Elsevier

Neuroscience Letters

Volume 667, 22 February 2018, Pages 66-74
Neuroscience Letters

Review article
High-frequency oscillations and mesial temporal lobe epilepsy

https://doi.org/10.1016/j.neulet.2017.01.047Get rights and content

Highlights

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    High-frequency oscillations reflect the activity of networks that sustain seizures and could serve as biomarkers of epilepsy.

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    We review here the recent findings on the cellular mechanisms of ripples and fast ripples in mesial temporal lobe epilepsy.

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    We also address the effects of anti-epileptic drugs in animal models and patients.

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    We raise some questions and issues related to the definition of high-frequency oscillations.

Abstract

The interest of epileptologists has recently shifted from the macroscopic analysis of interictal spikes and seizures to the microscopic analysis of short events in the EEG that are not visible to the naked eye but are observed once the signal has been filtered in specific frequency bands. With the use of new technologies that allow multichannel recordings at high sampling rates and the development of computer algorithms that permit the automated analysis of extensive amounts of data, it is now possible to extract high-frequency oscillations (HFOs) between 80 and 500 Hz from the EEG; HFOs have been further categorised as ripples (80–200 Hz) and fast ripples (250–500 Hz). Within the context of epileptic disorders, HFOs should reflect the pathological activity of neural networks that sustain seizure generation, and could serve as biomarkers of epileptogenesis and ictogenesis. We review here the presumptive cellular mechanisms of ripples and fast ripples in mesial temporal lobe epilepsy. We also focus on recent findings regarding the occurrence of HFOs during epileptiform activity observed in in vitro models of epileptiform synchronization, in in vivo models of mesial temporal lobe epilepsy and in epileptic patients. Finally, we address the effects of anti-epileptic drugs on HFOs and raise some questions and issues related to the definition of HFOs.

Introduction

Epilepsy is the most prevalent neurological disorder according to the World Health Organization, with a prevalence of over 50 million and an incidence of 2.4 million per year. Focal epileptic disorders represent 60% of these cases, with mesial temporal lobe epilepsy (MTLE) being the most prevailing syndrome. MTLE is characterised by seizures that recur following a latent period of up to many years after an initial brain insult such as status epilepticus (SE), traumatic brain injury, encephalitis or febrile convulsions [1], [2]. These recurrent seizures originate from the hippocampus, entorhinal cortex (EC) or amygdala [3] and are often refractory to medication, making surgical resection of epileptic tissue the only therapeutic alternative [4]. Epileptologists are therefore trying to find biomarkers of MTLE that will lead to a better delineation of the seizure onset zone as well as to a better understanding of the disease. Approximately 15 years ago, the analysis of EEGs obtained from epileptic patients and from animal models mimicking this disease revealed the occurrence of high-frequency oscillations (HFOs) that appeared to be closely related to the paroxysmal activity generated from the epileptic tissue [5]. These HFOs have been categorised by many investigators into two groups, based on their frequency content: (i) ripples that comprise events between 80 and 200 Hz and (ii) fast ripples that include events between 250 and 500 Hz [6]. Ripples were initially discovered in the hippocampus of control animals during periods of immobility and consummatory behavior [7] but they are also observed in the epileptic tissue [6], [8], [9]. In addition, in both non-epileptic animals [10] and humans [11], [12], fast ripples are recorded in the somatosensory cortex during sensory evoked potentials. In the epileptic tissue, fast ripples have been found in hippocampal and para-hippocampal regions [10], [11], [20], [21], and in seizure onset zones [16], [17].

Here, we will first address the cellular mechanisms that are presumably underlying ripples and fast ripples. Next, we will review data obtained from in vitro and in vivo experiments as well as from clinical studies in which the roles of HFOs in ictogenesis and epileptogenesis have been analysed. Then, we will consider the changes in HFOs that occur during treatments with anti-epileptic drugs (AEDs), and finally we will discuss some issues that are related to the definition of HFOs.

Section snippets

Cellular mechanisms

Under physiological conditions, ripples are mainly recorded from immobile or sleeping animal [16], and are often phase-locked to the negative phase of sharp waves in the pyramidal cell layer of the CA1 subfield of the hippocampus [7], [19]. It has been proposed that ripples may be triggered by population bursts of highly interconnected CA3 neurons that would induce excitatory postsynaptic potentials (EPSPs) on pyramidal cells and on interneurons located in CA1 [20]; the depolarization of CA1

Cellular mechanisms

Some evidence suggest that fast ripples would be generated by a small volume of brain tissue (less than 1 mm3) that comprise small clusters of hyperexcitable pyramidal cells [48], [49], [50]. However, since they may also be recorded with macroelectrodes, the generator could be as large as 1 cm3 [51]. In fact, fast ripples can also be recorded in epileptic patients with the use of scalp electrodes [52]. These results indicate that fast ripples could emerge from a large networks of hyperexcitable

High-frequency oscillations and anti-epileptic drugs

Only few studies have explored the relationship between AEDs and HFOs. The results obtained so far indicate that under the influence of AEDs, HFOs “behave” like seizures since a reduction in AEDs in epileptic patients induces an increase in HFO occurrence and duration [79], [80], [81]. In animal models of MTLE, few studies have so far investigated the effect of varying antiepileptic medication, but pilocarpine-treated animals that are treated with a continuous but long-term administration of

Issues in the definition of high-frequency oscillations

We are currently lacking a solid definition of HFOs due to the fact that we do not understand so far the precise mechanisms underlying ripples and fast ripples. We have no definitive evidence that pathological ripples between 80 and 200 Hz rely only on interneuronal synchronization and that fast ripples between 250 and 500 Hz only depend on the in phase or out-of-phase firing of principal cells. The difference between interictal and ictal HFOs is also unclear as well as the difference between

Concluding remarks

We have reviewed here the most recent findings on ripples and fast ripples recorded in vitro and in vivo, as well as in epileptic patients. Evidence obtained to date suggest that interictal fast ripples are better markers of epileptogenesis than ripples and interictal spikes. In addition, ictal HFOs, both ripples and fast ripples, may be indicative of the underlying mechanisms that sustain different patterns of seizure onset. Pathological HFOs are therefore promising biomarkers of ictogenesis

Conflicts of interest

None of the authors have any conflict of interest to disclose.

Acknowledgments

This review was supported by the Canadian Institutes of Health Research (grants 8109 and 74609). We are grateful to Drs. Charles Behr, Aleksandra Bortel, Margherita D’Antuono, Rochelle Herrington, Pariya Salami and Shabnam Hamidi for contributing to the original experiments reviewed in this paper.

References (79)

  • G. Foffani et al.

    Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus

    Neuron

    (2007)
  • E. van Diessen et al.

    Are high frequency oscillations associated with altered network topology in partial epilepsy?

    Neuroimage

    (2013)
  • P. Salami et al.

    Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy

    Neurobiol. Dis.

    (2014)
  • C. Behr et al.

    Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy

    Epilepsy Res.

    (2015)
  • F. Cendes et al.

    Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study

    Neurology

    (1993)
  • J.A. French et al.

    Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination

    Ann. Neurol.

    (1993)
  • S.S. Spencer et al.

    Entorhinal-hippocampal interactions in medial temporal lobe epilepsy

    Epilepsia

    (1994)
  • J. Engel et al.

    Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial

    J. Am. Med. Assoc.

    (2012)
  • A. Bragin et al.

    High-frequency oscillations in human brain

    Hippocampus

    (1999)
  • G. Buzsaki et al.

    High-frequency network oscillation in the hippocampus

    Science

    (1992)
  • R.J. Staba et al.

    Quantitative analysis of high-frequency oscillations (80–500 Hz) recorded in human epileptic hippocampus and entorhinal cortex

    J. Neurophysiol

    (2002)
  • E. Urrestarazu et al.

    Interictal high-frequency oscillations (100–500 Hz) in the intracerebral EEG of epileptic patients

    Brain

    (2007)
  • A. Kandel et al.

    Cellular-synaptic generation of sleep spindles spike-and-wave discharges, and evoked thalamocortical responses in the neocortex of the rat

    J. Neurosci. Off. J. Soc. Neurosci.

    (1997)
  • A. Bragin et al.

    Hippocampal and entorhinal cortex high-frequency oscillations (100–500 Hz) in human epileptic brain and in kainic acid?treated rats with chronic seizures

    Epilepsia

    (1999)
  • A. Bragin et al.

    High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis

    Epilepsia

    (2004)
  • J.D. Jirsch et al.

    High-frequency oscillations during human focal seizures

    Brain J. Neurol.

    (2006)
  • A. Bragin et al.

    Interictal high-frequency oscillations (80–500 Hz) in the human epileptic brain: entorhinal cortex

    Ann. Neurol.

    (2002)
  • A. Ylinen et al.

    Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms

    J. Neurosci. Off. J. Soc. Neurosci

    (1995)
  • J.J. Chrobak et al.

    High-frequency oscillations in the output networks of the Hippocampal–Entorhinal axis of the freely behaving rat

    J. Neurosci.

    (1996)
  • T. Klausberger et al.

    Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations

    Science

    (2008)
  • T. Klausberger et al.

    Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo

    Nat. Neurosci.

    (2004)
  • A. Draguhn et al.

    Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro

    Nature

    (1998)
  • F. Grenier et al.

    Focal synchronization of ripples (80–200 Hz) in neocortex and their neuronal correlates

    J. Neurophysiol.

    (2001)
  • J.G.R. Jefferys et al.

    Limbic network synchronization and temporal lobe epilepsy

  • M. D’Antuono et al.

    Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices

    J. Neurosci. Res.

    (2005)
  • D. Schlingloff et al.

    Mechanisms of sharp wave initiation and ripple generation

    J. Neurosci.

    (2014)
  • J. Jacobs et al.

    Interictal high-frequency oscillations (80–500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain

    Epilepsia

    (2008)
  • C. Haegelen et al.

    High-frequency oscillations, extent of surgical resection, and surgical outcome in drug-resistant focal epilepsy

    Epilepsia

    (2013)
  • B. Frauscher et al.

    Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves

    Brain

    (2015)

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      It has been highly desirable to correlate the electrophysiological findings, especially characteristics in the frequency domain, with behavioral seizures. Recent system electrophysiological studies on epileptic seizures tend to be focused more on the functional correlates of high frequency oscillations (>30 Hz; Bragin et al., 1999; Hughes, 2008; Jiruska et al., 2017; Lévesque et al., 2018) or even fast ripples (250–600 Hz; Dzhala and Staley, 2004; Tao et al., 2005; de la Prida et al., 2006; Engel Jr. et al., 2009; Gulyás and Freund, 2015). These high-frequency oscillations are very likely confounded by interference and superharmonics and thus disguised from the low-frequency intrinsic rhythms.

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      In in vitro preparations, HFOs are mainly associated to epileptiform activity and rarely occur alone (Panuccio et al., 2012; Hamidi et al., 2014). It has been proposed that ripples mirror summated Cl− dependent, inhibitory postsynaptic potentials mainly generated by the soma of pyramidal cells in response to GABA released from interneurons, suggesting that they mainly rest on GABAergic transmission, and specifically on GABAA receptor signaling (Jefferys et al., 2012; Jiruska et al., 2017; Lévesque et al., 2018). Fast ripples would instead mirror the uncontrolled “in-phase” or “out-of-phase” firing of principal cells due to a collapse of perisomatic inhibition (Jefferys et al., 2012; Jiruska et al., 2017; Lévesque et al., 2018).

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