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Fast ripples reflect increased excitability that primes epileptiform spikes.

ABSTRACT: The neuronal circuit disturbances that drive interictal and ictal epileptiform discharges remains elusive. Using a combination of extraoperative macro- and micro-electrode interictal recordings in six presurgical patients during non-rapid eye movement (REM) sleep we found that, exclusively in the seizure onset zone, fast ripples (FR; 200-600Hz), but not ripples (80-200 Hz), frequently occur <300 msec before an interictal intracranial EEG (iEEG) spike with a probability exceeding chance (bootstrapping, p<1e-5). Such FR events are associated with higher spectral power (p<1e-10) and correlated with more vigorous neuronal firing than solitary FR (generalized linear mixed-effects model, GLMM, p<1e-3) irrespective of FR power. During the iEEG spike that follows a FR, action potential firing is lower than during a iEEG spike alone (GLMM, p<1e-10), reflecting an inhibitory restraint of iEEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike FR in a separate cohort of 23 patients implanted with stereo EEG electrodes who underwent resections. In non-REM sleep recordings, sites containing a high proportion of FR preceding iEEG spikes correlate with brain areas where seizures begin more than solitary FR (p<1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that FR preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating interictal epileptiform discharges.

SUBMITTER: Weiss SA

PROVIDER: S-EPMC10081394 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Fast ripples reflect increased excitability that primes epileptiform spikes.

Weiss Shennan A SA Fried Itzhak I Engel Jerome J Sperling Michael R MR Wong Robert K S RKS Nir Yuval Y Staba Richard J RJ

medRxiv : the preprint server for health sciences 20230419

The neuronal circuit disturbances that drive interictal and ictal epileptiform discharges remains elusive. Using a combination of extraoperative macro- and micro-electrode interictal recordings in six presurgical patients during non-rapid eye movement (REM) sleep we found that, exclusively in the seizure onset zone, fast ripples (FR; 200-600Hz), but not ripples (80-200 Hz), frequently occur <300 msec before an interictal intracranial EEG (iEEG) spike with a probability exceeding chance (bootstra ...[more]

PMID: 37034609

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Project description:The epileptic network hypothesis and epileptogenic zone hypothesis are two theories of ictogenesis. The network hypothesis posits that coordinated activity among interconnected nodes produces seizures. The epileptogenic zone hypothesis posits that distinct regions are necessary and sufficient for seizure generation. High-frequency oscillations, and particularly fast ripples, are thought to be biomarkers of the epileptogenic zone. We sought to test these theories by comparing high-frequency oscillation rates and networks in surgical responders and non-responders, with no appreciable change in seizure frequency or severity, within a retrospective cohort of 48 patients implanted with stereo-EEG electrodes. We recorded inter-ictal activity during non-rapid eye movement sleep and semi-automatically detected and quantified high-frequency oscillations. Each electrode contact was localized in normalized coordinates. We found that the accuracy of seizure onset zone electrode contact classification using high-frequency oscillation rates was not significantly different in surgical responders and non-responders, suggesting that in non-responders the epileptogenic zone partially encompassed the seizure onset zone(s) (P > 0.05). We also found that in the responders, fast ripple on oscillations exhibited a higher spectral content in the seizure onset zone compared with the non-seizure onset zone (P < 1 × 10-5). By contrast, in the non-responders, fast ripple had a lower spectral content in the seizure onset zone (P < 1 × 10-5). We constructed two different networks of fast ripple with a spectral content >350 Hz. The first was a rate-distance network that multiplied the Euclidian distance between fast ripple-generating contacts by the average rate of fast ripple in the two contacts. The radius of the rate-distance network, which excluded seizure onset zone nodes, discriminated non-responders, including patients not offered resection or responsive neurostimulation due to diffuse multifocal onsets, with an accuracy of 0.77 [95% confidence interval (CI) 0.56-0.98]. The second fast ripple network was constructed using the mutual information between the timing of the events to measure functional connectivity. For most non-responders, this network had a longer characteristic path length, lower mean local efficiency in the non-seizure onset zone, and a higher nodal strength among non-seizure onset zone nodes relative to seizure onset zone nodes. The graphical theoretical measures from the rate-distance and mutual information networks of 22 non- responsive neurostimulation treated patients was used to train a support vector machine, which when tested on 13 distinct patients classified non-responders with an accuracy of 0.92 (95% CI 0.75-1). These results indicate patients who do not respond to surgery or those not selected for resection or responsive neurostimulation can be explained by the epileptic network hypothesis that is a decentralized network consisting of widely distributed, hyperexcitable fast ripple-generating nodes.

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Fast ripples reflect increased excitability that primes epileptiform spikes.

Publications

Fast ripples reflect increased excitability that primes epileptiform spikes.

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