Rhythmic neuronal activity in S2 somatosensory and insular cortices contribute to the initiation of absence‐related spike‐and‐wave discharges

Abstract

SUMMARYPurpose: The origin of bilateral synchronous spike-andwave discharges (SWDs) that underlie absence seizures has been widely debated. Studies in genetic rodent models suggest that SWDs originate from a restricted region in the somatosensory cortex. The properties of this initiation site remain unknown. Our goal was to characterize the interictal, preictal and ictal neuronal activity in the primary and secondary cortical regions (S1, S2) and in the adjacent insular cortex (IC) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Methods: We performed electroencephalography (EEG) recordings in combination with multisite local field potential (LFP) and single cell juxtacellular recordings, and cortical electrical stimulations, in freely moving rats and those under neurolept-anesthesia.Key Findings: The onset of the SWDs was preceded by 5-9 Hz field potential oscillations, which were detected earlier in S2 and IC than in S1. Sustained SWDs could be triggered by a 2-s train of 7-Hz electrical stimuli at a lower current intensity in S2 than in S1. In S2 and IC, subsets of neurons displayed rhythmic firing (5-9 Hz) in between seizures. S2 and IC layers V and VI neurons fired during the same time window, whereas in S1 layer VI, neurons fired before layer V neurons. Just before the spike component of each SW complex, short-lasting high-frequency oscillations consistently occurred in IC 20 msec before S1. Significance: Our findings demonstrate that the S2/IC cortical areas are a critical component of the macronetwork that is responsible for the generation of absencerelated SWDs.

Spatiotemporal dynamics of optogenetically induced and spontaneous seizure transitions in primary generalized epilepsy

“…Similarly, in the first study providing evidence for a cortical focus in WAG/Rij rats using an electrocorticography (ECoG) grid on SI, Meeren et al (2002) systematically found the leading sites of seizures on the most posterior and lateral electrodes. Still, as shown by Zheng et al (2012) in GAERS rats, it is not excluded that the focus is actually located in more lateral regions. Our planar MEAs showed variable patterns across animals, probably due to the local somatotopy of SI and to small differences in implantation sites.…”

“…In that study, it is unknown if afterdischarges originated from the stimulated region, which could explain the differences in duration between SI and MI, or if they recruited the natural focus as shown here. Another study by Zheng et al (2012) has shown that electrical stimulation (2-s trains, 7 Hz) of SI, SII, and insular cortex (IC) induces self-sustained SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), with lower current thresholds for SII and IC. Again, because of the lack of array recordings, the authors did not investigate the precise spatiotemporal dynamics of the induced SWDs.…”

“…Several studies, however, have revealed focal cortical features in human patients with primary generalized epilepsy (Ferrie 2005;Holmes et al 2004;Lombroso 1997;Westmijse et al 2009) and in rat models of absence epilepsy, specifically the inbred Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) and genetic absence epilepsy rats from Strasbourg (GAERS) (Gurbanova et al 2006;Klein et al 2004;Lüttjohann et al 2011;Meeren et al 2002;Polack et al 2007Polack et al , 2009Zheng et al 2012). Yet it remains unknown what events within these potential cortical foci may actually trigger generalized seizures.…”

Moderate Cortical Cooling Eliminates Thalamocortical Silent States during Slow Oscillation

“…Previous studies have shown that the transitions between sleep and waking are controlled by neuromodulatory systems (Steriade et al, 1993b;Saper, 2006;Lee and Dan, 2012). During slow-wave sleep or anesthesia, when neuromodulatory tone is low, the cortical network generates slow waves that, at an intracellular level, appear as an alternation of hyperpolarized or silent states with minimal levels of synaptic activity and depolarized or active states with high levels of synaptic activities (Steriade et al, 2001;Timofeev et al, 2001a;Chauvette et al, 2011). An elevated level of neuromodulators during wakefulness and rapid eye movement (REM) sleep strongly reduces the activity of the membrane potassium channels, which depolarizes multiple types of cortical neurons (Krnjević et al, 1971;McCormick, 1992;Hasselmo and McGaughy, 2004;Steriade and McCarley, 2005).…”

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…As mentioned above, a bilaterally present, hyperexcitable, focal area within the deep layers (V and VI) of the perioral somatosensory cortex (S1po) has been identified as the seizure onset zone (Meeren et al, 2002;Polack et al, 2007) or rather near in the S2 or insular cortex (Zheng et al, 2012) and the necessity of this focal area(s) for SWD generation has been validated by several independent research groups exploiting different experimental techniques (for review see (van Luijtelaar and Sitnikova, 2006). It can be noted, that such a focal cortical onset zone, although not located within the somatosensory cortex, but rather in fronto-temporal cortical regions, has also been identified in children with absence epilepsy in several EEG, MEG (magnetoencephalogram) and EEG-fMRI studies (Holmes et al, 2004;Moeller et al, 2008;Westmijse et al, 2009).…”