Summary:Purpose: To investigate the temporal relation between high-frequency oscillations (HFOs) in the dentate gyrus and recurrent spontaneous seizures after intrahippocampal kainite-induced status epilepticus.Methods: Recording microelectrodes were implanted bilaterally in different regions of hippocampus and entorhinal cortex. A guide cannula for microinjection of kainic acid (KA) was implanted above the right posterior CA3 area of hippocampus. After recording baseline electrical activity, KA (0.4 µg/0.2 µl) was injected. Beginning on the next day, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for ≥30 days.Results: Of the 26 rats studied, 19 revealed the appearance of sharp-wave activity and HFOs in the frequency range of 80 to 500 Hz in the dentate gyrus ipsilateral to the KA injection. In the remaining seven rats, no appreciable activity was noted in this frequency range. In some rats with recurrent seizures, HFOs were in the ripple frequency range (100-200 Hz); in others, HFOs were in the fast ripple frequency range (200-500 Hz), or a mixture of both oscillation frequencies was found.The time of detection of the first HFOs after status epilepticus varied between 1 and 30 days, with a mean of 6.3 ± 2.0 (SEM). Of the 19 rats in which HFO activity appeared, all later developed recurrent spontaneous seizures, whereas none of the rats without HFOs developed seizures. The sooner HFO activity was detected after status epilepticus, the sooner the first spontaneous seizure occurred. A significant inverse relation was found between the time to the first HFO detection and the subsequent rate of spontaneous seizures.Conclusions: A strong correlation was found between a decreased time to detection of HFOs and an increased rate of spontaneous seizures, as well as with a decrease in the duration of the latent period between KA injection and the detection of spontaneous seizures. Two types of HFOs were found after KA injection, one in the frequency range of 100 to 200 Hz, and the other, in the frequency range of 200 to 500 Hz, and both should be considered pathological, suggesting that both are epileptogenic. Key Words: EpileptogenesisHigh-frequency oscillations-Dentate gyrus-Kainic acidRat.Processes leading to recurrent spontaneous seizures after an initial precipitating event remain obscure. After status epilepticus induced by intrahippocampal injection of kainic acid (KA), ∼50% of rats develop recurrent spontaneous seizures, which appear to arise from the region of the injected hippocampus and adjacent entorhinal cortex (1). The dentate gyrus (DG) is believed to play an important role in the mediation of seizure generation (2,3).High-frequency oscillations (HFOs) with a frequency range of 100 to 200 Hz, called ripples, occur in the normal rat hippocampus and entorhinal cortex, but not in DG (4-6). Evidence suggests that normal ripples reflect activity of interneurons that facilitate information transfer by

Summary:Purpose: The goal of this study was to analyze the transition period between interictal and ictal activity in freely moving rats with recurrent spontaneous seizures after unilateral intrahippocampal kainic acid (KA) injection.Methods: Pairs of tungsten electrodes (50 µm O/D) were implanted bilaterally under anesthesia at symmetrical points in the dentate gyrus (DG) and CA1 regions of anterior and posterior hippocampi and entorhinal cortex of adult Wistar rats. Stimulating electrodes were placed in the right angular bundle and KA was injected into the right posterior CA3 area of hippocampus after 1 week of baseline EEG recording. Beginning 24 h after injection, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for 60 days.Results: Seventy percent of seizures started locally in the DG ipsilateral to injection, with an increase in frequency of interictal EEG spikes (hypersynchronous type, HYP), and 26% of seizures started with a decrease of EEG amplitude with parallel increase in frequency (low-voltage fast type, LVF). During HYP seizures, a significant increase was observed in amplitude of beta-gamma range frequencies, ripple frequency, and fast ripple (FR) frequency, whereas during LVF seizure, an increase was noted only in the beta-gamma range. In all cases but one, an EEG wave preceded ripple and FR oscillations. Before seizure onset, the amplitude of DG-evoked responses to single pulses decreased, whereas the amplitude of the response to the second pulse delivered at 30-ms interval increased.Conclusions: If ripple and FR oscillations indicate the seizuregenerating neuronal substrate, these areas must be small and widespread, so that the probability of recording from them directly is very low. The decreased response to electrical stimulation before seizures could indicate a protective inhibitory mechanism that contains or prevents seizure occurrence. The presence of decreased paired-pulse suppression could indicate a network predisposition to follow an external input with a certain frequency.

Summary Objective To investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model. Methods Experiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 µm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28–189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group. Results Pathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15–40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10–16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures. Significance pHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis.

The current study aimed to investigate the spatial and temporal patterns of high-frequency oscillations (HFOs) in the intra-/extrahippocampal areas during epileptogenesis. Local field potentials were bilaterally recorded from hippocampus (CA1), thalamus, motor cortex, and prefrontal cortex in 13 rats before and after intrahippocampal kainic acid (KA) lesions. HFOs in the ripple (100-200 Hz) and fast ripple (250-500 Hz) ranges were detected and their rates were computed during different time periods (1-5 weeks) after KA-induced status epilepticus (SE). Recurrent spontaneous seizures were observed in 7 rats after SE, and the other 6 rats did not develop epilepsy. During the latent period, the rate of hippocampal HFOs increased at the ipsilateral site of the KA lesion in both groups, and the HFO rate was significantly higher in the animals that later developed epilepsy. Animals that later developed epilepsy also demonstrated widespread appearance of HFOs, in both the ripple and the fast ripple range, whereas animals that did not develop epilepsy only exhibited changes in the ipsilateral intrahippocampal HFO rate. This study demonstrates an association between an increased rate of widespread HFOs and the later development of epilepsy, suggesting the formation of large-scale distributed pathological networks during epileptogenesis.

This study investigates the temporal dynamics of ictal electrical activity induced by injection of the GABA A receptor antagonist bicuculline, and the glutamate agonist kainic acid, into the CA3 area of hippocampus. Experiments were conducted in freely moving adult Wistar rats implanted with microelectrodes in multiple brain areas. Wide-band electrical activity (0.1-3000 Hz) was recorded, and the latency of seizure onset as well as the pattern of electrical activity were investigated for each drug. The latencies between injection and the occurrence of first epileptiform events were 3.93 Ϯ 2.76 (ϮSTD) min for bicuculline and 6.37 Ϯ 7.66 min for kainic acid, suggesting the existence of powerful seizure-suppressive mechanisms in the brain. Bicuculline evoked high-amplitude rhythmic epileptiform events at the site of injection which resembled interictal EEG spikes and rapidly propagated to adjacent and remote brain areas. Kainic acid evoked a completely different pattern with a gradual increase in the amplitude of 30 -80 Hz activity. Whereas there was strong temporal correlation between EEG events at the site of bicuculline injection and discharges in distant areas, much less correlation was seen with kainic acid injection. Both patterns were followed by generalized ictal EEG discharges and behavioral seizures. Our results illustrate that the same area of the brain can trigger seizures with different electrographic patterns. The knowledge of the network mechanisms underlying these two distinct electrographic patterns might be helpful in designing differential strategies for preventing seizure occurrence.