Dataset Information

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures.

ABSTRACT: High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.

SUBMITTER: Smith EH

PROVIDER: S-EPMC7645614 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures.

Smith Elliot H EH Merricks Edward M EM Liou Jyun-You JY Casadei Camilla C Melloni Lucia L Thesen Thomas T Friedman Daniel J DJ Doyle Werner K WK Emerson Ronald G RG Goodman Robert R RR McKhann Guy M GM Sheth Sameer A SA Rolston John D JD Schevon Catherine A CA

Scientific reports 20201105 1

High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequenc ...[more]

PMID: 33154490

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Project description:Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this problem, we slightly modified previous methods and show robust seizures are common and frequent in both male and female mice. We employed continuous wideband video-EEG monitoring from 4 recording sites to best demonstrate the seizures. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 s) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE. SIGNIFICANCE: Although the IHKA model has been widely used in mice for epilepsy research, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent convulsive seizures that are robust, meaning they are >10 s and associated with complex high frequency rhythmic activity recorded from 2 hippocampal and 2 cortical sites. Seizure onset patterns usually matched the low-voltage fast and hypersynchronous seizures in TLE. Importantly, there is low mortality, and both sexes can be used. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression, and other topics of broad interest to the epilepsy research community. Finally, the results have implications for preclinical drug screening because seizure frequency increased in approximately half of the mice after a 6 wk interval, suggesting that the typical 2 wk period for monitoring seizure frequency is insufficient.

Project description:High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.

Project description:PurposeTo investigate the characteristics of intracranial ictal high-frequency oscillations (HFOs).MethodsAmong neocortical epilepsy patients who underwent intracranial monitoring and surgery, we studied patients with well-defined, unifocal seizure onsets characterized by discrete HFOs (≥70 Hz). Patients with multifocal or bilateral independent seizure onsets, electroencephalography (EEG) acquired at <1,000 Hz sampling rate, and nonresective surgery were excluded. Based on a prospectively defined protocol, we defined the seizure-onset zone (SOZ) presurgically to include only those channels with HFOs that showed subsequent sustained evolution (HFOs+ channels) but not the channels that lacked evolution (HFOs- channels). We then resected the SOZ as defined above, 1 cm of the surrounding cortex, and immediate spread area, modified by the presence of eloquent cortex in the vicinity. For purposes of this study, we also defined the SOZ based on the conventional frequency activity (CFA, <70 Hz) at seizure onset, although that information was not considered for preoperative determination of the surgical boundary. We investigated the temporal and spatial characteristics of the ictal HFOs post hoc by visual and spectral methods, and also compared them to the seizure onset defined by the CFA.Key findingsOf 14 consecutive neocortical epilepsy patients, six patients met the inclusion criteria. Magnetic resonance imaging (MRI) was normal or showed heterotopia. All had subdural electrodes, with additional intracerebral depth electrodes in some. Electrode coverage was extensive (median 94 channels), including limited contralateral coverage. Seizure onsets were lobar or multilobar. Resections were performed per protocol, except in two patients where complete resection of the SOZ could not be done due to overlap with speech area. Histology was abnormal in all patients. Postoperative outcome was class I/II (n = 5, 83%) or class III over a mean follow-up of 27 months. Post hoc analysis of 15 representative seizures showed that the ictal HFOs were widespread at seizure onset but evolved subsequently with different characteristics. In contrast to HFOs-, the HFOs+ were significantly higher in peak frequency (97.1 vs. 89.1 Hz, p = 0.001), more robust (nearly twofold higher peak power, p < 0.0001), and spatially restricted [mean 12.2 vs. 22.4 channels; odds ratio (OR) 0.51, 95% confidence interval (CI) 0.42-0.62; p < 0.0001]. The seizure onset defined by HFOs+ was earlier (by an average of 0.41 s), and occurred in a significantly different and smaller distribution (OR 0.27, 95% CI 0.21-0.34, p < 0.0001), than the seizure onset defined by the CFA. As intended, the HFOs+ channels were 10 times more likely to have been resected than the HFOs- channels (OR 9.7, 95% CI 5-17, p < 0.0001).SignificanceOur study demonstrates the widespread occurrence of ictal HFOs at seizure onset, outlines a practical method to localize the SOZ based on their restricted pattern of evolution, and highlights the differences between the SOZs defined by HFOs and CFA. We show that smaller resections, restricted mainly to the HFOs channels with evolution, can lead to favorable seizure outcome. Our findings support the notion of widespread epileptic networks underlying neocortical epilepsy.

Dataset Information

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures.

Publications

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures.

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