Elsevier

Clinical Neurophysiology

Volume 128, Issue 9, September 2017, Pages 1673-1681
Clinical Neurophysiology

High frequency activity overriding cortico-cortical evoked potentials reflects altered excitability in the human epileptic focus

https://doi.org/10.1016/j.clinph.2017.06.249Get rights and content

Highlights

  • We analyzed high frequency activity (HFA) of cortico-cortical evoked potentials (CCEPs) in epilepsy.

  • The HFA power of early CCEPs in seizure onset zone (SOZ) increased more than that in non-SOZ.

  • HFA overriding CCEPs may be a surrogate marker of cortical excitability in human focal epilepsy.

Abstract

Objective

We aimed to clarify that high frequency activity (HFA) of cortico-cortical evoked potentials (CCEPs), elicited by single pulse electrical stimulation (SPES), reflects cortical excitability.

Methods

We recruited 16 patients with refractory partial epilepsy who had chronic subdural electrode implantation for presurgical evaluation. A repetitive SPES was given to (1) the seizure onset zone (SOZ) and (2) the control cortices (non-seizure onset zone: nSOZ). CCEPs were recorded from the neighboring cortices within SOZ and nSOZ. We applied short-time Fourier transform to obtain the induced responses for the timing of early (<50 ms after SPES) and late CCEP components and analyzed the logarithmic power change for ripple (<200 Hz) and fast ripple (>200 Hz) bands.

Results

Twenty-one clear CCEPs were recorded for both the SOZ and nSOZ. The HFA power of early CCEPs in SOZ significantly increased compared to that in nSOZ in both frequency bands, particularly in mesial temporal lobe epilepsy (MTLE).

Conclusion

Similar to the features of spontaneous pathological HFOs, the power of stimulus-induced HFAs in SOZ were greater than that outside SOZ, particularly in MTLE.

Significance

HFA overriding CCEPs can be a surrogate marker of cortical excitability in epileptic focus.

Introduction

The localization of the “epileptogenic zone” is a crucial factor in epilepsy surgery for patients with medically refractory partial epilepsy. While several non-invasive examinations, such as scalp electroencephalogram (EEG), magnetoencephalography, magnetic resonance imaging (MRI), F-18-fluorodeoxyglucose – Positron Emission Tomography (FDG-PET), and ictal single-photon emission computed tomography (SPECT), are useful to evaluate the epileptogenic zone, these results are occasionally insufficient (Lesser et al., 2010), requiring an additional intracranial EEG evaluation. In addition to conventional intracranial ictal EEG onset and interictal spike recordings, presumably epileptic high frequency oscillations (HFOs) have been recently recorded as possible surrogate markers of epileptogenesis even with macroelectrodes (Bragin et al., 1999, Urrestarazu et al., 2007, Zijlmans et al., 2009, Crepon et al., 2010, Jacobs et al., 2010). Epileptic HFOs are usually divided into ripple (R: 100–200 Hz) and fast ripple (FR: >250 Hz) by their frequencies. However, the analyses of spontaneous interictal HFOs are dependent on their occurrence and require technique expertise.

The measurement of cortical responses to single pulse electrical stimulation (SPES) is a straightforward way to evaluate epileptogenicity. We focused on the very early responses that are time-locked to the stimuli, specifically cortico-cortical evoked potentials (CCEPs), while others have focused on the late responses (e.g., delayed or repetitive responses) that are not time-locked and can occur with various delays (Valentin et al., 2002, Valentin et al., 2005a, Valentin et al., 2005b, Alarcon et al., 2012). The CCEPs are typically composed of an early and a late negative component, which we labeled N1 and N2, respectively. By utilizing CCEP as a dynamic index of cortical excitability, the modulation of cortical excitability especially around the epileptic focus has been investigated (Matsumoto et al., 2005, Iwasaki et al., 2010, Enatsu et al., 2012b). CCEPs, or the early cortical responses to 1 Hz SPES, have been extensively employed to evaluate the cortico-cortical networks associated with various brain functions (Matsumoto et al., 2004, Matsumoto et al., 2007, Matsumoto et al., 2011, Matsumoto et al., 2012, Greenlee et al., 2007, Lacruz et al., 2007, Conner et al., 2011, Swann et al., 2012, Terada et al., 2012, Matsuzaki et al., 2013, Entz et al., 2014), and seizure propagation (Enatsu et al., 2012a). Recently, we demonstrated that stimulus-induced high frequency activities (HFAs) on the CCEPs can be recorded in normal human cerebral cortices (Kobayashi et al., 2015, Usami et al., 2015). In the present study, we sought to clarify HFA overriding CCEPs and its involvement in human epileptogenesis. We hypothesized that HFA overriding CCEPs would be strongly associated with epileptogenicity. We compared the HFA overriding CCEPs in the seizure onset zone (SOZ) with that outside the SOZ.

Section snippets

Patients

We recruited 16 patients with medically intractable partial epilepsy who underwent chronic subdural electrode implantation for pre-surgical evaluation, including 8 patients of mesial temporal lobe epilepsy (MTLE), 7 of non-MTLE (nMTLE), and 1 of MTLE + nMTLE (dual pathology) (Table 1). In one patient who had dual pathology (Patient 9), two independent SOZs were located in the mesial temporal area and basal frontal area. Thus we cumulatively counted 17 SOZs across 16 patients. The SOZs were

Time-frequency profile of stimulus-induced HFAs

Twenty-one pairs of electrodes were stimulated at both the SOZ (11 in MTLE and 10 in nMTLE) and nSOZ (12 in MTLE and 9 in nMTLE) regions. All stimulations generated reproducible and large CCEP responses at the surrounding electrodes. Clinical seizures were not induced by SPES in all patients. After discharges were induced only once during the SOZ stimulation (Patient 7). However, a subsequent examination could be performed successfully without ADs at the same intensity in this patient. SPES

Discussion

The present study provided new insight into the HFOs and HFAs in focal epilepsy by means of analysis of CCEP and its HFA correlates. The main findings were (1) HFAN1 and HFAN2 behaved differently, such that HFAN1 had a power increase and HFAN2 had a power decrease in both ripple and fast ripple bands compared to baseline activity, irrespective of the stimulation sites (SOZ and nSOZ); (2) HFAN1 power in the SOZ was significantly increased compared to the nSOZ in both bands, particularly in the

Conclusion

Altogether, HFA overriding CCEP, especially N1, may be a dynamic surrogate marker of cortical excitability for the detection of the SOZ more safely and efficiently. Further case accumulation is warranted to investigate the HFA features among different pathologies, and to develop this method to improve and define its sensitivity and specificity. Thorough analyses of stimulus-induced early HFAs, such as stimulating all possible stimulus sites as in the SPES-induced early and delayed HFAs (van't

Conflict of interest

Department of Epilepsy, Movement Disorders and Physiology is an endowment department, supported with a grant from GlaxoSmithKline K.K., NIHON KOHDEN CORPORATION, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd.

Funding

This work was partly supported by JSPS KAKENHI [Grant Nos. 26560465, 26282218, 26293209, 17H05907, 15H05874 (Non-linear Neuro-oscillology)], and the Research Grant from the Japan Epilepsy Research Foundation.

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