High-frequencyoscillations(HFOs;80 -500Hz)arethoughttomirrorthepathophysiologicalchangesoccurringinepilepticbrains.However,the distribution of HFOs during seizures remains undefined. Here, we recorded from the hippocampal CA3 subfield, subiculum, entorhinal cortex, and dentate gyrus to quantify the occurrence of ripples (80 -200 Hz) and fast ripples (250 -500 Hz) during low-voltage fast-onset (LVF) and hypersynchronous-onset (HYP) seizures in the rat pilocarpine model of temporal lobe epilepsy. We discovered in LVF seizures that (1) progressionfrompreictaltoictalactivitywascharacterizedinseizure-onsetzonesbyanincreaseofrippleratesthatwerehigherwhencomparedwithfast ripple rates and (2) ripple rates during the ictal period were higher compared with fast ripple rates in seizure-onset zones and later in regions of secondary spread. In contrast, we found in HYP seizures that (1) fast ripple rates increased during the preictal period and were higher compared with ripple rates in both seizure-onset zones and in regions of secondary spread and (2) they were still higher compared with ripple rates in both seizure-onset zones and regions of secondary spread during the ictal period. Our findings demonstrate that ripples and fast ripples show distinct time-and region-specific patterns during LVF and HYP seizures, thus suggesting that they play specific roles in ictogenesis.

Mesial temporal lobe epilepsy (MTLE) is characterized in humans and in animal models by a seizure-free latent phase that follows an initial brain insult; this period is presumably associated to plastic changes in temporal lobe excitability and connectivity. Here, we analyzed the occurrence of interictal spikes and high frequency oscillations (HFOs; ripples: 80-200 Hz and fast ripples: 250-500 Hz) from 48 h before to 96 h after the first seizure in the rat pilocarpine model of MTLE.Interictal spikes recorded with depth EEG electrodes from the hippocampus CA3 area and entorhinal cortex (EC) were classified as type 1 (characterized by a spike followed by a wave) or type 2 (characterized by a spike with no wave). We found that: (i) there was a switch in the distribution of both types of interictal spikes before and after the occurrence of the first seizure; during the latent phase both types of interictal spikes predominated in the EC whereas during the chronic phase both types of spikes predominated in CA3; (ii) type 2 spike duration decreased in both regions from the latent to the chronic phase; (iii) type 2 spikes associated to fast ripples occurred at higher rates in EC compared to CA3 during the latent phase while they occurred at similar rates in both regions in the chronic phase; and (iv) rates of fast ripples outside of spikes were higher in EC compared to CA3 during the latent phase. Our findings demonstrate that the transition from the latent to the chronic phase is paralleled by dynamic changes in interictal spike and HFO expression in EC and CA3. We propose that these changes may represent biomarkers of epileptogenicity in MTLE.

Low-voltage fast (LVF)- and hypersynchronous (HYP)-seizure onset patterns can be recognized in the EEG of epileptic animals and patients with temporal lobe epilepsy. Ripples (80-200 Hz) and fast ripples (250-500 Hz) have been linked to each pattern, with ripples predominating during LVF seizures and fast ripples predominating during HYP seizures in the rat pilocarpine model. This evidence led us to hypothesize that these two seizure-onset patterns reflect the contribution of neural networks with distinct transmitter signaling characteristics. Here, we tested this hypothesis by analyzing the seizure activity induced with the K(+) channel blocker 4-aminopyridine (4AP, 4-5 mg/kg ip), which enhances both glutamatergic and GABAergic transmission, or the GABAA receptor antagonist picrotoxin (3-5 mg/kg ip); rats were implanted with electrodes in the hippocampus, the entorhinal cortex, and the subiculum. We found that LVF onset occurred in 82% of 4AP-induced seizures whereas seizures after picrotoxin were always HYP. In addition, high-frequency oscillation analysis revealed that 4AP-induced LVF seizures were associated with higher ripple rates compared with fast ripples (P < 0.05), whereas picrotoxin-induced seizures contained higher rates of fast ripples compared with ripples (P < 0.05). These results support the hypothesis that two distinct patterns of seizure onset result from different pathophysiological mechanisms.