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1.  The spatial and signal characteristics of physiologic high frequency oscillations 
Epilepsia  2014;55(12):1986-1995.
Summary
Objectives
To study the incidence, spatial distribution, and signal characteristics of high frequency oscillations (HFOs) outside the epileptic network.
Methods
We included patients who underwent invasive evaluations at Yale Comprehensive Epilepsy Center from 2012 to 2013, had all major lobes sampled, and had localizable seizure onsets. Segments of non–rapid eye movement (NREM) sleep prior to the first seizure were analyzed. We implemented a semiautomated process to analyze oscillations with peak frequencies >80 Hz (ripples 80–250 Hz; fast ripples 250–500 Hz). A contact location was considered epileptic if it exhibited epileptiform discharges during the intracranial evaluation or was involved ictally within 5 s of seizure onset; otherwise it was considered nonepileptic.
Results
We analyzed recordings from 1,209 electrode contacts in seven patients. The nonepileptic contacts constituted 79.1% of the total number of contacts. Ripples constituted 99% of total detections. Eighty-two percent of all HFOs were seen in 45.2% of the nonepileptic contacts (82.1%, 47%, 34.6%, and 34% of the occipital, parietal, frontal, and temporal nonepileptic contacts, respectively). The following sublobes exhibited physiologic HFOs in all patients: Perirolandic, basal temporal, and occipital subregions. The ripples from nonepileptic sites had longer duration, higher amplitude, and lower peak frequency than ripples from epileptic sites. A high HFO rate (>1/min) was seen in 110 nonepileptic contacts, of which 68.2% were occipital. Fast ripples were less common, seen in nonepileptic parietooccipital regions only in two patients and in the epileptic mesial temporal structures.
Conclusions
There is consistent occurrence of physiologic HFOs over vast areas of the neocortex outside the epileptic network. HFOs from nonepileptic regions were seen in the occipital lobes and in the perirolandic region in all patients. Although duration of ripples and peak frequency of HFOs are the most effective measures in distinguishing pathologic from physiologic events, there was significant overlap between the two groups.
doi:10.1111/epi.12851
PMCID: PMC5123742  PMID: 25470216
High frequency oscillations; Intracranial EEG; Ripples; Epilepsy; Electrocorticography
2.  High frequency oscillations are associated with cognitive processing in human recognition memory 
Brain  2014;137(8):2231-2244.
High frequency oscillations have been associated with focal epilepsy, but their role in human cognition is less clear. During intracranial recordings in patients undergoing seizure monitoring, Kucewicz et al. detect high gamma, ripple and fast ripple oscillations that are induced by image processing, and modulated by memory encoding and recall.
High frequency oscillations are associated with normal brain function, but also increasingly recognized as potential biomarkers of the epileptogenic brain. Their role in human cognition has been predominantly studied in classical gamma frequencies (30–100 Hz), which reflect neuronal network coordination involved in attention, learning and memory. Invasive brain recordings in animals and humans demonstrate that physiological oscillations extend beyond the gamma frequency range, but their function in human cognitive processing has not been fully elucidated. Here we investigate high frequency oscillations spanning the high gamma (50–125 Hz), ripple (125–250 Hz) and fast ripple (250–500 Hz) frequency bands using intracranial recordings from 12 patients (five males and seven females, age 21–63 years) during memory encoding and recall of a series of affectively charged images. Presentation of the images induced high frequency oscillations in all three studied bands within the primary visual, limbic and higher order cortical regions in a sequence consistent with the visual processing stream. These induced oscillations were detected on individual electrodes localized in the amygdala, hippocampus and specific neocortical areas, revealing discrete oscillations of characteristic frequency, duration and latency from image presentation. Memory encoding and recall significantly modulated the number of induced high gamma, ripple and fast ripple detections in the studied structures, which was greater in the primary sensory areas during the encoding (Wilcoxon rank sum test, P = 0.002) and in the higher-order cortical association areas during the recall (Wilcoxon rank sum test, P = 0.001) of memorized images. Furthermore, the induced high gamma, ripple and fast ripple responses discriminated the encoded and the affectively charged images. In summary, our results show that high frequency oscillations, spanning a wide range of frequencies, are associated with memory processing and generated along distributed cortical and limbic brain regions. These findings support an important role for fast network synchronization in human cognition and extend our understanding of normal physiological brain activity during memory processing.
doi:10.1093/brain/awu149
PMCID: PMC4107742  PMID: 24919972
high frequency oscillations; cognitive processing; memory; gamma oscillations; neural networks
3.  Two Seizure-Onset Types Reveal Specific Patterns of High-Frequency Oscillations in a Model of Temporal Lobe Epilepsy 
High-frequency oscillations(HFOs; 80–500 Hz ) are thought to mirror the pathophysiological changes occurring in epileptic brains. However, the distribution of HFOs during seizures remains undefined. Here, we recorded from the hippocampal CA3 subfield, subiculum, entorhinal cortex, and dentate gyrus to quantify the occurrence of ripples (80–200 Hz) and fast ripples (250–500 Hz) during low-voltage fast-onset (LVF) and hypersynchronous-onset (HYP) seizures in the rat pilocarpine model of temporal lobe epilepsy. We discovered in LVF seizures that (1) progression from preictal to ictal activity was characterized in seizure-onset zones by an increase of ripple rates that were higher when compared with fast ripple rates and (2) ripple rates during the ictal period were higher compared with fast ripple rates in seizure-onset zones and later in regions of secondary spread. In contrast, we found in HYP seizures that (1) fast ripple rates increased during the preictal period and were higher compared with ripple rates in both seizure-onset zones and in regions of secondary spread and (2) they were still higher compared with ripple rates in both seizure-onset zones and regions of secondary spread during the ictal period. Our findings demonstrate that ripples and fast ripples show distinct time- and region-specific patterns during LVF and HYP seizures, thus suggesting that they play specific roles in ictogenesis.
doi:10.1523/JNEUROSCI.5086-11.2012
PMCID: PMC4878898  PMID: 22993442 CAMSID: cams5642
4.  Ictal onset patterns of local field potentials, high frequency oscillations, and unit activity in human mesial temporal lobe epilepsy 
Epilepsia  2015;57(1):111-121.
Summary
Objective
To characterize local field potentials, high frequency oscillations, and single unit firing patterns in microelectrode recordings of human limbic onset seizures.
Methods
Wide bandwidth local field potential recordings were acquired from microelectrodes implanted in mesial temporal structures during spontaneous seizures from six patients with mesial temporal lobe epilepsy.
Results
In the seizure onset zone, distinct epileptiform discharges were evident in the local field potential prior to the time of seizure onset in the intracranial EEG. In all three seizures with hypersynchronous (HYP) seizure onset, fast ripples with incrementally increasing power accompanied epileptiform discharges during the transition to the ictal state (p < 0.01). In a single low voltage fast (LVF) onset seizure a triad of evolving HYP LFP discharges, increased single unit activity, and fast ripples of incrementally increasing power were identified ~20 s prior to seizure onset (p < 0.01). In addition, incrementally increasing fast ripples occurred after seizure onset just prior to the transition to LVF activity (p < 0.01). HYP onset was associated with an increase in fast ripple and ripple rate (p < 0.05) and commonly each HYP discharge had a superimposed ripple followed by a fast ripple. Putative excitatory and inhibitory single units could be distinguished during limbic seizure onset, and heterogeneous shifts in firing rate were observed during LVF activity.
Significance
Epileptiform activity is detected by microelectrodes before it is detected by depth macroelectrodes, and the one clinically identified LVF ictal onset was a HYP onset at the local level. Patterns of incrementally increasing fast ripple power are consistent with observations in rats with experimental hippocampal epilepsy, suggesting that limbic seizures arise when small clusters of synchronously bursting neurons increase in size, coalesce, and reach a critical mass for propagation.
doi:10.1111/epi.13251
PMCID: PMC4862409  PMID: 26611159
Hypersynchronous; Low voltage fast; High frequency oscillation; Ripple; Fast ripple; Limbic seizure
5.  Relationship between high-frequency oscillations and spikes in a case of temporal lobe epilepsy 
Objective
The aim of this case report was to study the relationship between high-frequency oscillations (HFOs), spikes, and seizures in a patient with temporal lobe epilepsy.
Introduction
During intracranial electroencephalography (EEG), HFOs are thought to be a marker for the seizure onset zone (SOZ). High-frequency oscillations are classified into ripples with frequencies of 70–200 Hz and fast ripples with frequencies of 200–500 Hz. Although HFOs are thought to be a marker for the SOZ, their relationship to spikes has not been studied in detail, especially within the SOZ.
Methods
We studied the time course of ripples and spikes in a patient undergoing intracranial EEG. Medications were discontinued on day one. She suffered three seizures on day three. Her SOZ was in the left hippocampus, which displayed abundant ripples and spikes. Ripples, spikes with simultaneous ripples, and spikes without ripples were counted for this study.
Results
We found that ripples and spikes in the SOZ had a marked diurnal variation. Ripples, spikes with ripples, and spikes without ripples increased and decreased in concert until just before seizure onset, when ripples and spikes with ripples increased markedly. Spikes without ripples did not increase.
Conclusions
These results support ripples as a marker for SOZ and show that they co-occur with spikes. Seizure onset was heralded by an increase in ripples and spikes with ripples, without an increase in spikes without ripples. We hypothesize that spikes associated with ripples may have a somewhat different pathophysiological mechanism than spikes not associated with ripples, differences that may be relevant for the timing of seizure onset.
doi:10.1016/j.ebcr.2016.04.006
PMCID: PMC5118559  PMID: 27896067
Seizure; High-frequency oscillation; Epileptiform spikes with high-frequency oscillations; EEG; Human temporal lobe epilepsy; Epilepsy surgery
6.  Occurrence of scalp-fast oscillations among patients with different spiking rate and their role as epileptogenicity marker 
Epilepsy research  2013;106(3):345-356.
Summary
Introduction
We aim to analyze the fast oscillations in the scalp EEG of focal epilepsy patients with low-to-high rates of interictal epileptiform discharges (IEDs), in order to determine how this neurophysiological feature influences fast oscillation occurrence and their significance as markers of the seizure onset zone (SOZ).
Methods
Thirty-two patients were studied, subdivided in four categories based on IED frequency: groups A, B and C respectively with high, intermediate and low IED rate, and group D with no IED. Thirty minutes of slow-wave sleep EEG, low-pass filtered at 300 Hz and sampled at 1000 Hz, were reviewed. IEDs and fast oscillations (gamma activity, 40–80 Hz; and ripples, >80 Hz) were marked. Each channel was classified as inside or outside the irritative zone and the SOZ. We calculated the number and rates of IEDs and fast oscillation, their co-occurrence, their frequency in the irritative zone and SOZ, and the specificity, sensitivity and accuracy to determine the SOZ in the overall population and separately for each group.
Results
We analyzed 984 channels. Group A (high IED rate) showed the highest fast oscillation rate (gamma: 0.37 ± 0.73; ripples: 0.17 ± 0.26), followed by group B (gamma: 0.08 ± 0.06; ripples: 0.07 ± 0.05), group C (gamma: 0.06 ± 0.06; ripples: 0.04 ± 0.01), and finally group D, with very low values (gamma: 0.03 ± 0; ripples: 0.03 ± 0). IEDs co-occurred with gamma in 9.5% and with ripples in 3.2%; and gamma and ripples co-occurred with IEDs in 46.2% and 44.4%, respectively. The fast oscillations were more frequent inside than outside the irritative zone and the SOZ (p < 0.001). Compared to the IEDs, the fast oscillations were less sensitive (sensitivity: IEDs 78%, gamma 66% and ripples 48%) but more specific (specificity: IEDs 50%, gamma 76% and ripples 83%) and accurate (accuracy: IEDs 54%, gamma 74% and ripples 77%) in identifying the SOZ; the same results were reproduced for the different groups separately.
Conclusions
This study confirms that fast oscillations can be recorded from the scalp EEG. Gamma activity and ripples are more frequent in patients with frequent IEDs and, in general, inside the irritative zone. However, compared to IEDs, gamma and ripples are less sensitive but more specific and accurate in identifying the SOZ, and this remains in patients with low fast oscillation rates. These findings suggest that IEDs and fast oscillations could share some common neuronal network, but gamma activity and ripples are a better biomarker of epileptogenicity
doi:10.1016/j.eplepsyres.2013.06.003
PMCID: PMC4490901  PMID: 23932079 CAMSID: cams4871
Fast oscillations; Scalp EEG; IEDs; Irritative zone; Seizure onset zone
7.  High-frequency (80–500 Hz) oscillations and epileptogenesis in temporal lobe epilepsy 
Neurobiology of disease  2011;42(3):231-241.
High-frequency oscillations (HFOs), termed ripples (80–200 Hz) and fast ripples (250–600 Hz), are recorded in the EEG of epileptic patients and in animal epilepsy models; HFOs are thought to reect pathological activity and seizure onset zones. Here, we analyzed the temporal and spatial evolution of interictal spikes with and without HFOs in the rat pilocarpine model of temporal lobe epilepsy. Depth electrode recordings from dentate gyrus (DG), CA3 region, subiculum and entorhinal cortex (EC), were obtained from rats between the 4th and 15th day after a status epilepticus (SE) induced by i.p. injection of pilocarpine. The first seizure occurred 6.1±2.5 days after SE (n=7 rats). Five of 7 animals exhibited interictal spikes that co-occurred with fast ripples accounting for 4.9±4.6% of all analyzed interictal spikes (n=12,886) while all rats showed interictal spikes co-occurring with ripples, accounting for 14.3±3.4% of all events. Increased rates of interictal spikes without HFOs in the EC predicted upcoming seizures on the following day, while rates of interictal spikes with fast ripples in CA3 reflected periods of high seizure occurrence. Finally, interictal spikes co-occurring with ripples did not show any specific relation to seizure occurrence. Our findings identify different temporal and spatial developmental patterns for the rates of interictal spikes with or without HFOs in relation with seizure occurrence. These distinct categories of interictal spikes point at dynamic processes that should bring neuronal networks close to seizure generation.
doi:10.1016/j.nbd.2011.01.007
PMCID: PMC4873283  PMID: 21238589 CAMSID: cams5639
High frequency oscillations; Fast ripples; Ripples; Interictal spikes; Epileptogenesis; Pilocarpine
8.  Interictal high-frequency oscillations (80–500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain 
Epilepsia  2008;49(11):1893-1907.
Summary
Purpose
High-frequency oscillations (HFOs) known as ripples (80–250 Hz) and fast ripples (250–500 Hz) can be recorded from macroelectrodes inserted in patients with intractable focal epilepsy. They are most likely linked to epileptogenesis and have been found in the seizure onset zone (SOZ) of human ictal and interictal recordings. HFOs occur frequently at the time of interictal spikes, but were also found independently. This study analyses the relationship between spikes and HFOs and the occurrence of HFOs in nonspiking channels.
Methods
Intracerebral EEGs of 10 patients with intractable focal epilepsy were studied using macroelectrodes. Rates of HFOs within and outside spikes, the overlap between events, event durations, and the percentage of spikes carrying HFOs were calculated and compared according to anatomical localization, spiking activity, and relationship to the SOZ.
Results
HFOs were found in all patients, significantly more within mesial temporal lobe structures than in neocortex. HFOs could be seen in spiking as well as nonspiking channels in all structures. Rates and durations of HFOs were significantly higher in the SOZ than outside. It was possible to establish a rate of HFOs to identify the SOZ with better sensitivity and specificity than with the rate of spikes.
Discussion
HFOs occurred to a large extent independently of spikes. They are most frequent in mesial temporal structures. They are prominent in the SOZ and provide additional information on epileptogenicity independently of spikes. It was possible to identify the SOZ with a high specificity by looking at only 10 min of HFO activity.
doi:10.1111/j.1528-1167.2008.01656.x
PMCID: PMC3792077  PMID: 18479382 CAMSID: cams3466
Epilepsy; High-frequency oscillations; Spikes; Seizure onset zone; Intracranial electrodes
9.  Clinical Utility of Interictal High-Frequency Oscillations Recorded with Subdural Macroelectrodes in Partial Epilepsy 
Background and Purpose
There is growing interest in high-frequency oscillations (HFO) as electrophysiological biomarkers of the epileptic brain. We evaluated the clinical utility of interictal HFO events, especially their occurrence rates, by comparing the spatial distribution with a clinically determined epileptogenic zone by using subdural macroelectrodes.
Methods
We obtained intracranial electroencephalogram data with a high temporal resolution (2000 Hz sampling rate, 0.05-500 Hz band-pass filter) from seven patients with medically refractory epilepsy. Three epochs of 5-minute, artifact-free data were selected randomly from the interictal period. HFO candidates were first detected by an automated algorithm and subsequently screened to discard false detections. Validated events were further categorized as fast ripple (FR) and ripple (R) according to their spectral profiles. The occurrence rate of HFOs was calculated for each electrode contact. An HFO events distribution map (EDM) was constructed for each patient to allow visualization of the spatial distribution of their HFO events.
Results
The subdural macroelectrodes were capable of detecting both R and FR events from the epileptic neocortex. The occurrence rate of HFO events, both FR and R, was significantly higher in the seizure onset zone (SOZ) than in other brain regions. Patient-specific HFO EDMs can facilitate the identification of the location of HFO-generating tissue, and comparison with findings from ictal recordings can provide additional useful information regarding the epileptogenic zone.
Conclusions
The distribution of interictal HFOs was reasonably consistent with the SOZ. The detection of HFO events and construction of spatial distribution maps appears to be useful for the presurgical mapping of the epileptogenic zone.
doi:10.3988/jcn.2012.8.1.22
PMCID: PMC3325429  PMID: 22523510
partial epilepsy; high-frequency oscillations; fast ripple; ripple; intracranial EEG; seizure onset zone
10.  Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy 
Neurobiology of disease  2014;67:97-106.
Mesial temporal lobe epilepsy (MTLE) is characterized in humans and in animal models by a seizure-free latent phase that follows an initial brain insult; this period is presumably associated to plastic changes in temporal lobe excitability and connectivity. Here, we analyzed the occurrence of interictal spikes and high frequency oscillations (HFOs; ripples: 80–200 Hz and fast ripples: 250–500 Hz) from 48 h before to 96 h after the first seizure in the rat pilocarpine model of MTLE. Interictal spikes recorded with depth EEG electrodes from the hippocampus CA3 area and entorhinal cortex (EC) were classified as type 1 (characterized by a spike followed by a wave) or type 2 (characterized by a spike with no wave). We found that: (i) there was a switch in the distribution of both types of interictal spikes before and after the occurrence of the first seizure; during the latent phase both types of interictal spikes predominated in the EC whereas during the chronic phase both types of spikes predominated in CA3; (ii) type 2 spike duration decreased in both regions from the latent to the chronic phase; (iii) type 2 spikes associated to fast ripples occurred at higher rates in EC compared to CA3 during the latent phase while they occurred at similar rates in both regions in the chronic phase; and (iv) rates of fast ripples outside of spikes were higher in EC compared to CA3 during the latent phase. Our findings demonstrate that the transition from the latent to the chronic phase is paralleled by dynamic changes in interictal spike and HFO expression in EC and CA3. We propose that these changes may represent biomarkers of epileptogenicity in MTLE.
doi:10.1016/j.nbd.2014.03.012
PMCID: PMC4878896  PMID: 24686305 CAMSID: cams5659
Temporal lobe epilepsy; Epileptogenesis; High-frequency oscillations; Interictal spikes
11.  Interictal scalp fast oscillations as a marker of the seizure onset zone 
Neurology  2011;77(6):524-531.
Objective:
This study aims to identify if oscillations at frequencies higher than the traditional EEG can be recorded on the scalp EEG of patients with focal epilepsy and to analyze the association of these oscillations with interictal discharges and the seizure onset zone (SOZ).
Methods:
The scalp EEG of 15 patients with focal epilepsy was studied. We analyzed the rates of gamma (40–80 Hz) and ripple (>80 Hz) oscillations, their co-occurrence with spikes, the number of channels with fast oscillations inside and outside the SOZ, and the specificity, sensitivity, and accuracy of gamma, ripples, and spikes to determine the SOZ.
Results:
Gamma and ripples frequently co-occurred with spikes (77.5% and 63% of cases). For all events, the proportion of channels with events was consistently higher inside than outside the SOZ: spikes (100% vs 70%), gamma (82% vs 33%), and ripples (48% vs 11%); p < 0.0001. The mean rates (events/min) were higher inside than outside the SOZ: spikes (2.64 ± 1.70 vs 0.69 ± 0.26, p = 0.02), gamma (0.77 ± 0.71 vs 0.20 ± 0.25, p = 0.02), and ripples (0.08 ± 0.12 vs 0.04 ± 0.09, p = 0.04). The sensitivity to identify the SOZ was spikes 100%, gamma 82%, and ripples 48%; the specificity was spikes 30%, gamma 68%, and ripples 89%; and the accuracy was spikes 43%, gamma 70%, and ripples 81%.
Conclusion:
The rates and the proportion of channels with gamma and ripple fast oscillations are higher inside the SOZ, indicating that they can be used as interictal scalp EEG markers for the SOZ. These fast oscillations are less sensitive but much more specific and accurate than spikes to delineate the SOZ.
doi:10.1212/WNL.0b013e318228bee2
PMCID: PMC3149155  PMID: 21753167
12.  Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy 
Epilepsy research  2015;115:8-16.
Objective
Nearly one third of patients presenting with mesial temporal lobe epilepsy (MTLE), the most prevalent lesion-related epileptic disorder in adulthood, do not respond to currently available antiepileptic medications. Thus, there is a need to identify and characterize new antiepileptic drugs. In this study, we used the pilocarpine model of MTLE to establish the effects of a third generation drug, lacosamide (LCM), on seizures, interictal spikes and high-frequency oscillations (HFOs, ripples: 80–200 Hz, fast ripples: 250–500 Hz).
Methods
Sprague–Dawley rats (250–300 g) were injected with pilocarpine to induce a status epilepticus (SE) that was pharmacologically terminated after 1 h. Eight pilocarpine-treated rats were then injected with LCM (30 mg/kg, i.p.) 4 h after SE and daily for 14 days. Eight pilocarpine-treated rats were used as controls and treated with saline. Three days after SE, all rats were implanted with bipolar electrodes in the hippocampal CA3 region, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored from day 4 to day 14 after SE.
Results
LCM-treated animals showed lower rates of seizures (0.21 (±0.11) seizures/day) than controls (2.6 (±0.57), p < 0.05), and a longer latent period (LCM: 11 (±1) days, controls: 6.25 (±1), p < 0.05). Rates of interictal spikes in LCM-treated rats were significantly lower than in controls in CA3 and subiculum (p < 0.05). Rates of ripples and fast ripples associated with interictal spikes in CA3 and subiculum as well as rates of fast ripples occurring outside of interictal spikes in CA3 were also significantly lower in LCM-treated animals. In controls, interictal spikes and associated HFOs correlated to seizure clustering, while this was not the case for isolated HFOs.
Significance
Our findings show that early treatment with LCM has powerful anti-ictogenic properties in the pilocarpine model of MTLE. These effects are accompanied by decreased rates of interictal spikes and associated HFOs. Isolated HFOs were also modulated by LCM, in a manner that appeared to be unrelated to its antiictogenic effects. These results thus suggest that distinct mechanisms may underlie interictal-associated and isolated HFOs in the pilocarpine model of MTLE.
doi:10.1016/j.eplepsyres.2015.05.006
PMCID: PMC4878889  PMID: 26220372 CAMSID: cams5688
Epilepsy; Seizures; Interictal spikes; High-frequency oscillations; Hippocampus
13.  High frequency oscillations in intracranial EEGs mark epileptogenicity rather than lesion type 
Brain : a journal of neurology  2009;132(0 4):1022-1037.
High frequency oscillations (HFOs) called ripples (80–250 Hz) and fast ripples (FR, 250–500 Hz) can be recorded from intracerebral EEG macroelectrodes in patients with intractable epilepsy. HFOs occur predominantly in the seizure onset zone (SOZ) but their relationship to the underlying pathology is unknown. It was the aim of this study to investigate whether HFOs are specific to the SOZ or result from pathologically changed tissue, whether or not it is epileptogenic. Patients with different lesion types, namely mesial temporal atrophy (MTA), focal cortical dysplasia (FCD) and nodular heterotopias (NH) were investigated. Intracranial EEG was recorded from depth macroelectrodes with a sampling rate of 2000 Hz. Ripples (80–250 Hz) and Fast Ripples (250–500 Hz) were visually marked in 12 patients: five with MTA, four with FCD and three with NH. Rates of events were statistically compared in channels in four areas: lesional SOZ, non-lesional SOZ, lesional non-SOZ and non-lesional non-SOZ. HFO rates were clearly more linked to the SOZ than to the lesion. They were highest in areas in which lesion and SOZ overlap, but in patients with a SOZ outside the lesion, such as in NHs, HFO rates were clearly higher in the non-lesional SOZ than in the inactive lesions. No specific HFO pattern could be identified for the different lesion types. The findings suggest that HFOs represent a marker for SOZ areas independent of the underlying pathology and that pathologic tissue changes alone do not lead to high rates of HFOs.
doi:10.1093/brain/awn351
PMCID: PMC3792079  PMID: 19297507 CAMSID: cams3471
high frequency oscillations; focal cortical dysplasia; nodular heterotopia; temporal atrophy; seizure onset zone; intracranial EEG
14.  High-frequency Oscillations and the Seizure Onset Zones in Neocortical Epilepsy 
Chinese Medical Journal  2015;128(13):1724-1727.
Background:
To study the characters of high-frequency oscillations (HFOs) in the seizure onset zones (SOZ) and the nonseizure onset zones (NSOZ) in the electrocorticography (ECoG) of patients with neocortical epilepsy.
Methods:
Only patients with neocortical epilepsy who were seizure-free after surgery as determined with ECoG were included. We selected patients with normal magnetic resonance imaging before surgery in order to avoid the influence of HFOs by other lesions. Three minutes preictal and 10 min interictal ECoG as recorded in 39 channels in the SOZ and 256 channels in the NSOZ were analyzed. Ripples and fast ripples (FRs) were analyzed by Advanced Source Analysis software (ASA, The Netherlands). Average duration of HFOs was analyzed in SOZ and NSOZ separately.
Results:
For ripples, the permillage time occupied by HFOs was 0.83 in NSOZ and 1.17 in SOZ during the interictal period. During preictal period, they were 2.02 in NSOZ and 7.93 in SOZ. For FRs, the permillage time occupied by HFOs was 0.02 in NSOZ and 0.42 in SOZ during the interictal period. During preictal period, they were 0.03 in NSOZ and 2 in SOZ.
Conclusions:
High-frequency oscillations are linked to SOZ in neocortical epilepsy. Our study demonstrates the prevalent occurrence of HFOs in SOZ. More and more burst of HFOs, especially FRs, means the onset of seizures.
doi:10.4103/0366-6999.159342
PMCID: PMC4733720  PMID: 26112710
Electrocorticography; Epilepsy; High-frequency Oscillations; Seizure Onset Zones
15.  High-frequency oscillations, extent of surgical resection, and surgical outcome in drug-resistant focal epilepsy 
Epilepsia  2013;54(5):848-857.
Summary
Purpose
Removal of areas generating high-frequency oscillations (HFOs) recorded from the intracerebral electroencephalography (iEEG) of patients with medically intractable epilepsy has been found to be correlated with improved surgical outcome. However, whether differences exist according to the type of epilepsy is largely unknown. We performed a comparative assessment of the impact of removing HFO-generating tissue on surgical outcome between temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE). We also assessed the relationship between the extent of surgical resection and surgical outcome.
Methods
We studied 30 patients with drug-resistant focal epilepsy, 21 with TLE and 9 with ETLE. Two thirds of the patients were included in a previous report and for these, clinical and imaging data were updated and follow-up was extended. All patients underwent iEEG investigations (500 Hz high-pass filter and 2,000 Hz sampling rate), surgical resection, and postoperative magnetic resonance imaging (MRI). HFOs (ripples, 80–250 Hz; fast ripples, >250 Hz) were identified visually on a 5–10 min interictal iEEG sample. HFO rates inside versus outside the seizure-onset zone (SOZ), in resected versus nonresected tissue, and their association with surgical outcome (ILAE classification) were assessed in the entire cohort, and in the TLE and ETLE subgroups. We also tested the correlation of resected brain hippocampal and amygdala volumes (as measured on postoperative MRIs) with surgical outcome.
Key Findings
HFO rates were significantly higher inside the SOZ than outside in the entire cohort and TLE subgroup, but not in the ETLE subgroup. In all groups, HFO rates did not differ significantly between resected and nonresected tissue. Surgical outcome was better when higher HFO rates were included in the surgical resection in the entire cohort and TLE subgroup, but not in the ETLE subgroup. Resected brain hippocampal and amygdala volumes were not correlated with surgical outcome.
Significance
In TLE, removal of HFO-generating areas may lead to improved surgical outcome. Less consistent findings emerge from ETLE, but these may be related to sample size limitations of this study. Size of resection, a factor that was ignored and that could have affected results of earlier studies did not influence results.
doi:10.1111/epi.12075
PMCID: PMC3712982  PMID: 23294353 CAMSID: cams2976
High-frequency oscillations; Intracerebral EEG; Epilepsy surgery; Temporal lobe epilepsy; Extra-temporal lobe epilepsy
16.  Gamma oscillations precede interictal epileptiform spikes in the seizure onset zone 
Neurology  2015;84(6):602-608.
Objective:
To investigate the generation, spectral characteristics, and potential clinical significance of brain activity preceding interictal epileptiform spike discharges (IEDs) recorded with intracranial EEG.
Methods:
Seventeen adult patients with drug-resistant temporal lobe epilepsy were implanted with intracranial electrodes as part of their evaluation for epilepsy surgery. IEDs detected on clinical macro- and research microelectrodes were analyzed using time-frequency spectral analysis.
Results:
Gamma frequency oscillations (30–100 Hz) often preceded IEDs in spatially confined brain areas. The gamma-IEDs were consistently observed 35 to 190 milliseconds before the epileptiform spike waveforms on individual macro- and microelectrodes. The gamma oscillations associated with IEDs had longer duration (p < 0.001) and slightly higher frequency (p = 0.045) when recorded on microelectrodes compared with clinical macroelectrodes. Although gamma-IEDs comprised only a subset of IEDs, they were strongly associated with electrodes in the seizure onset zone (SOZ) compared with the surrounding brain regions (p = 0.004), in sharp contrast to IEDs without preceding gamma oscillations that were often also detected outside of the SOZ. Similar to prior studies, isolated pathologic high-frequency oscillations in the gamma (30–100 Hz) and higher (100–600 Hz) frequency range, not associated with an IED, were also found to be associated with SOZ.
Conclusions:
The occurrence of locally generated gamma oscillations preceding IEDs suggests a mechanistic role for gamma in pathologic network activity generating IEDs. The results show a strong association between SOZ and gamma-IEDs. The potential clinical application of gamma-IEDs for mapping pathologic brain regions is intriguing, but will require future prospective studies.
doi:10.1212/WNL.0000000000001234
PMCID: PMC4335986  PMID: 25589669
17.  Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy 
Brain  2010;133(5):1380-1390.
High-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (>100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy.
doi:10.1093/brain/awq070
PMCID: PMC2859153  PMID: 20400525
high-frequency activity; epilepsy; seizure onset; ripples; fast ripples; ictogenesis; temporal lobe epilepsy; non-lesional
18.  Ictal High Frequency Oscillations in Neocortical Epilepsy: Implications for Seizure Localization and Surgical Resection 
Epilepsia  2011;52(10):1792-1801.
SUMMARY
Purpose
To investigate the characteristics of intracranial ictal high frequency oscillations (HFOs).
Methods
Among 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, EEG acquired at <1,000 Hz sampling rate and non-resective 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+ev channels) but not the channels that lacked evolution (HFOs-ev 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 Findings
Out of 14 consecutive neocortical epilepsy patients, six patients met the inclusion criteria. 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-ev, the HFOs+ev were significantly higher in peak frequency (97.1 versus 89.1 Hz, p=0.001), more robust (nearly 2-fold higher peak power, p<0.0001), and spatially restricted [mean 12.2 versus 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+ev was earlier (by an average of 0.41 sec), 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+ev channels were 10 times more likely to have been resected than the HFOs-ev channels (OR 9.7, 95% CI 5–17, p<0.0001).
Significance
Our 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.
doi:10.1111/j.1528-1167.2011.03165.x
PMCID: PMC3188690  PMID: 21762451
Epilepsy surgery; High frequency oscillations; Intracranial EEG; HFOs; Seizure
19.  Effect of sleep stage on interictal high-frequency oscillations recorded from depth macroelectrodes in patients with focal epilepsy 
Epilepsia  2009;50(4):617-628.
Summary
Purpose
To investigate the effect of sleep stage on the properties of high-frequency oscillations (HFOs) recorded from depth macroelectrodes in patients with focal epilepsy.
Methods
Ten-minute epochs of wakefulness (W), stage 1–2 non-REM (N1-N2), stage 3 non-REM (N3) and REM sleep (R) were identified from stereo- electroencephalography (SEEG) data recorded at 2 kHz in nine patients. Rates of spikes, ripples (>80 Hz), and fast ripples (>250 Hz) were calculated, as were HFO durations, degree of spike–HFO overlap, HFO rates inside and outside of spikes, and inside and outside of the seizure-onset zone (SOZ).
Results
Ripples were observed in nine patients and fast ripples in eight. Spike rate was highest in N1-N2 in 5 of 9 patients, and in N3 in 4 of 9 patients, whereas ripple rate was highest in N1-N2 in 4 of 9 patients, in N3 in 4 of 9 patients, and in Win 1 of 9 patients. Fast ripple rate was highest in N1-N2 in 4 of 8 patients, and in N3 in 4 of 8 patients. HFO properties changed significantly with sleep stage, although the absolute effects were small. The difference in HFO rates inside and outside of the SOZ was highly significant (p < 0.000001) in all stages except for R and, for fast ripples, only marginally significant (p = 0.018) in W.
Conclusions
Rates of HFOs recorded from depth macroelectrodes are highest in non-REM sleep. HFO properties were similar in stages N1-N2 and N3, suggesting that accurate sleep staging is not necessary. The spatial specificity of HFO, particularly fast ripples, was affected by sleep stage, suggesting that recordings excluding REM sleep and wakefulness provide a more reliable indicator of the SOZ.
doi:10.1111/j.1528-1167.2008.01784.x
PMCID: PMC3792080  PMID: 18801037 CAMSID: cams3468
Intracerebral EEG; High-frequency oscillations; Sleep
20.  High frequency oscillations (80–500 Hz) in the preictal period in patients with focal seizures 
Epilepsia  2009;50(7):1780-1792.
Summary
Purpose
Intracranial depth macroelectrode recordings from patients with focal seizures demonstrate interictal and ictal high frequency oscillations (HFOs, 80–500 Hz). These HFOs are more frequent in the seizure-onset zone (SOZ) and reported to be linked to seizure genesis. We evaluated whether HFO activity changes in a systematic way during the preictal period.
Methods
Fifteen minutes of preictal intracranial electroencephalography (EEG) recordings were evaluated in seven consecutive patients with well-defined SOZ. EEG was filtered at 500 Hz and sampled at 2,000 Hz. Ripples (80–250 Hz) and fast ripples (250–500 Hz) were visually marked, and spectral analysis was performed in seizure-onset as well as nonseizure-onset channels. Linear regressions fitted to the power trends corresponding to intervals of 1, 5, and 15 min before the seizure onset was calculated.
Results
Total rates of HFOs were significantly higher in the SOZ than outside. Preictal increases and decreases in HFO rates and band power could be detected in all patients, and they were not limited to the SOZs. These measures were very variable, and nosystematic trends were observed when comparing patients or seizures in the same patient.
Discussion
High frequencies in the range of 80–500 Hz are present during the preictal period and are more prominent in the SOZ. They do not change in a systematic way before seizure onset for the horizons we tested. The 80–500 Hz band may be used for the localization of seizure-onset areas but may be more difficult to use for seizure prediction purposes.
doi:10.1111/j.1528-1167.2009.02067.x
PMCID: PMC3764053  PMID: 19400871 CAMSID: cams3402
Intracranial EEG; Epilepsy; Ripples; Fast ripples; Seizure prediction
21.  EEG desynchronization during phasic REM sleep suppresses interictal epileptic activity in humans 
Epilepsia  2016;57(6):879-888.
Summary
Objective
Rapid eye movement (REM) sleep has a suppressing effect on epileptic activity. This effect might be directly related to neuronal desynchronization mediated by cholinergic neurotransmission. We investigated whether interictal epileptiform discharges (IEDs) and high frequency oscillations—a biomarker of the epileptogenic zone—are evenly distributed across phasic and tonic REM sleep. We hypothesized that IEDs are more suppressed during phasic REM sleep because of additional cholinergic drive.
Methods
Twelve patients underwent polysomnography during long‐term combined scalp‐intracerebral electroencephalography (EEG) recording. After sleep staging in the scalp EEG, we identified segments of REM sleep with rapid eye movements (phasic REM) and segments of REM sleep without rapid eye movements (tonic REM). In the intracerebral EEG, we computed the power in frequencies <30 Hz and from 30 to 500 Hz, and marked IEDs, ripples (>80 Hz) and fast ripples (>250 Hz). We grouped the intracerebral channels into channels in the seizure‐onset zone (SOZ), the exclusively irritative zone (EIZ), and the normal zone (NoZ).
Results
Power in frequencies <30 Hz was lower during phasic than tonic REM sleep (p < 0.001), most likely reflecting increased desynchronization. IEDs, ripples and fast ripples, were less frequent during phasic than tonic REM sleep (phasic REM sleep: 39% of spikes, 35% of ripples, 18% of fast ripples, tonic REM sleep: 61% of spikes, 65% of ripples, 82% of fast ripples; p < 0.001). In contrast to ripples in the epileptogenic zone, physiologic ripples were more abundant during phasic REM sleep (phasic REM sleep: 73% in NoZ, 30% in EIZ, 28% in SOZ, tonic REM sleep: 27% in NoZ, 70% in EIZ, 72% in SOZ; p < 0.001).
Significance
Phasic REM sleep has an enhanced suppressive effect on IEDs, corroborating the role of EEG desynchronization in the suppression of interictal epileptic activity. In contrast, physiologic ripples were increased during phasic REM sleep, possibly reflecting REM‐related memory consolidation and dreaming.
doi:10.1111/epi.13389
PMCID: PMC4949560  PMID: 27112123
Epilepsy; Intracerebral EEG; Polysomnography; High‐frequency oscillations; Sleep
22.  Removing interictal fast ripples on electrocorticography linked with seizure freedom in children (e–Pub ahead of print)  
Neurology  2010;75(19):1686-1694.
Background:
Fast ripples (FR, 250-500 Hz) detected with chronic intracranial electrodes are proposed biomarkers of epileptogenesis. This study determined whether resection of FR-containing neocortex recorded during intraoperative electrocorticography (ECoG) was associated with postoperative seizure freedom in pediatric patients with mostly extratemporal lesions.
Methods:
FRs were retrospectively reviewed in 30 consecutive pediatric cases. ECoGs were recorded at 2,000 Hz sampling rate and visually inspected for FR, with reviewer blinded to the resection and outcome.
Results:
Average age at surgery was 9.1 ± 6.7 years, ECoG duration was 11.8 ± 8.1 minutes, and postoperative follow-up was 27 ± 4 months. FRs were undetected in 6 ECoGs with remote or extensive lesions. FR episodes (n = 273) were identified in ECoGs from 24 patients, and in 64% FRs were independent of spikes, sharp waves, voltage attenuation, and paroxysmal fast activity. Of these 24 children, FR-containing cortex was removed in 19 and all became seizure-free, including 1 child after a second surgery. The remaining 5 children had incomplete FR resection and all continued with seizures postoperatively. In 2 ECoGs, the location of electrographic seizures matched FR location. FR-containing cortex was found outside of MRI and FDG-PET abnormalities in 6 children.
Conclusion:
FRs were detected during intraoperative ECoG in 80% of pediatric epilepsy cases, and complete resection of FR cortex correlated with postoperative seizure freedom. These findings support the view that interictal FRs are excellent surrogate markers of epileptogenesis, can be recorded during brief ECoG, and could be used to guide future surgical resections in children.
GLOSSARY
= antiepileptic drug;
= analysis of variance;
= cortical dysplasia;
= electrocorticography;
= 18fluoro-deoxyglucose PET;
= fast ripples;
= high-frequency oscillation;
= tuberous sclerosis complex;
= University of California, Los Angeles.
doi:10.1212/WNL.0b013e3181fc27d0
PMCID: PMC3033604  PMID: 20926787
23.  Invasive Evaluations for Epilepsy Surgery: A Review of the Literature 
Neurologia medico-chirurgica  2016;56(5):221-227.
Invasive evaluations play important roles in identifying epileptogenic zones and functional areas in patients with intractable focal epilepsy. This article reviews the usefulness, methods, and limitations of invasive evaluations for epilepsy surgery. Invasive evaluations include various types of intracranial electrodes such as stereotactically implanted intracranial depth electrodes (stereo-EEG), chronic subdural electrodes, and intraoperative electrocorticography. Scalp EEG is distorted by the skull, meninges, and skin. On the other hand, intracranial electrodes provide spatial information with higher resolution than scalp electrodes, thereby enabling further delineation of epileptogenic zones and mapping of functional areas with electrical stimulation. In addition, intracranial electrodes record a wide frequency range of electrical activity, which is not possible with scalp electrodes. The very slow potentials in ictal recordings, known as ictal direct current (DC) shifts and ictal/interictal high frequency oscillations, such as ripples (100–200 Hz) and fast ripples (200–500 Hz), have been correlated with the ictal onset zone and are a sensitive and specific marker for epileptogenicity. Furthermore, several studies reported that the electrical stimulation of epileptogenic zones elicited enhanced cortical evoked potentials, abnormal delayed or repetitive responses, and fast ripples. These responses may assist in the delineation of the epileptogenic cortex as a potential new marker. There are definite risks of complications associated with the use of intracranial electrodes. However, when an invasive evaluation is selected based on careful consideration of the risks and benefits, it provides useful information for establishing a strategy for epilepsy surgery.
doi:10.2176/nmc.ra.2015-0319
PMCID: PMC4870176  PMID: 26948700
intracranial electrodes; functional mapping; cortical stimulation; electrocorticography; focal epilepsy
24.  The anti-ictogenic effects of levetiracetam are mirrored by interictal spiking and high-frequency oscillation changes in a model of temporal lobe epilepsy 
Seizure  2014;25:18-25.
Purpose
Mesial temporal lobe epilepsy (MTLE) is the most prevalent type of partial epileptic disorders. In this study, we have analyzed the impact of levetiracetam (LEV) in the pilocarpine model of MTLE.
Methods
Sprague-Dawley rats (n = 19) were injected with pilocarpine (380 mg/kg, i.p.) to induce a status epilepticus. Twelve animals were used as controls and seven were treated with LEV. They were implanted with bipolar electrodes in the CA3 subfield of the hippocampus, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored continuously from day 4 to day 14 after SE.
Results
Only 29% of LEV-treated animals had seizures compared to all controls following a latent period that was similar in duration. Seizure rates were lower in LEV-treated animals. In LEV-treated animals without seizures, lower interictal spike rates were found in all regions compared to controls. Analysis of interictal high-frequency oscillations (HFOs) revealed that LEV-treated animals without seizures had lower rates of interictal spikes with ripples (80–200 Hz) in CA3, EC and subiculum (p < 0.01), whereas rates of interictal spikes with fast ripples (250–500 Hz) were significantly lower in CA3 and subiculum, compared to controls.
Conclusion
Our findings indicate that the anti-ictogenic properties of LEV are mirrored by decreases of interictal spike rate in temporal lobe regions, and are accompanied by subregion-specific decreases of HFO occurrence in CA3 and subiculum. Overall, this evidence suggest that LEV may inhibit neural network activity in regions that are known to play important roles in MTLE.
doi:10.1016/j.seizure.2014.11.008
PMCID: PMC4880465  PMID: 25645630 CAMSID: cams5680
Levetiracetam; Pilocarpine; Seizures; Interictal spikes; High-frequency oscillations
25.  A comparison between automated detection methods of high-frequency oscillations (80–500 Hz) during seizures 
Journal of neuroscience methods  2012;211(2):265-271.
High-frequency oscillations (HFOs, ripples: 80–200 Hz, fast ripples: 250–500 Hz) recorded from the epileptic brain are thought to reflect abnormal network-driven activity. They are also better markers of seizure onset zones compared to interictal spikes. There is thus an increasing number of studies analysing HFOs in vitro, in vivo and in the EEG of human patients with refractory epilepsy. However, most of these studies have focused on HFOs during interictal events or at seizure onset, and few have analysed HFOs during seizures. In this study, we are comparing three different automated methods of HFO detection to two methods of visual analysis, during the pre-ictal, ictal and post-ictal periods on multiple channels using the rat pilocarpine model of temporal lobe epilepsy. The first method (method 1) detected HFOs using the average of the normalised period, the second (method 2) detected HFOs using the average of the normalised period in 1 s windows and the third (method 3) detected HFOs using the average of a reference period before seizure onset. Overall, methods 2 and 3 showed higher sensitivity compared to method 1. When dividing the analysed traces in pre-, ictal and post-ictal periods, method 3 showed the highest sensitivity during the ictal period compared to method 1, while method 2 was not significantly different from method 1. These findings suggest that method 3 could be used for automated and reliable detection of HFOs on large data sets containing multiple channels during the ictal period.
doi:10.1016/j.jneumeth.2012.09.003
PMCID: PMC4879612  PMID: 22983173 CAMSID: cams5643
High frequency oscillation; Automated detection; Analysis; Epilepsy; Seizure

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