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.
PMID: 19297507 CAMSID: cams3471
high frequency oscillations; focal cortical dysplasia; nodular heterotopia; temporal atrophy; seizure onset zone; intracranial EEG
EEG power and high frequency activity in the seizure onset zone has been increasingly considered for its relationship with seizures in animal and human studies of epilepsy. We examine the relationship between quantitative EEG measures and metabolic imaging in epilepsy patients undergoing intracranial EEG (icEEG) analysis for seizure localization. Patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy (NE) were studied. Metabolic imaging was performed with MR spectroscopic imaging using N-acetyl aspartate (NAA) and creatine (Cr). All data were acquired from the mesial temporal lobe such that a direct comparison of the same anatomical regions between the two groups could be performed. While no difference was seen in the total power recorded from the mesial temporal lobe, the MTLE group had significantly greater power in the high frequency bands. There was a significant positive exponential relationship between total icEEG power with NAA/Cr in MTLE, R= +0.84 p<0.001, which was not seen in NE. There was also a significant negative relationship between fractional gamma power with NAA/Cr in MTLE R= −0.66 p<0.02, also not seen in NE. These data argue that within the seizure onset zone, the tight correlation between total power and NAA/Cr suggests that total electrical output is powered by available mitochondrial function. These data are also consistent with the hypothesis that high frequency activity is an abnormal manifestation of tissue injury.
intracranial EEG; gamma power; N-acetyl aspartate; human
High frequency oscillations (HFOs) have been associated with epileptogenicity. In rats, the extent of HFOs (>200 Hz) is correlated with seizure frequency. We studied whether the same applies to patients with focal epilepsy. Thirty-nine patients with intracerebral EEG sampled at 2000 Hz were studied for interictal ripples (80–250 Hz), fast ripples (FR, 250–500 Hz) and spikes. Seizure frequency before implantation was compared to numbers of channels with HFOs (>1/min). Analyses were repeated for HFO rates of >5, >10 and >20. Separate analyses were done for 25 patients with temporal lobe epilepsy only and for a selection of similar unilateral temporal channels in 12 patients. No linear correlation or trend was found relating the number of channels with HFOs and seizure frequency. There was a linear positive correlation between the number of channels with more than 20 FRs/min and seizure frequency. The hypothesis that the more tissue generating HFOs, the higher the seizure frequency, was not confirmed, though there might be a correlation for high FR rates.
PMID: 19403269 CAMSID: cams3403
Intracranial electrodes; Epilepsy surgery; Ripple; Fast ripple; Seizure prediction
High frequency oscillations (HFOs) can be recorded with depth electrodes in focal epilepsy patients. They occur during seizures and interictally and seem important in seizure genesis. We investigated whether interictal and ictal HFOs occur in the same regions and how they relate to epileptiform spikes.
In 25 patients, spikes, ripples (80–250 Hz) and fast ripples (FR: 250–500 Hz) and their co-occurrences were marked during interictal slow wave sleep (5–10 min), during 10 preictal seconds and 5 s following seizure onset. We compared occurrence and spatial distribution between these periods.
HFOs and spikes increased from interictal to ictal periods: the percentage of time occupied by ripples increased from 2.3% to 6.5%, FR from 0.2% to 0.8%, spikes from 1.1% to 4.8%. HFOs increased from interictal to preictal periods in contrast to spikes. Spikes were in different channels in the interictal, preictal and ictal periods whereas HFOs largely remained in the same channels.
HFOs remain confined to the same, possibly epileptogenic, area, during interictal and ictal periods, while spikes are more widespread during seizures than interictally.
Ictal and interictal HFOs represent the same (epileptogenic) area and are probably similar phenomena.
PMID: 21030302 CAMSID: cams3344
High frequency oscillations; Focal epilepsy; Epilepsy surgery; Depth EEG; Ictogenesis
There is compelling evidence that pathological high frequency oscillations (HFOs) called Fast Ripples (FR, 150–500 Hz) reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy.
Interictal HFOs were recorded from hippocampal microelectrodes in ten patients with MTLE. Rates of FR and Ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3D MRI hippocampal modeling.
Rates of FR discharge were three times higher in areas of significant local HA compared to rates in non-atrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of Ripple discharge between local atrophic and non-atrophic areas.
The proximity between local HA and microelectrode-recorded FR suggest morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a non-invasive means to localize epileptogenic regions in hippocampus.
High-frequency oscillations (HFOs) can be recorded in epileptic patients with clinical intracranial EEG. HFOs have been associated with seizure genesis because they occur in the seizure focus and during seizure onset. HFOs are also found interictally, partly co-occurring with epileptic spikes. We studied how HFOs are influenced by antiepileptic medication and seizure occurrence, to improve understanding of the pathophysiology and clinical meaning of HFOs.
Intracerebral depth EEG was partly sampled at 2,000 Hz in 42 patients with intractable focal epilepsy. Patients with five or more usable nights of recording were selected. A sample of slow-wave sleep from each night was analyzed, and HFOs (ripples: 80–250 Hz, fast ripples: 250–500 Hz) and spikes were identified on all artifact-free channels. The HFOs and spikes were compared before and after seizures with stable medication dose and during medication reduction with no intervening seizures.
Twelve patients with five to eight nights were included. After seizures, there was an increase in spikes, whereas HFO rates remained the same. Medication reduction was followed by an increase in HFO rates and mean duration.
Contrary to spikes, high-frequency oscillations (HFOs) do not increase after seizures, but do so after medication reduction, similarly to seizures. This implies that spikes and HFOs have different pathophysiologic mechanisms and that HFOs are more tightly linked to seizures than spikes. HFOs seem to play an important role in seizure genesis and can be a useful clinical marker for disease activity.
PMID: 19289737 CAMSID: cams3470
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.
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.
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.
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.
PMID: 18479382 CAMSID: cams3466
Epilepsy; High-frequency oscillations; Spikes; Seizure onset zone; Intracranial electrodes
Electrical stimulation (ES) is used during intracranial electroencephalography (EEG) investigations to delineate epileptogenic areas and seizure-onset zones (SOZs) by provoking afterdischarges (ADs) or patients’ typical seizure. High frequency oscillations (HFOs—ripples, 80–250 Hz; fast ripples, 250–500 Hz) are linked to seizure onset. This study investigates whether interictal HFOs are more frequent in areas with a low threshold to provoke ADs or seizures.
Intracranial EEG studies were filtered at 500 Hz and sampled at 2,000 Hz. HFOs were visually identified. Twenty patients underwent ES, with gradually increasing currents. Results were interpreted as agreeing or disagreeing with the intracranial study (clinical-EEG seizure onset defined the SOZ). Current thresholds provoking an AD or seizure were correlated with the rate of HFOs of each channel.
ES provoked a seizure in 12 and ADs in 19 patients. Sixteen patients showed an ES response inside the SOZ, and 10 had additional areas with ADs. The response was more specific for mesiotemporal than for neocortical channels. HFO rates were negatively correlated with thresholds for ES responses; especially in neo-cortical regions; areas with low threshold and high HFO rate were colocalized even outside the SOZ.
Areas showing epileptic HFOs colocalize with those reacting to ES. HFOs may represent a pathologic correlate of regions showing an ES response; both phenomena suggest a more widespread epileptogenicity.
PMID: 19845730 CAMSID: cams3394
Ripple; Fast ripple; Electrical stimulation; Seizure-onset zone
To investigate the effect of sleep stage on the properties of high-frequency oscillations (HFOs) recorded from depth macroelectrodes in patients with focal epilepsy.
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).
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.
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.
PMID: 18801037 CAMSID: cams3468
Intracerebral EEG; High-frequency oscillations; Sleep
Electroencephalography (EEG) has an important role in the diagnosis and classification of epilepsy. It can provide information for predicting the response to antiseizure drugs and to identify the surgically remediable epilepsies. In temporal lobe epilepsy (TLE) seizures could originate in the medial or lateral neocortical temporal region, and many of these patients are refractory to medical treatment. However, majority of patients have had excellent results after surgery and this often relies on the EEG and magnetic resonance imaging (MRI) data in presurgical evaluation. If the scalp EEG data is insufficient or discordant, invasive EEG recording with placement of intracranial electrodes could identify the seizure focus prior to surgery. This paper highlights the general information regarding the use of EEG in epilepsy, EEG patterns resembling epileptiform discharges, and the interictal, ictal and postictal findings in mesial temporal lobe epilepsy using scalp and intracranial recordings prior to surgery. The utility of the automated seizure detection and computerized mathematical models for increasing yield of non-invasive localization is discussed. This paper also describes the sensitivity, specificity, and predictive value of EEG for seizure recurrence after withdrawal of medications following seizure freedom with medical and surgical therapy.
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.
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.
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.
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.
PMID: 19400871 CAMSID: cams3402
Intracranial EEG; Epilepsy; Ripples; Fast ripples; Seizure prediction
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).
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.
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%.
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.
Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80–250Hz) and fast ripple (250–1000Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC − 9000Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 ± 49.3 Hz versus 116.3 ± 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.
high-frequency oscillations; ripple; fast ripple; intracranial EEG; epilepsy
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.
high-frequency activity; epilepsy; seizure onset; ripples; fast ripples; ictogenesis; temporal lobe epilepsy; non-lesional
High-frequency oscillations (HFOs) in the intracerebral electroencephalogram (EEG) have been linked to the seizure onset zone (SOZ). We investigated whether HFOs can delineate epileptogenic areas even outside the SOZ by correlating the resection of HFO-generating areas with surgical outcome.
Twenty patients who underwent a surgical resection for medically intractable epilepsy were studied. All had presurgical intracerebral EEG (500Hz filter and 2,000Hz sampling rate), at least 12-month postsurgical follow-up, and a postsurgical magnetic resonance imaging (MRI). HFOs (ripples, 80 –250Hz; fast ripples, >250Hz) were identified visually during 5 to 10 minutes of slow-wave sleep. Rates and extent of HFOs and interictal spikes in resected versus nonresected areas, assessed on postsurgical MRIs, were compared with surgical outcome (Engel’s classification). We also evaluated the predictive value of removing the SOZ in terms of surgical outcome.
The mean duration of follow-up was 22.7 months. Eight patients had good (Engel classes 1 and 2) and 12 poor (classes 3 and 4) surgical outcomes. Patients with a good outcome had a significantly larger proportion of HFO-generating areas removed than patients with a poor outcome. No such difference was seen for spike-generating regions or the SOZ.
The correlation between removal of HFO-generating areas and good surgical outcome indicates that HFOs could be used as a marker of epileptogenicity and may be more accurate than spike-generating areas or the SOZ. In patients in whom the majority of HFO-generating tissue remained, a poor surgical outcome occurred.
PMID: 20225281 CAMSID: cams3398
Epilepsy represents a multifaceted group of disorders divided into two broad categories, partial and generalized, based on the seizure onset zone. The identification of the neuroanatomic site of seizure onset depends on delineation of seizure semiology by a careful history together with video-EEG, and a variety of neuroimaging technologies such as MRI, fMRI, FDG-PET, MEG, or invasive intracranial EEG recording. Temporal lobe epilepsy (TLE) is the commonest form of focal epilepsy and represents almost 2/3 of cases of intractable epilepsy managed surgically. A history of febrile seizures (especially complex febrile seizures) is common in TLE and is frequently associated with mesial temporal sclerosis (the commonest form of TLE). Seizure auras occur in many TLE patients and often exhibit features that are relatively specific for TLE but few are of lateralizing value. Automatisms, however, often have lateralizing significance. Careful study of seizure semiology remains invaluable in addressing the search for the seizure onset zone.
Fast ripples are high-frequency, 250-600 Hz field potential oscillations which can be recorded from hippocampal or neocortical structures. In the neocortex, fast ripples occur during both sensory information processing and under pathological, epileptic conditions. In the hippocampus and entorhinal cortex, fast ripples are exclusively associated with epilepsy and perhaps even mark the epileptogenic focus. In contrast to ripples, which regularly also occur in normal tissue and which are thought to reflect population spike bursts at 100 to 200 Hz paced and synchronised by recurrent inhibition, the fast ripple frequency range exceeds the maximal firing frequency of most neurones. Hence, particularly in the hippocampus, fast ripples must emerge as a network phenomenon and cannot reflect the activity of single spiking neurones. In this review, current views on the mechanisms and processes underlying fast ripples are discussed.
ripples; fast ripples; oscillations; hippocampus; neocortex; epilepsy; GABA
Patients with temporal lobe epilepsy (TLE) are refractory to antiepileptic drugs in about 30% of cases. Surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20–30% of TLE patients. Several reasons have been identified to explain these surgical failures. This paper will address the five most common causes of TLE surgery failure (a) insufficient resection of epileptogenic mesial temporal structures, (b) relapse on the contralateral mesial temporal lobe, (c) lateral temporal neocortical epilepsy, (d) coexistence of mesial temporal sclerosis and a neocortical lesion (dual pathology); and (e) extratemporal lobe epilepsy mimicking TLE or temporal plus epilepsy. Persistence of epileptogenic mesial structures in the posterior temporal region and failure to distinguish mesial and lateral temporal epilepsy are possible causes of seizure persistence after TLE surgery. In cases of dual pathology, failure to identify a subtle mesial temporal sclerosis or regions of cortical microdysgenesis is a likely explanation for some surgical failures. Extratemporal epilepsy syndromes masquerading as or coexistent with TLE result in incomplete resection of the epileptogenic zone and seizure relapse after surgery. In particular, the insula may be an important cause of surgical failure in patients with TLE.
A novel type of statistical time-frequency analysis was developed to elucidate changes of high-frequency EEG activity associated with epileptic spikes.
The method uses the Gabor Transform and detects changes of power in comparison to background activity using t-statistics that are controlled by the false discovery rate (FDR) to correct type I error of multiple testing. The analysis was applied to EEGs recorded at 2000 Hz from three patients with mesial temporal lobe epilepsy.
Spike-related increase of high-frequency oscillations (HFOs) was clearly shown in the FDR-controlled t-spectra: it was most dramatic in spikes recorded from the hippocampus when the hippocampus was the seizure onset zone (SOZ). Depression of fast activity was observed immediately after the spikes, especially consistently in the discharges from the hippocampal SOZ. It corresponded to the slow wave part in case of spike-and-slow-wave complexes, but it was noted even in spikes without apparent slow waves. In one patient, a gradual increase of power above 200 Hz preceded spikes.
FDR-controlled t-spectra clearly detected the spike-related changes of HFOs that were unclear in standard power spectra.
We developed a promising tool to study the HFOs that may be closely linked to the pathophysiology of epileptogenesis.
PMID: 19394892 CAMSID: cams3472
High-frequency; Time-frequency analysis; False discovery rate; Hippocampus; Mesial temporal lobe epilepsy; Spike
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.
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.
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.
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.
partial epilepsy; high-frequency oscillations; fast ripple; ripple; intracranial EEG; seizure onset zone
Continuous, long-term (up to 10 days) electrophysiological monitoring using hybrid intracranial electrodes is an emerging tool for presurgical epilepsy evaluation and fundamental investigations of seizure generation. Detection of high-frequency oscillations and microseizures could provide valuable insights into causes and therapies for the treatment of epilepsy, but requires high spatial and temporal resolution. Our group is currently using hybrid arrays composed of up to 320 micro- and clinical macroelectrode arrays sampled at 32 kHz per channel with 18-bits of A/D resolution. Such recordings produce approximately 3 terabytes of data per day. Existing file formats have limited data compression capabilities, and do not offer mechanisms for protecting patient identifying information or detecting data corruption during transmission or storage. We present a novel file format that employs range encoding to provide a high degree of data compression, a three-tiered 128-bit encryption system for patient information and data security, and a 32-bit cyclic redundancy check to verify the integrity of compressed data blocks. Open-source software to read, write, and process these files are provided.
To investigate the characteristics of intracranial ictal high frequency oscillations (HFOs).
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.
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).
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.
Epilepsy surgery; High frequency oscillations; Intracranial EEG; HFOs; Seizure
Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30–100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG (<100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure-areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) post-surgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain.
Epileptic network; Interictal epileptic discharge; Pathological gamma oscillation; Detection; Mapping; Data-mining
High Frequency Oscillations (HFOs), including Ripples (80–250 Hz) and Fast Ripples (250– 500 Hz), can be recorded from intracranial macroelectrodes in patients with intractable epilepsy. We implemented a procedure to establish the duration for which a stable measurement of rate of HFOs is achieved.
To determine concordance, Kappa coefficient was computed. The information gained when increasing the duration was analyzed in terms of HFO rates and ranking of channels with respect to HFO and spike rates.
In a group of 30 patients, Kappa was 0.7 for ripples, 0.7 for fast ripples and 0.67 for spikes. Five minutes provided the same information as 10 min in terms of rates in 9/10 patients and with respect to ranking of channels in 8/10 patients; 5/30 patients did not achieve stable measurements of HFOs or spikes and needed marking for 10 min.
We propose that 5 min provides in most cases the same information as a longer interval when identifying HFOs and spikes in slow wave sleep, and present methods to identify when this is not the case.
This procedure is useful to control for consistency between readers and to evaluate if the selected interval provides stable information, for automatic and visual identification of events.
PMID: 19576848 CAMSID: cams3407
High Frequency Oscillations, Ripple; Fast ripple; Kappa; Jensen-Shannon Divergence; Ranking Distance
Epilepsy is one of the most frequent neurological diseases. In focal medically refractory epilepsies, successful surgical treatment largely depends on the identification of epileptogenic zone. High-frequency oscillations (HFOs) between 80 and 500 Hz, which can be recorded with EEG, may be novel markers of the epileptogenic zone. This review discusses the clinical importance of HFOs as markers of epileptogenicity and their application in different types of epilepsies. HFOs are clearly linked to the seizure onset zone, and the surgical removal of regions generating them correlates with a seizure free post-surgical outcome. Moreover, HFOs reflect the seizure-generating capability of the underlying tissue, since they are more frequent after the reduction of antiepileptic drugs. They can be successfully used in pediatric epilepsies such as epileptic spasms and help to understand the generation of this specific type of seizures. While mostly recorded on intracranial EEGs, new studies suggest that identification of HFOs on scalp EEG or magnetoencephalography (MEG) is possible as well. Thus not only patients with refractory epilepsies and invasive recordings but all patients might profit from the analysis of HFOs. Despite these promising results, the analysis of HFOs is not a routine clinical procedure; most results are derived from relatively small cohorts of patients and many aspects are not yet fully understood. Thus the review concludes that even if HFOs are promising biomarkers of epileptic tissue, there are still uncertainties about mechanisms of generation, methods of analysis, and clinical applicability. Large multicenter prospective studies are needed prior to widespread clinical application.
Epilepsy; Ripple; Fast ripple; EEG; Seizure; Infantile spasms