Abstract
Low- and High-Frequency Oscillations Reveal Distinct Absence Seizure Networks
Tenney JR, Fujiwara H, Horn PS, Vannest J, Xiang J, Glauser TA, Rose DF. Ann Neurol 2014;76:558–567.
OBJECTIVE: The aim of this study was to determine the frequency-dependent, spatiotemporal involvement of corticothalamic networks to the generation of absence seizures. METHODS: Magnetoencephalography recordings were obtained in 12 subjects (44 seizures) with untreated childhood absence seizures. Time-frequency analysis of each seizure was performed to determine bandwidths with significant power at ictal onset. Source localization was then completed to determine brain regions contributing to generalized spike and wave discharges seen on electroencephalogram. RESULTS: Significant power in the time-frequency analysis was seen within 1 to 20Hz, 20 to 70Hz, and 70 to 150Hz bandwidths. Source localization revealed that sources localized to the frontal cortex similarly for the low- and gamma-frequency bandwidths, whereas at the low-frequency bandwidth (3–20Hz) significantly more sources localized to the parietal cortex (odds ratio [OR] = 16.7). Cortical sources within the high-frequency oscillation (HFO) bandwidth (70–150Hz) localized primarily to the frontal region compared to the parietal (OR = 7.32) or temporal (OR = 2.78) areas. INTERPRETATION: Neuromagnetic activity within frontal and parietal cortical regions provides further confirmation of hemodynamic changes reported using functional magnetic resonance imaging that have been associated with absence seizures. The frequency-dependent nature of these networks has not previously been reported, and the presence of HFOs during absence seizures is a novel finding. Co-occurring frontal and parietal corticothalamic networks may interact to produce a pathological state that contributes to the generation of spike and wave discharges. The clinical and pathophysiological implications of HFOs within the frontal cortical region are unclear and should be further investigated.
Commentary
Let's consider a series of observations:
Observation 1: “I believe that epileptic petit mal and epileptic grand mal are, when regarded from the anatomical and physiological point of view, simply different degrees, that is to say, that they depend on different strengths of discharge, beginning in and spreading from the same parts of the brain. The discharge in each begins in the very highest centres of the cerebral hemispheres, that is to say, in the anatomical substrata of consciousness” (emphasis added) (1). Hughlings Jackson made these statements in 1876, based entirely on clinical observation.
Observation 2: “The bilaterally synchronous onset of the familiar wave and spike discharge, and the almost perfect timing of the mirrored waves in homologous regions of the two hemispheres” (emphasis added) led Jasper and Kershman (2) to propose a subcortical pacemaker in 1941. In the same year, Penfield and Erickson concluded that “[petit] mal attacks must have their origin in diencephalic structures having ready access to homologous cortical areas of both hemispheres” (emphasis added) (3).
Observation 3: In 1949, Hunter and Jasper used electrocorticography in cats to show that stimulation of the intralaminar regions of the thalamus produced a generalized recruitment of the rhythmic activity of the cortex and the generalized changes in behavior, which they have termed the “arrest reaction”. (4). During the “petit mal-like seizures” seen in their experimental cats, a bilaterally synchronous 3-per-second spike-and-wave discharge was recorded from the cortex and was associated with a similar type of wave form in the thalamus. During the “grand mal-like attacks, the electrocorticogram and electrothalamogram showed rapid high high-voltage activity simulating closely the form of the EEG at the onset of such attacks in man. Therefore, they concluded from observations in the cat that “the diffuse thalamocortical projection system which [they] have called the thalamic reticular system has a very widespread and profound effect on behaviour as a whole and may be involved in the mechanism of petit mal and generalized convulsive seizures as seen in man” (emphasis added) (4).
Observation 4: In 1965, as the understanding of evoked potentials grew, Weir noted while observing the morphology of the generalized spike wave complex that “even in apparently simple complexes, there are usually two negative spikes, a positive transient, and a negative wave” (5). He further concluded that “the initial positivity of the spike-wave complex of petit mal may have a similar basis to the initial positivity of specific somatosensory and transcallosal evoked responses,” as he hypothesized that the striking initial positivity of the spike-wave complex reflects a depth negative sharp wave that is a summation of EPSP and associated cell membrane depolarizations from the thalamus to the somatosensory cortex (5).
Observation 5: In 2008, Moeller et al. performed simultaneous EEG-fMRI on 10 children with newly diagnosed childhood absence epilepsy and analyzed blood oxygen level dependent (BOLD) signal changes associated with ictal EEG activity (i.e., periods of 3-per-second generalized spike-waves) in pre-defined regions-of-interests, which included the precuneus, parietal lobe, and caudate nucleus (6). They found that “the 3-per-second generalized spike-wave complexes were associated with regional BOLD signal decreases in parietal areas, precuneus, and caudate nucleus along with a bilateral increase in the BOLD signal in the medial thalamus” (emphasis added) (6). Taking into account the normal delay in the hemodynamic response, temporal analysis showed that the onset of BOLD signal changes coincided with the onset of the generalized spike-wave complexes. Highlighting a critical role of selective cortical networks in producing the “generalized” spike-wave complexes was consistent with observations made by Holmes in 2004: He applied source localization with equivalent dipole (BESA) and smoothed linear dipole (LORETA) methodology to 256-channel scalp EEG on 25 absence seizures in five subjects and found that the onset of seizures was typically associated with activation of discrete, often unilateral, areas of dorsolateral frontal or orbitofrontal lobe (7). Although each patient showed unique features, the absence seizures of all patients showed rapid, stereotyped evolution to engage both mesial frontal and orbitofrontal cortex sources during the repeating cycles of spike-wave activity.
In the 2014 article chosen for this commentary, Tenney et al. used MEG followed by time-frequency analysis and source localization. They found that at the lower-frequency bandwidth (3–20Hz), sources tended to localize within the cortex more posteriorly, in the parietal region as well as the thalamus. At the gamma-frequency bandwidth (20–70Hz), there was more anterior localization of sources within the frontal cortex and, in many instances, to a focal region of the lateral prefrontal and orbitofrontal cortex. At the high-frequency oscillation (HFO) bandwidth (70–150Hz), source localization was almost exclusively confined to the prefrontal and orbitofrontal cortex as well as some subcortical localization in the thalamus. Lateralized HFOs within the prefrontal cortex were a reproducible finding across subjects, and the side of lateralization was consistent at the intrasubject but not intersubject level.
A common thread can be deciphered throughout all these observations spanning a century and a half: 1) there is no question about a central pacemaker (thalamus) in generalized/absence epilepsy; 2) there is general agreement that this pacemaker (thalamus) is incapable, by itself, of generating the full electroclinical syndrome of absence epilepsy; and 3) there is always a lot of work involved in using the technologies of the time [clinical observation (1), scalp EEG (2,3), ECoG (4), evoked potentials (5), functional MRI (6) or EEG-f-MRI (7), and now MEG] to define the extent and role of cortical involvement in both the generation and spread of the generalized spike-wave discharge. Regardless of the methodology used, there is a consistent demonstration of bilateral activation of the frontal and parietal (mesial or lateral) networks at different stages of ictal evolution. This critical role of the frontal and parietal cortex was present in the undertones of observations 1 to 3 above, took more shape with the parallels drawn with an evoked somatosensory response in observation 4, and was more developed in the subsequent studies highlighted here.
Another interesting observation that somehow escaped the spotlight thus far is the fact that any evidence we choose to highlight a “focal” cortical involvement in generalized epilepsy seems to be patient-dependent, with significant inter- but not intra-subject variability. One could then go beyond the circular argument of the presence versus absence of an overlap between focal and generalized epilepsy to speculate that such an overlap, whenever present, may have an underlying patient-specific substrate. Although cortical excitability in the general sense is increased in some patients with generalized epilepsy (8), focal areas of microdysgenesis were found in the cortex of some patients with primary generalized epilepsy on pathological studies (9), and focal cortical (mostly mesial or basal frontal) atrophic changes have been documented on brain MRI in some children with new onset generalized epilepsy (10). Further, focal seizure semiologies have been observed in some patients with clearly generalized epilepsy syndromes (11). The more we study this overlap, the more we marvel at how the lines blur between “focal” and “generalized” epilepsy, while the answer to why they blur may lie in better understanding the patient-specific variability.