Evolution of temporal and spectral dynamics of pathologic high‐frequency oscillations (pHFOs) during epileptogenesis

Abstract

Objective In temporal lobe epilepsy (TLE) pathological high frequency oscillations (pHFOs, 200–600 Hz) are present in the hippocampus, especially the dentate gyrus (DG). The pHFOs emerge during a latent period prior to the onset of spontaneous generalized seizures. We used a unilateral suprahippocampal injection of kainic acid (KA) mouse model of TLE to characterize the properties of hippocampal pHFOs during epileptogenesis. Methods In awake head-fixed mice, 4–14 days after KA-induced status epilepticus (SE), we recorded local field potentials (LFP) with 64-channel silicon probes spanning from CA1 alveus to the DG hilus, or with glass pipettes in the DC mode in the CA1 str radiatum. Results The pHFOs, are observed simultaneously in the CA1 and the DG, or in the DG alone, as early as 4 days post-SE. The pHFOs ride on top of DC deflections, occur during motionless periods, persist through the onset of TLE, and are generated in bursts. Burst parameters remain remarkably constant during epileptogenesis, with a random number of pHFOs generated per burst. In contrast, pHFO duration and spectral dynamics evolve from short events at 4 days post-SE to prolonged discharges with complex spectral characteristics by 14 days post-SE. Simultaneous dural EEG recordings were exceedingly unreliable for detecting hippocampal pHFOs, hence such recordings may deceptively indicate a “silent” period even when massive hippocampal activity is present. Significance Our results demonstrate that hippocampal pHFOs exhibit a dynamic evolution during the epileptogenic period following SE, consistent with their role in transitioning to the chronic stage of TLE.

Extrahippocampal high‐frequency oscillations during epileptogenesis

“…Increased HFO rates after SE have been widely observed in experimental models of TLE, in HP, dentate gyrus, and entorhinal cortex . Bragin et al suggested that HFOs in both the ripple and FR ranges can be pathological after SE .…”

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

“…1; 67 More recently, investigators used a unilateral supra-hippocampal injection of kainic acid in mice that produced cell loss in the ipsilateral CA3, CA1, and hilar regions, as well granule cell dispersion and mossy fiber sprouting within two weeks after the injection. 68 The contralateral hippocampus, however, was relatively unaffected. Overall the histopathological changes seen in these experiments along with the appearance of seizures from the injected hippocampus reproduced several aspects of human TLE.…”

Interictal high-frequency oscillations in focal human epilepsy

“…Kaplan-Meir curves show 5-year seizure freedom for patients with unilateral mesial temporal sclerosis (MTS) is 72%, lesional MRI excluding MTS is 70%, and normal MRI temporal lobe epilepsy and extratemporal lobe epilepsy is ~60% [62,63] and 28% [64 ▪▪ ], respectively. Normal MRI patients have worse long-term outcomes, and for all patients the risk of seizure recurrence extends well beyond 1 year.…”

“…2 [61–63]). There is evidence in rodent epilepsy models that pHFOs (200–600 Hz) are a biomarker of epileptogenesis [59,64 ▪▪ ]. This is a critically important topic for epilepsy surgery, given that many patients that are initially seizure free suffer late recurrence of their seizures.…”