Elsevier

Experimental Neurology

Volume 251, January 2014, Pages 30-38
Experimental Neurology

Dynamic modulation of epileptic high frequency oscillations by the phase of slower cortical rhythms

https://doi.org/10.1016/j.expneurol.2013.10.019Get rights and content

Highlights

  • Pathological high frequency oscillations are modulated by the phase of slower cortical rhythms in epileptic cortex.

  • Cross-frequency coupling occurs at a consistent oscillatory phase at seizure termination.

  • Cross-frequency coupling may be a marker of epileptogenicity and useful as a target for future interventions.

  • These findings are relevant for understanding oscillatory dynamics underlying seizures.

Abstract

Pathological high frequency oscillations (pHFOs) have been proposed to be robust markers of epileptic cortex. Oscillatory activity below this frequency range has been shown to be modulated by phase of lower frequency oscillations. Here, we tested the hypothesis that dynamic cross-frequency interactions involving pHFOs are concentrated within the epileptogenic cortex. Intracranial electroencephalographic recordings from 17 children with medically-intractable epilepsy secondary to focal cortical dysplasia were obtained. A time-resolved analysis was performed to determine topographic concentrations and dynamic changes in cross-frequency amplitude-to-phase coupling (CFC). CFC between pHFOs and the phase of theta and alpha rhythms was found to be significantly elevated in the seizure-onset zone compared to non-epileptic regions (p < 0.01). Data simulations showed that elevated CFC could not be attributed to the presence of sharp transients or other signal properties. The phase of low frequency oscillations at which pHFO amplitudes were maximal was inconsistent at seizure initiation, yet consistently at the trough of the low frequency rhythm at seizure termination. Amplitudes of pHFOs were most significantly modulated by the phase of alpha-band oscillations (p < 0.01). These results suggest that increased CFC between pHFO amplitude and alpha phase may constitute a marker of epileptogenic brain areas and may be relevant for understanding seizure dynamics.

Introduction

The human brain is intrinsically organized into dynamic cell assemblies supported by synchronous neuronal oscillations at various frequencies (Buzsaki, 2010). This oscillatory activity is thought to result in rhythmic fluctuations in neuronal excitability, creating temporal windows for inter-regional communication (Fries, 2005). Frequency-specific oscillations may subserve perceptual binding (Fries, 2005), synaptic plasticity (Buzsaki and Draguhn, 2004), and the coordination of distinct brain regions (Lachaux et al., 2005). Low-frequency rhythms modulate activity over large spatial regions and across long temporal windows, whereas high frequencies are restricted to small regions and short temporal windows (Canolty and Knight, 2010, von Stein and Sarnthein, 2000). Interactions among neural oscillations at different frequency bands have accordingly been proposed to regulate neural processing occurring across multiple spatiotemporal scales (Canolty and Knight, 2010, Lakatos et al., 2005).

The regulation of neural activity and inter-regional communication through cross-frequency coupling (CFC) has been the subject of considerable recent interest. Slow rhythms have been shown to co-exist with fast, transient oscillations (Buzsaki and Draguhn, 2004) and the phase of low frequency theta rhythms has been reported to modulate the power of high gamma activity (80–150 Hz) (Canolty et al., 2006). CFC may also generalize to interactions among oscillations in other frequency bands (Lakatos et al., 2005, Palva et al., 2005). Two principal forms of cross-frequency interactions have been proposed: (a) amplitude-independent phase synchrony; and (b) nested oscillations reflecting the locking of high frequency amplitude to lower frequency oscillations (Vanhatalo et al., 2004). Less characterized amplitude–amplitude interactions have also been reported (Shirvalkar et al., 2010). CFC has been implicated in a variety of cognitive functions, (Sederberg et al., 2003) suggesting that it represents a physiological process regulating cortical processing.

Epilepsy is a disorder of neuronal synchrony within specific networks, resulting in recurrent, unprovoked seizures. One increasingly recognized feature of epileptic cortex is its tendency to express excessive pathological high frequency oscillations (pHFOs; pathological ripple frequencies: 80–150 Hz; pathological fast-ripple frequencies > 200 Hz) (Akiyama et al., 2011, Jacobs et al., 2010, Ochi et al., 2007). Epileptic pHFOs are thought to occur through different mechanisms than their physiological counterparts, which are discrete oscillations at less than 100 ms generated by perisomatic inhibitory interneuron activity (Mann et al., 2005). PHFOs may represent out-of-phase firing of neural assemblies in the absence of physiologically-relevant inhibitory and/or regulatory mechanisms (see Jefferys and colleagues for review (Jefferys et al., 2012)). Resection of cortical areas expressing pHFOs has been associated with improved seizure outcomes (Akiyama et al., 2011, Jacobs et al., 2010, Ochi et al., 2007). Recent studies have also suggested that the epileptic cortex may also demonstrate atypical cross-frequency interactions (Alvarado-Rojas et al., 2011, Cotic et al., 2011, Vanhatalo et al., 2004) and that these cross-frequency interactions may themselves predict seizure onset (Alvarado-Rojas et al., 2011) and occur in regions demonstrating high inter-regional epileptic network connectivity (Cotic et al., 2011). The phase of low frequency signals reflects fluctuations in neuronal excitability (Canolty and Knight, 2010), and has also been shown to modulate the occurrence of interictal epileptic activity during sleep (Vanhatalo et al., 2004).

It remains unclear, however, whether CFC during seizures is concentrated in the epileptogenic zone, or whether ictal CFC dynamics are related to progression of seizures or pHFOs. Furthermore, the clinical utility of CFC in the localization of epileptogenic cortex for pre-surgical planning has not been determined. Using electrocorticographic (ECoG) collected from 17 children with focal medically-refractory epilepsy secondary to focal cortical dysplasia (FCD), we first tested the hypothesis that excessive CFC involving pHFOs is concentrated within the epileptogenic cortex. Second, we evaluate whether these topographically specific increases in CFC were strongest during seizures and investigated the frequencies at which ictal CFC within epileptogenic brain areas was most reliable. Data simulations were performed to evaluate whether observed CFC increases were attributable to true phase–amplitude coupling or other signal characteristics. Finally, we also tested the hypothesis that reliable cross-frequency phase–amplitude relationships would vary with seizure progression to study the role of CFC in ictal dynamics.

Section snippets

Subjects

Analysis was performed on data obtained from seventeen consecutive children with medically-intractable localization-related epilepsy secondary to FCD undergoing pre-surgical invasive monitoring as well as simulated signals (Supplementary Fig. S1). The subjects included 9 males and 8 females with a mean age of 9.9 years (range 5–16 years) and a mean epilepsy duration of 4.8 years (range 1–11 years). A comprehensive description of the subjects' clinical demographics and epilepsy syndromes is

Ictal modulation of pHFOs by the phase of slow oscillations during seizures is concentrated in the epileptogenic cortex

Within the seizure onset zone, it was found that theta and alpha frequency (~ 6–14 Hz) phase modulated broad band activity encompassing the pathological ripple and fast-ripple frequencies (Fig. 2; p < 0.05, Bonferroni corrected). Electrodes that were resected, but were not the site of seizure origin (i.e. the early propagation zone) also demonstrated considerable CFC between the same frequency bands; however these values did not reach the threshold for statistical significance following Bonferroni

Discussion

The current study provides the first evidence that the ictal CFC involving pHFOs is significantly elevated in SOZ relative to the non-resected cortex. Data simulations indicate that these observations are not attributable to other signal characteristics such as increased pHFO amplitude or sharp transients. We also demonstrate that the relationship between high frequency amplitude and low frequency phase becomes markedly consistent at seizure termination, implicating cross-frequency interactions

Conclusions

The current study provides evidence for cross-frequency phase-amplitude coupling in the regulation of epileptic pHFOs. We also uniquely demonstrate that the SOZ is a site of significant ictal cross-frequency coupling, a finding which may be useful in presurgical planning. We present the first characterization of dynamic changes in coupling between high and low frequency bands as seizures progress and terminate, which is associated with the occurrence of maximal pHFO amplitude at the trough of

Acknowledgments

This research was supported by the Canadian Institutes of Health Research (CIHR) Vanier Canada Graduate Scholarship, the CIHR Bisby Fellowship, The Hospital for Sick Children Foundation Student Scholarship Program, The Hospital for Sick Children Centre for Brain and Behaviour, the EpLink program of the Ontario Brain Institute, the Wiley Family and Jack Beqaj Funds for Epilepsy Surgery Research, the University of Toronto Surgeon-Scientist Program, and the Royal College of Physicians and Surgeons

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