLD signal changes related to GSWD were localized to the thalamus (in 80%), but increased BOLD signal was also noted in other, widespread cortical areas including all head regions in 5/15, anterior head regions in 6/15, and predominantly posterior activation in 3/15 (69
). Subsequently, several other studies confirmed these results and showed thalamic and cortical BOLD signal increases but the temporal trajectory of BOLD signal changes has not been examined in detail thus far. Of note is that one of the more recent studies focusing on absence seizures during EEG/fMRI found mainly thalamic BOLD signal increases with only minimal and either coinciding or delayed signal decreases in other cortical areas (18
). While our results in adults with prolonged bursts of GSWD suggestive of absence seizures during the EEG/fMRI procedure appear to contradict these results, the discrepancy appears to be only superficial. The main difference between these studies is that children studied by Moeller et al. were drug-naïve and once started on valproic acid all became seizure-free. This is in contrast to the patients enrolled in this study, none of whom had their epilepsy controlled at the time of scanning despite many medication trials. While several of these patients became subsequently seizure-free () they require ≥2 AEDs (or VNS) for seizure control. Hence, all these patients have R-IGE that may be a result of an atypical (not thalamic) seizure generation.
Some weaknesses of this study warrant discussion. EEG/fMRI data associated with seizure activity were subjected to three analytical approaches attempting to discern relationships between pertinent cortical regions and the thalamus. The primary analysis used mean T-scores from time-shifted GLMs to assess the progression of brain activity from cortical to thalamic regions. Cross-correlation of the BOLD signal between various pairs of ROIs over a window of time straddling each seizure served as another measure of relative timing that provided a measure of seizure-to-seizure variation. Finally, the presence or absence of causal relationships between relevant cortical ROIs and the thalamus was determined. All three approaches are deeply influenced by the nature of the HRF. Implicit in the primary analysis is the assumption that the HRF is fixed: it is the same between subjects, between regions, and between sessions. It is well understood, however, that this may not be the case (73
). Evidence exists for variation of as much as a few seconds in the timing of the HRF peak between subjects and from region to region in the brain (74
). In fact, variation on the order of seconds in BOLD response timing has been observed between sessions of the same subject in voxels that do not activate consistently. There appears to be no clear evidence from these studies, however, that HRF timing differences are systematic between brain regions, particularly between cortical and subcortical domains. Another consideration here is the reference of the relative HRF peak to the EEG GSWD onset at time t = 0 sec. This reference point assumes that the HRF corresponding to GSWD activity has the same morphology as the canonical HRF. However, this assumption has not been validated and could lead to systematic shifts or increased variance in the shift of the measured peak responses in the brain regions considered relative to the EEG reference point defined by the SWD onset. Given the sources of variance in the HRF timing, it is not, therefore, surprising that this study finds considerable seizure to seizure variation for cross-correlation and Granger causality measures ( and ). This multi-level variance limited the ability to find significant relative timing and causal relationships between brain regions, given 36 events over which to average. Despite this, a small but significant mean causal link directed from the frontal to the thalamic regions was discerned as well as a significant mean precedence of cortical vs. thalamic response. Still, although unlikely, it cannot be ruled out that these outcomes are indeed the result of subtle consistent regional differences in the HRF time-to-peak.
The relatively large number of EEG/fMRI sessions with absence seizure available for analyses was extracted from an ongoing, large study of epilepsy patients. In the parent EEG/fMRI study the fMRI parameters are designed to obtain functional scans of the entire brain with a TR of 3 seconds. This long TR is not optimal when the aim is to determine timing differences and causal links between brain regions. The effectiveness of Granger analysis, in particular, is well understood to be diminished by a low sampling rate, leading to reduction in the ability to discern causal links, i.e. more of the interdependence is rendered as instantaneous (37
). Acquisition of the functional imaging component of an EEG/fMRI study like this one at a higher sampling rate should allow for improvement in effective connectivity outcomes.
The lack of negative activation in the group composite for any time shift in this study disagrees with some earlier results (17
). Individual activation trends included negative response in parietal and frontal regions as shown in . It is apparent, however, that negative activation was not consistent per voxel at any particular time shift among the individuals included in this study. It is conceivable that heterogeneity of this subject group regarding diagnosis, history, or AEDs, as detailed in , contributes to this variability in negative activation. This suggests future studies designed with subgroups of adequate sample size to allow discernment of potential differences in activation patterns. Another potential source of variability of activation or timing is differences in seizure characteristics. GSWD burst durations varied from 2.0 to 11.9 seconds, but no significant correlative relationships were found between burst duration and either the cross-correlation or the Granger connectivity outcomes.