Elsevier

Progress in Neurobiology

Volume 98, Issue 3, September 2012, Pages 250-264
Progress in Neurobiology

Mechanisms of physiological and epileptic HFO generation

https://doi.org/10.1016/j.pneurobio.2012.02.005Get rights and content

Abstract

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs.

Highlights

High Frequency Oscillations (HFOs) are brain activities faster than 30 Hz; within this wide frequency range the band between 30 and 100 Hz is generally termed gamma. Best practice is to make the frequency range of HFOs explicit in every study. ► HFOs of the same frequency are not necessarily the same biological activity. ► Oscillators can be in single neurons and in networks for neurons, or both combined. ► HFOs: physiological or pathological, depending on location, frequency and behavioural and clinical context. ► Hippocampal fast ripples (>250 Hz) are a biomarker for epileptogenic tissue.

Introduction

High frequency oscillations (HFOs) constitute a novel trend in neurophysiology that is fascinating neuroscientists in general, and epileptologists in particular. But what are HFOs? What is the frequency range of HFOs? Are there different types of HFOs, physiological and pathological? How are HFOs generated? Can HFOs represent temporal codes for cognitive processes? These questions are pressing, to which this review paper attempts to give constructive answers. In these introductory remarks we will consider the most basic question: what are HFOs and how should these be designated? To deal with this question it is useful to consider briefly how neurophysiologists have characterized neuronal oscillations in general, as reflected in local field potentials and therefore in EEG and MEG signals.

Since the early days of human neurophysiology scientists have been fascinated by the variety of oscillations that may be recorded from the scalp and directly from within the brain. Empirically a classification of these oscillations in a series of frequency bands emerged, which were designated by Greek letters (δ, θ, α/μ, β, γ) a classification that was supported by multivariate statistical analysis of EEG spectral values in the seventies (Lopes da Silva, 2011). Nonetheless the limits of the EEG frequency bands are fuzzy. Ultra-slow (near-DC) oscillations (Aladjalova, 1957, Vanhatalo et al., 2004) and ultra-fast frequency components have also been described. Here we concentrate primarily on the fast frequency components.

In the early descriptions of EEG the issue of frequency components higher than about 30 Hz was an unchartered continent. Two main factors changed this picture in the last three decades: (i) the rise of broad-band digital EEG, which made possible recording of signals beyond the traditional low-pass filtered EEG at 70 Hz, extended the recordings to frequencies as high as 500 Hz and beyond; (ii) novel findings in animal neurophysiology showing the existence of oscillations at frequencies in the γ band range of 38–100 Hz in several cortical and sub-cortical brain areas (for early literature on this subject see Bressler and Freeman (1980)). Currently, while there is some disagreement on whether the term HFO includes the γ frequency range, perhaps the most general usage is γ for frequency components between 30 and 100 Hz, and HFOs for frequencies beyond 100 Hz. However, we will review some aspects of γ oscillations, partly because they shed some light on HFO mechanisms, and partly because there can be overlap between γ and “ripples”, a transient hippocampal HFO in the 100 Hz to 200–250 Hz band. Functionally γ and ripples can coexist under physiological conditions and share mechanisms (Sullivan et al., 2011), or can be linked under the term fast γ (90–150 Hz, with slow γ at 30–50 Hz and mid γ 50–90 Hz) (Belluscio et al., 2012), while other authors call oscillations from ∼60 to 200–250 Hz “high γ” (Crone et al., 2006, Edwards et al., 2005).

Among physiological HFOs a number of specific phenomena attracted particular attention: γ oscillations around 40 Hz in the visual cortex associated with visual perception (reviewed in Singer and Gray (1995)), and in the sensorimotor cortex related to motor activity (Murthy and Fetz, 1996). The former were proposed to form the mechanism by which various features of a visual scene may be bound together into a percept—the “binding hypothesis”. Beyond this observation, it was also shown that γ oscillations may operate as a general mechanism that is capable of binding together, by a process of phase synchronization, not only the firing of neurons at the local level, but also neural activities of spatially separate cortical areas (Roelfsema et al., 1997). Furthermore, the discovery of hippocampal ripples during behavioral immobility, consummatory behaviors and slow-wave sleep (Buzsáki et al., 1992), kindled the interest for understanding the functional significance of HFOs in the process of memory consolidation. The subsequent finding that similar short transient oscillations, named “fast ripples”, can be observed in the local field potential recorded from the hippocampus and the temporal cortex of epileptic humans and rodents (Bragin et al., 1999b) stimulated the interest for these oscillatory phenomena as possible biomarkers of epileptogenic neural networks. These high frequency components recorded in local field potentials (LFPs), electrocorticograms (ECoG) and EEG/MEG signals received, collectively, the designation of HFOs.

We should note, however, that these terms are purely descriptive and do not have a precise definition. The term HFO can mean phenomena with a variety of characteristics: HFOs may be band-limited or broad-band, transient (burst-like) phenomenon or steady-state, event-related or not. Furthermore, HFOs may be encountered under physiological or under pathological conditions; for the latter the symbol pHFO has been used. This, however, is a secondary characterization that depends on the demonstration that this kind of HFO is significantly associated with a pathological brain condition such as epileptogenicity. One proposal distinguishes these pHFOs from physiological kinds of HFOs according to frequency content (“fast ripples” vs “ripples”) (Bragin et al., 1999b), and is currently a matter of intense experimental scrutiny.

In order to promote clarity regarding the phenomenon under consideration it may be useful to take into consideration the following items in characterizing HFOs: (i) frequency range of the HFOs indicated between brackets, similarly to what is used in protein biochemistry to indicate a sequence of constitutive amino-acids: for example, HFO (80–150 Hz); (ii) whether the HFOs are phase-locked to a stimulus or event-related but not phase-locked to the precise timing of the event; (iii) whether HFOs are a transient (burst-like) or continuous (steady-state) phenomenon; (iv) location within the brain.

A better understanding of the significance of HFOs depends on a deeper analysis of the mechanisms of generation of different kinds of HFOs that typically are at the crossroads between intrinsic membrane properties and synaptic interactions. The complexity of these processes makes the development of relevant computational models most compelling.

In this overview we primarily consider cortical (including hippocampal) oscillations under normal and epileptic conditions, but we should note that subcortical HFOs exist, for instance in the basal ganglia where they are faster (∼300 Hz) in Parkinson's Disease patients than in patients with other conditions (∼200 Hz) (Danish et al., 2007, Foffani et al., 2003). We will first address general mechanisms of oscillations, at the level of cells and networks, and an account of experimental in vitro and in vivo models being used to investigate HFOs; this is followed by a section where the focus lies on the role of HFOs in experimental and clinical epilepsy and the underlying mechanisms; in the final part the contribution of computational modeling is reviewed.

Section snippets

Cells and networks for oscillations

The fundamental idea that brain activity is associated with oscillations has a long history, back to the α and β oscillations of Berger (1929) and perhaps the earliest account of HFOs by Adrian (1935). A key question is whether oscillations depend on the intrinsic properties of individual neurons or on the collective properties of networks of neurons.

Preparations and physiological oscillations

Experimental models are essential to investigating basic neuronal mechanisms in the brain, certainly at the cellular and local network levels, which are our primary concerns here. Models need to be accessible to the measurements and experimental interventions needed to unravel those mechanisms, here mainly microelectrode and other invasive recordings, while embodying key aspects of the phenomena to be studied. In vitro methods, particularly brain slices, have played a crucial role in

Evidence for HFOs in experimental and clinical epilepsy

Pathological HFOs were first described in the intrahippocampal KA model of chronic epilepsy (Bragin et al., 1999b). These oscillations, in the frequency band 250–500 Hz, were observed in the dentate gyrus and they were considered as pathological because in the dentate gyrus of normal rats the maximum frequency of recorded electrical activity was up to 100 Hz (Bragin et al., 1995, Bragin et al., 2004, Buzsáki, 1986). These fast ripples or pHFOs provided a marker for epileptogenesis because they

Cellular sources of local EEG activity

In order to understand the mechanisms underlying the generation of pathological HFOs one has to deal with a challenge task to dissect and interpret the signals contributing to the local field potentials. While in the normal brain the slower synaptic currents are the major components of the local EEG (Nunez and Srinivasan, 2006), several lines of evidence suggest basic differences between normal and epileptic brain, e.g. (Bragin et al., 1999b, Grenier et al., 2003b, Grenier et al., 2001) and

The need for integrative approaches

As described in Section 5, a number of hypotheses were formulated regarding the mechanisms responsible for the generation of high frequencies oscillations that may exceed maximal neuronal firing rates. Among the mechanisms proposed we may note alterations in the timing of action potentials (APs) generated in neighbouring pyramidal cells (Foffani et al., 2007), enhanced recurrent excitatory synaptic transmission (Dzhala and Staley, 2004, Staley, 2007), unreliable firing of epileptic neurons in

Conclusions

There are several kinds of gamma oscillations and HFOs, which can be distinguished on their dynamics (e.g. ripples, fast ripples, or steady-state rhythmic activity), spatial extent and distributions (e.g. recorded with micro or macroelectrodes, located in cortical or sub-cortical regions), neurocognitive correlates (sensory processing, motor programming, memory). In addition to occurring in the normal brain, certain types of HFOs are associated with pathological excitability states,

References (238)

  • B.W. Colder et al.

    Interspike intervals during interictal periods in human temporal lobe epilepsy

    Brain Res.

    (1996)
  • N.E. Crone et al.

    High-frequency gamma oscillations and human brain mapping with electrocorticography

    Event-related Dynam. Brain Oscill.

    (2006)
  • G. Curia et al.

    The pilocarpine model of temporal lobe epilepsy

    J. Neurosci. Methods

    (2008)
  • S.F. Danish et al.

    High-frequency oscillations (> 200 Hz) in the human non-parkinsonian subthalamic nucleus

    Brain Res. Bull.

    (2007)
  • M. Deschenes et al.

    Thalamic bursting mechanism - an inward slow current revealed by membrane hyperpolarization

    Brain Res.

    (1982)
  • R. Dingledine et al.

    Penicillin blocks hippocampal IPSPs unmasking prolonged EPSPs

    Brain Res.

    (1979)
  • F.E. Dudek et al.

    Kainate-induced status epilepticus: a chronic model of acquired epilepsy

  • G. Foffani et al.

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

    Neuron

    (2007)
  • F. Frohlich et al.

    Endogenous electric fields may guide neocortical network activity

    Neuron

    (2010)
  • Y. Fujiwara-Tsukamoto et al.

    Excitatory GABA input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells

    Neuroscience

    (2003)
  • F. Grenier et al.

    Spontaneous field potentials influence the activity of neocortical neurons during paroxysmal activities in vivo

    Neuroscience

    (2003)
  • J.R. Huguenard et al.

    Thalamic synchrony and dynamic regulation of global forebrain oscillations

    Trends Neurosci.

    (2007)
  • B. Hutcheon et al.

    Resonance, oscillation and the intrinsic frequency preferences of neurons

    Trends Neurosci.

    (2000)
  • E.D. Adrian

    Discharge frequencies in the cerebral and cerebellar cortex

    J. Physiol. Lond.

    (1935)
  • N.A. Aladjalova

    Infra-slow rhythmic oscillations of the steady potential of the cerebral cortex

    Nature

    (1957)
  • B.E. Alger et al.

    GABA-mediated biphasic inhibitory responses in hippocampus

    Nature

    (1979)
  • F. Amzica et al.

    Spatial buffering during slow and paroxysmal sleep oscillations in cortical networks of glial cells in vivo

    J. Neurosci.

    (2002)
  • P. Andersen et al.

    Unit analysis of hippocampal polulation spikes

    Exp. Brain Res.

    (1971)
  • P. Andersen et al.

    The role of inhibition in the phasing of spontaneous thalamocortical discharge

    J. Physiol.

    (1964)
  • P. Andersen et al.

    Ventro-basal complex of thalamus—types of cells their responses and their functional organization

    J. Physiol. Lond.

    (1964)
  • M. Avoli et al.

    Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro

    J. Neurosci.

    (1996)
  • A.P. Bagshaw et al.

    Effect of sleep stage on interictal high-frequency oscillations recorded from depth macroelectrodes in patients with focal epilepsy

    Epilepsia

    (2009)
  • M. Bartos et al.

    Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

    Nat. Rev. Neurosci.

    (2007)
  • C.J. Behrens et al.

    Effects of the GABAA receptor antagonists bicuculline and gabazine on stimulus-induced sharp wave-ripple complexes in adult rat hippocampus in vitro

    Eur. J. Neurosci.

    (2007)
  • M. Beierlein et al.

    A network of electrically coupled interneurons drives synchronized inhibition in neocortex

    Nat. Neurosci.

    (2000)
  • M.A. Belluscio et al.

    Cross-frequency phase-phase coupling between theta and gamma oscillations in the hippocampus

    J. Neurosci.

    (2012)
  • Y. Ben-Ari

    Fast ripples: what do new data about gap junctions and disrupted spike firing reveal about underlying mechanisms?

    Epilepsy Curr.

    (2009)
  • H. Berger

    Über das elektroenkephalogramm des menschen

    Arch. Psychiat.

    (1929)
  • M. Bikson et al.

    Neuronal aggregate formation underlies spatiotemporal dynamics of nonsynaptic seizure initiation

    J. Neurophysiol.

    (2003)
  • M. Bikson et al.

    Depolarization block of neurons during maintenance of electrographic seizures

    J. Neurophysiol.

    (2003)
  • J.A. Blanco et al.

    Unsupervised classification of high-frequency oscillations in human neocortical epilepsy and control patients

    J. Neurophysiol.

    (2010)
  • S. Boucetta et al.

    Focal generation of paroxysmal fast runs during electrographic seizures

    Epilepsia

    (2008)
  • E. Bracci et al.

    On the synchronising mechanisms of tetanically induced hippocampal oscillations

    J. Neurosci.

    (1999)
  • H.M. Brace et al.

    Long-term changes in hippocampal physiology and in learning ability of rats after intrahippocampal tetanus toxin

    J. Physiol.

    (1985)
  • A. Bragin et al.

    Further evidence that pathologic high-frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus

    Epilepsia

    (2011)
  • A. Bragin et al.

    High-frequency oscillations in human brain

    Hippocampus

    (1999)
  • 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.

    Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection

    Epilepsia

    (1999)
  • A. Bragin et al.

    Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat

    J. Neurosci.

    (1995)
  • A. Bragin et al.

    Local generation of fast ripples in epileptic brain

    J. Neurosci.

    (2002)
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