High frequency activity overriding cortico-cortical evoked potentials reflects altered excitability in the human 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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2023, Clinical NeurophysiologyCitation Excerpt :For example, how do the responses within a mesial temporal SOZ compare to those within a SOZ in cortical regions? There may be expected variation since the effect of epileptogenicity on evoked responses to SPES has been shown to be greater in mesial temporal structures (Kobayashi et al., 2017; Guo et al., 2020; Hays et al., 2021a). The anatomical locations of SOZ for the patients included in this study did vary and did include those with mesial temporal lobe epilepsy.
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2021, Clinical NeurophysiologyCitation Excerpt :For instance, Alarcón et al. reported that SPES induced excitation immediately after stimuli and that this was occasionally followed by inhibition (Alarcón et al., 2012). By evaluating the CCEPs and their counterparts in high-frequency activities in the areas adjacent to the stimulus sites, as well as in remotely connected areas, we recently showed the pathological and physiological changes of high gamma power induced by SPESs (Usami et al., 2015; Kobayashi et al., 2017). These dynamic transitions of cortical excitability induced by SPES may partly influence the ADs and stimulus-induced clinical seizures, resulting in differences in their occurrence rates between SOZ and non-SOZ stimulation, as seen in the present study.
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2020, Clinical NeurophysiologyCitation Excerpt :Therefore, these seizure onset zones could be regarded as components of a seizure-onset network. We evaluated ictal HFOs by time–frequency analysis using a short-time Fourier transform (STFT) (Imamura et al., 2011; Kanazawa et al., 2015; Kobayashi et al., 2017). We analyzed the first ES from each of the six clusters, since the distribution of HFOs became widely distributed as the ES repeated.
Electrical cortical stimulations modulate spike and post-spike slow-related high-frequency activities in human epileptic foci
2020, Clinical NeurophysiologyCitation Excerpt :We used IIR (Butterworth) filter, as well as zero phase shift by applying 1st order filter bidirectionally, to obtain each range of activities. The time–frequency analyses for the IEDs were performed using the short-time Fourier transform, as previously reported (Kobayashi et al., 2017), and showed a dramatic decrease in the low gamma band power during PSS. Therefore, we also assessed the power of PSS-related low gamma activities in the ascending phase of PSS after the spike component and calculated the power of low gamma activities during 100 ms of the PSS ascending phase from its onset (Fig. 3C).