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1.  Detection of High-Frequency Oscillations by Hybrid Depth Electrodes in Standard Clinical Intracranial EEG Recordings 
High-frequency oscillations (HFOs) have been proposed as a novel marker for epileptogenic tissue, spurring tremendous research interest into the characterization of these transient events. A wealth of continuously recorded intracranial electroencephalographic (iEEG) data is currently available from patients undergoing invasive monitoring for the surgical treatment of epilepsy. In contrast to data recorded on research-customized recording systems, data from clinical acquisition systems remain an underutilized resource for HFO detection in most centers. The effective and reliable use of this clinically obtained data would be an important advance in the ongoing study of HFOs and their relationship to ictogenesis. The diagnostic utility of HFOs ultimately will be limited by the ability of clinicians to detect these brief, sporadic, and low amplitude events in an electrically noisy clinical environment. Indeed, one of the most significant factors limiting the use of such clinical recordings for research purposes is their low signal to noise ratio, especially in the higher frequency bands. In order to investigate the presence of HFOs in clinical data, we first obtained continuous intracranial recordings in a typical clinical environment using a commercially available, commonly utilized data acquisition system and “off the shelf” hybrid macro-/micro-depth electrodes. These data were then inspected for the presence of HFOs using semi-automated methods and expert manual review. With targeted removal of noise frequency content, HFOs were detected on both macro- and micro-contacts, and preferentially localized to seizure onset zones. HFOs detected by the offline, semi-automated method were also validated in the clinical viewer, demonstrating that (1) this clinical system allows for the visualization of HFOs and (2) with effective signal processing, clinical recordings can yield valuable information for offline analysis.
PMCID: PMC4123606  PMID: 25147541
epilepsy; high-frequency oscillations; clinical neurophysiology; mesial temporal lobe; ripples; fast ripples
2.  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.
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.
PMCID: PMC3325429  PMID: 22523510
partial epilepsy; high-frequency oscillations; fast ripple; ripple; intracranial EEG; seizure onset zone
3.  High-Frequency Oscillations as a New Biomarker in Epilepsy 
Annals of neurology  2012;71(2):169-178.
The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high-frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high-pass filter and increasing the time and amplitude scales, or EEG time-frequency maps can show the amount of high-frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research.
PMCID: PMC3754947  PMID: 22367988 CAMSID: cams3339
4.  Human Intracranial High Frequency Oscillations (HFOs) Detected by Automatic Time-Frequency Analysis 
PLoS ONE  2014;9(4):e94381.
High frequency oscillations (HFOs) have been proposed as a new biomarker for epileptogenic tissue. The exact characteristics of clinically relevant HFOs and their detection are still to be defined.
We propose a new method for HFO detection, which we have applied to six patient iEEGs. In a first stage, events of interest (EoIs) in the iEEG were defined by thresholds of energy and duration. To recognize HFOs among the EoIs, in a second stage the iEEG was Stockwell-transformed into the time-frequency domain, and the instantaneous power spectrum was parameterized. The parameters were optimized for HFO detection in patient 1 and tested in patients 2–5. Channels were ranked by HFO rate and those with rate above half maximum constituted the HFO area. The seizure onset zone (SOZ) served as gold standard.
The detector distinguished HFOs from artifacts and other EEG activity such as interictal epileptiform spikes. Computation took few minutes. We found HFOs with relevant power at frequencies also below the 80–500 Hz band, which is conventionally associated with HFOs. The HFO area overlapped with the SOZ with good specificity > 90% for five patients and one patient was re-operated. The performance of the detector was compared to two well-known detectors.
Compared to methods detecting energy changes in filtered signals, our second stage - analysis in the time-frequency domain - discards spurious detections caused by artifacts or sharp epileptic activity and improves the detection of HFOs. The fast computation and reasonable accuracy hold promise for the diagnostic value of the detector.
PMCID: PMC3983146  PMID: 24722663
5.  Potential for unreliable interpretation of EEG recorded with microelectrodes 
Epilepsia  2013;54(8):1391-1401.
Recent studies in epilepsy, cognition, and brain machine interfaces have shown the utility of recording intracranial EEG (iEEG) with greater spatial resolution. Many of these studies utilize microelectrodes connected to specialized amplifiers that are optimized for such recordings. We recently measured the impedances of several commercial microelectrodes and demonstrated that they will distort iEEG signals if connected to clinical EEG amplifiers commonly used in most centers. In this study we demonstrate the clinical implications of this effect and identify some of the potential difficulties in using microelectrodes.
Human iEEG data were digitally filtered to simulate the signal recorded by a hybrid grid (2 macro- and 8 microelectrodes) connected to a standard EEG amplifier. The filtered EEG data were read by three trained epileptologists, and high frequency oscillations (HFOs) detected with a well-known algorithm. The filtering method was verified experimentally by recording an injected EEG signal in a saline bath with the same physical acquisition system used to generate the model. Several electrodes underwent scanning electron microscopy (SEM).
Macroelectrode recordings were unaltered compared to the source iEEG signal, but microelectrodes attenuated low frequencies. The attenuated signals were difficult to interpret: all three clinicians changed their clinical scoring of slowing and seizures when presented with the same data recorded on different electrodes. The HFO detection algorithm was oversensitive with microelectrodes, classifying many more HFOs than when the same data were recorded with macroelectrodes. In addition, during experimental recordings the microelectrodes produced much greater noise as well as large baseline fluctuations, creating sharply-contoured transients, and superimposed “false” HFOs. SEM of these microelectrodes demonstrated marked variability in exposed electrode surface area, lead fractures, and sharp edges.
Microelectrodes should not be used with low impedance (< 1GΩ) amplifiers due to severe signal attenuation and variability that changes clinical interpretations. The current method of preparing microelectrodes can leave sharp edges and nonuniform amounts of exposed wire. Even when recorded with higher impedance amplifiers, microelectrode data is highly prone to artifacts that are difficult to interpret. Great care must be taken when analyzing iEEG from high impedance microelectrodes.
PMCID: PMC3731390  PMID: 23647099
electrodes; impedance; high frequency oscillations; electrocorticography
6.  High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings 
Brain : a journal of neurology  2008;131(Pt 4):928-937.
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.
PMCID: PMC2760070  PMID: 18263625
high-frequency oscillations; ripple; fast ripple; intracranial EEG; epilepsy
7.  A comparison between detectors of high frequency oscillations 
High frequency oscillations (HFOs) are a biomarker of epileptogenicity. Visual marking of HFOs is highly time-consuming and inevitably subjective, making automatic detection necessary. We compare four existing detectors on the same dataset.
HFOs and baselines were identified by experienced reviewers in intracerebral EEGs from 20 patients. A new feature of our detector to deal with channels where baseline cannot be found is presented. The original and an optimal configuration are implemented. Receiver operator curves, false discovery rate, and channel ranking are used to evaluate performance.
All detectors improve performance with the optimal configuration. Our detector had higher sensitivity, lower false positives than the others, and similar false detections. The main difference in performance was in very active channels.
Each detector was developed for different recordings and with different aims. Our detector performed better in this dataset, but was developed on data similar to the test data. Moreover, optimizing on a particular data type improves performance in any detector.
Automatic HFO detection is crucial to propel their clinical use as biomarkers of epileptogenic tissue. Comparing detectors on a single dataset is important to analyze their performance and to emphasize the issues involved in validation.
PMCID: PMC3782488  PMID: 21763191 CAMSID: cams3336
High frequency oscillations; HFO; Automatic detector; Intracerebral EEG
8.  High-frequency oscillations (HFOs) in clinical epilepsy 
Progress in neurobiology  2012;98(3):302-315.
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.
PMCID: PMC3674884  PMID: 22480752
Epilepsy; Ripple; Fast ripple; EEG; Seizure; Infantile spasms
9.  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.
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.
PMCID: PMC3792077  PMID: 18479382 CAMSID: cams3466
Epilepsy; High-frequency oscillations; Spikes; Seizure onset zone; Intracranial electrodes
10.  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.
PMCID: PMC3792079  PMID: 19297507 CAMSID: cams3471
high frequency oscillations; focal cortical dysplasia; nodular heterotopia; temporal atrophy; seizure onset zone; intracranial EEG
11.  Resection of ictal high-frequency oscillations leads to favorable surgical outcome in pediatric epilepsy 
Epilepsia  2012;53(9):1607-1617.
Intracranial electroencephalography (EEG) is performed as part of an epilepsy surgery evaluation when noninvasive tests are incongruent or the putative seizure-onset zone is near eloquent cortex. Determining the seizure-onset zone using intracranial EEG has been conventionally based on identification of specific ictal patterns with visual inspection. High-frequency oscillations (HFOs, >80 Hz) have been recognized recently as highly correlated with the epileptogenic zone. However, HFOs can be difficult to detect because of their low amplitude. Therefore, the prevalence of ictal HFOs and their role in localization of epileptogenic zone on intracranial EEG are unknown.
We identified 48 patients who underwent surgical treatment after the surgical evaluation with intracranial EEG, and 44 patients met criteria for this retrospective study. Results were not used in surgical decision making. Intracranial EEG recordings were collected with a sampling rate of 2,000 Hz. Recordings were first inspected visually to determine ictal onset and then analyzed further with time-frequency analysis. Forty-one (93%) of 44 patients had ictal HFOs determined with time-frequency analysis of intracranial EEG.
Key Findings
Twenty-two (54%) of the 41 patients with ictal HFOs had complete resection of HFO regions, regardless of frequency bands. Complete resection of HFOs (n = 22) resulted in a seizure-free outcome in 18 (82%) of 22 patients, significantly higher than the seizure-free outcome with incomplete HFO resection (4/19, 21%).
Our study shows that ictal HFOs are commonly found with intracranial EEG in our population largely of children with cortical dysplasia, and have localizing value. The use of ictal HFOs may add more promising information compared to interictal HFOs because of the evidence of ictal propagation and followed by clinical aspect of seizures. Complete resection of HFOs is a favorable prognostic indicator for surgical outcome.
PMCID: PMC3520059  PMID: 22905734
High-frequency oscillations; Intracranial EEG; Time-frequency analysis; Surgical outcome; Nonlesional epilepsy
12.  Contact size does not affect high frequency oscillation detection in intracerebral EEG recordings in a rat epilepsy model 
High frequency oscillations (HFOs) have been implicated in ictogenesis and epileptogenesis. The effect of contact size (in the clinical range: 1–10 mm2) on HFO detection has not been determined. This study assesses the feasibility of HFO detection in a rat epilepsy model using macrocontacts and clinical amplifiers, and the effect of contact size on HFO detection within the macrocontact range.
Eight epileptic rats were implanted with intracerebral electrodes containing three adjacent contacts of different sizes (0.02, 0.05 and 0.09 mm2). HFOs were manually marked on 5 min interictal EEG segments. HFO rates and durations were compared between the different contacts.
10,966 ripples and 1475 fast ripples were identified in the recordings from 30 contacts. There were no significant differences in spike or HFO rates between the different contact sizes, nor was there a significant difference in HFO duration.
HFOs can be detected in a rat epilepsy model using macrocontacts. Within the studied range, size did not significantly influence HFO detection.
Using comparative anatomy of rat and human limbic structures, these findings suggest that reducing the size of macrocontacts (compared to those commercially available) would not improve HFO detection rates.
PMCID: PMC3753291  PMID: 21429792 CAMSID: cams3346
High frequency oscillation; HFO; Ripple; Fast ripple; Intracerebral recording; Depth electrode; SEEG
13.  High-frequency oscillations mirror disease activity in patients with epilepsy 
Neurology  2009;72(11):979-986.
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.
PMCID: PMC3797085  PMID: 19289737 CAMSID: cams3470
14.  High frequency oscillations and infraslow activity in epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S99-S106.
In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy.
PMCID: PMC4001231  PMID: 24791097
Epilepsy; high frequency oscillations; infraslow activity; intracranial electroencephalogram; seizure
15.  The role of high-frequency oscillations in epilepsy surgery planning 
Epilepsy is a serious brain disorder characterized by recurrent unprovoked seizures. Approximately two-thirds of seizures can be controlled with antiepileptic medications (Kwan 2000). For some of the others, surgery can completely eliminate or significantly reduce the occurrence of disabling seizures. Localization of epileptogenic areas for resective surgery is far from perfect, and new tools are being investigated to more accurately localize the epileptogenic zone (the zone of the brain where the seizures begin) and improve the likelihood of freedom from postsurgical seizures. Recordings of pathological high-frequency oscillations (HFOs) may be one such tool.
To assess the ability of HFOs to improve the outcomes of epilepsy surgery by helping to identify more accurately the epileptogenic areas of the brain.
Search methods
We searched the Cochrane Epilepsy Group Specialized Register (15 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 3), MEDLINE (Ovid) (1946 to 15 April 2013), CINAHL (EBSCOhost) (15 April 2013), Web of Knowledge (Thomson Reuters) (15 April 2013), (15 April 2013), and the World Health Organization International Clinical Trials Registry Platform (15 April 2013).
Selection criteria
We included studies that provided information on the outcomes of epilepsy surgery at at least six months and which used high-frequency oscillations in making decisions about epilepsy surgery.
Data collection and analysis
The primary outcome of the review was the Engel Class Outcome System. Secondary outcomes were responder rate, International League Against Epilepsy (ILAE) epilepsy surgery outcome, frequency of adverse events from any source and quality of life outcomes. We intended to analyse outcomes via an aggregated data fixed-effect model meta-analysis.
Main results
Two studies met the inclusion criteria. Both studies were small non-randomised trials, with no control group and no blinding. The quality of evidence for all outcomes was very low. The combination of these two studies resulted in 11 participants who prospectively used ictal HFOs for epilepsy surgery decision making. Results of the postsurgical seizure freedom Engel class I to IV outcome were determined over a period of 12 to 38 months (average 23.4 months) and indicated that six participants had an Engel class I outcome (seizure freedom), two had class II (rare disabling seizures), three had class III (worthwhile improvement). No adverse effects were reported. Neither study compared surgical results guided by HFOs versus surgical results guided without HFOs.
Authors’ conclusions
No reliable conclusions can be drawn regarding the efficacy of using HFOs in epilepsy surgery decision making at present.
PMCID: PMC4248664  PMID: 24431136
*Decision Making; Electroencephalography [*methods]; Epilepsy [*surgery]; Seizures [surgery]; Treatment Outcome; Humans
16.  Ictal High Frequency Oscillations in Neocortical Epilepsy: Implications for Seizure Localization and Surgical Resection 
Epilepsia  2011;52(10):1792-1801.
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.
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).
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.
PMCID: PMC3188690  PMID: 21762451
Epilepsy surgery; High frequency oscillations; Intracranial EEG; HFOs; Seizure
17.  L-type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue 
Epilepsia  2011;52(3):531-540.
Human hypothalamic hamartomas (HH) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L-type calcium channel antagonist nifedipine blocks spontaneous firing and GABAA-induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L-type calcium channels attenuates emergent activity of HH neuronal networks.
A high-density multi-electrode array was used to record extracellular signals from surgically resected HH tissue slices. High frequency oscillations (HFOs: ripples and fast ripples), field potentials and multi-unit activity (MUA) were studied (1) under normal and provoked [4-aminopyridine (4-AP)] conditions, and (2) following nifedipine treatment.
Key Findings
Spontaneous activity occurred during normal aCSF conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials and increased the inter-HFO burst intervals. Notably, the number of active regions was decreased by 45±9% after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4-AP increased the number of events and, as the number of electrodes that detected activity increased 248±62%, promoted tissue-wide propagation of activity. During provocation with 4-AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, the number of active regions and limited propagation.
This is the first study to report (1) the presence of HFOs in human sub-cortical epileptic brain tissue in vitro; (2) the modulation of ‘pathologic’ high-frequency oscillations (i.e. fast ripples) in human epileptic tissue by L-type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L-type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions support a potential therapeutic usefulness of L-type calcium channel blockers in epileptic patients with HH.
PMCID: PMC3071288  PMID: 21269296
Epilepsy; high frequency oscillations; nifedipine; multi-electrode array; gelastic seizures; hypothalamus
18.  L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue 
Epilepsia  2011;52(3):531-540.
Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L-type calcium channel antagonist nifedipine blocks spontaneous firing and γ-aminobutyric acid (GABA)A–induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L-type calcium channels attenuates emergent activity of HH neuronal networks.
A high-density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High-frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4-aminopyridine (4-AP)] conditions; and (2) following nifedipine treatment.
Key Findings
Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter-HFO burst intervals. Notably, the number of active regions was decreased by 45 ± 9% (mean ± SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4-AP increased the number of events and, as the number of electrodes that detected activity increased 248 ± 62%, promoted tissue-wide propagation of activity. During provocation with 4-AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation.
This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of “pathologic” high-frequency oscillations (i.e., fast ripples) in human epileptic tissue by L-type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L-type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L-type calcium channel blockers in epileptic patients with HH.
PMCID: PMC3071288  PMID: 21269296
Epilepsy; High-frequency oscillations; Nifedipine; Multielectrode array; Gelastic seizures; Hypothalamus
19.  Value of electrical stimulation and high frequency oscillations (80–500 Hz) in identifying epileptogenic areas during intracranial EEG recordings 
Epilepsia  2009;51(4):573-582.
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.
PMCID: PMC3775780  PMID: 19845730 CAMSID: cams3394
Ripple; Fast ripple; Electrical stimulation; Seizure-onset zone
20.  Detection of seizure-associated high-frequency oscillations above 500 Hz 
Epilepsy research  2009;88(0):139-144.
High-frequency oscillations (HFOs) of up to 500 Hz in EEG are considered to have close relation with ictogenesis. We had the unique opportunity to record a seizure in EEG with intracerebral macroelectrodes and a sampling frequency of 10 kHz. Considering the notion that faster HFOs are likely more ictogenic, we investigated this ictal EEG data to find if even faster HFOs were present.
HFOs were investigated in interictal spikes and seizure activity using time–frequency spectra: t values corresponding to frequencies from 100 to 1000 Hz were obtained by comparison to the background and controlled by the false discovery rate (FDR).
The seizure had a right hippocampal onset. HFOs up to 800 Hz as well as HFOs below 500 Hz built up in the hippocampal discharges more at the beginning of the seizure and during the preictal period than in the interictal period. These HFOs were visually confirmed in temporally expanded EEG traces.
We demonstrated for the first time the existence of HFOs above 500 Hz and up to 800 Hz with intracerebral macroelectrodes in an epileptic patient; they occurred primarily in association with the seizure discharge. HFOs above 500 Hz possibly reflect facilitation of ictogenic neuronal hypersynchronization.
PMCID: PMC3769288  PMID: 19914804 CAMSID: cams3395
High-frequency oscillation; Mesial temporal lobe epilepsy; Ictal EEG; Time–frequency analysis; False discovery rate
21.  Grammatical Evolution for Features of Epileptic Oscillations in Clinical Intracranial Electroencephalograms 
Expert systems with applications  2011;38(8):9991-9999.
This paper presents grammatical evolution (GE) as an approach to select and combine features for detecting epileptic oscillations within clinical intracranial electroencephalogram (iEEG) recordings of patients with epilepsy. Clinical iEEG is used in preoperative evaluations of a patient who may have surgery to treat epileptic seizures. Literature suggests that pathological oscillations may indicate the region(s) of brain that cause epileptic seizures, which could be surgically removed for therapy. If this presumption is true, then the effectiveness of surgical treatment could depend on the effectiveness in pinpointing critically diseased brain, which in turn depends on the most accurate detection of pathological oscillations. Moreover, the accuracy of detecting pathological oscillations depends greatly on the selected feature(s) that must objectively distinguish epileptic events from average activity, a task that visual review is inevitably too subjective and insufficient to resolve. Consequently, this work suggests an automated algorithm that incorporates grammatical evolution (GE) to construct the most sufficient feature(s) to detect epileptic oscillations within the iEEG of a patient. We estimate the performance of GE relative to three alternative methods of selecting or combining features that distinguish an epileptic gamma (~65-95 Hz) oscillation from normal activity: forward sequential feature-selection, backward sequential feature-selection, and genetic programming. We demonstrate that a detector with a grammatically evolved feature exhibits a sensitivity and selectivity that is comparable to a previous detector with a genetically programmed feature, making GE a useful alternative to designing detectors.
PMCID: PMC3098450  PMID: 21607200
grammatical evolution; detector; epileptic oscillations; intracranial EEG
22.  Automatic detector of High Frequency Oscillations for human recordings with macroelectrodes 
High Frequency Oscillations (HFOs) in the EEG are a promising biomarker of epileptogenic tissue. Given that the visual marking of HFOs is highly time-consuming and subjective, automatic detectors are necessary. In this study, we present a novel automatic detector that detects HFOs by incorporating information of previously detected baselines. The detector was trained on 72 channels and tested on 278, achieving a mean sensitivity of 96.8% with a mean false positive rate of 4.86%. This low rate is reasonable since only visually marked baseline segments were considered as the true negatives. This detector could be useful for the systematic study of HFOs and for their eventual clinical application.
PMCID: PMC3764051  PMID: 21096802 CAMSID: cams3401
23.  High frequency oscillations (80–500 Hz) in the preictal period in patients with focal seizures 
Epilepsia  2009;50(7):1780-1792.
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.
PMCID: PMC3764053  PMID: 19400871 CAMSID: cams3402
Intracranial EEG; Epilepsy; Ripples; Fast ripples; Seizure prediction
24.  Spontaneous and visually-driven high-frequency oscillations in the occipital cortex: Intracranial recording in epileptic patients 
Human Brain Mapping  2011;33(3):569-583.
High-frequency oscillations (HFOs) at ≧80 Hz of nonepileptic nature spontaneously emerge from human cerebral cortex. In 10 patients with extra-occipital lobe epilepsy, we compared the spectral-spatial characteristics of HFOs spontaneously arising from the nonepileptic occipital cortex with those of HFOs driven by a visual task as well as epileptogenic HFOs arising from the extra-occipital seizure focus. We identified spontaneous HFOs at ≧80 Hz with a mean duration of 330 msec intermittently emerging from the occipital cortex during interictal slow-wave sleep. The spectral frequency band of spontaneous occipital HFOs was similar to that of visually-driven HFOs. Spontaneous occipital HFOs were spatially sparse and confined to smaller areas, whereas visually-driven HFOs involved the larger areas including the more rostral sites. Neither spectral frequency band nor amplitude of spontaneous occipital HFOs significantly differed from those of epileptogenic HFOs. Spontaneous occipital HFOs were strongly locked to the phase of delta activity, but the strength of delta-phase coupling decayed from 1 to 3 Hz. Conversely, epileptogenic extra-occipital HFOs were locked to the phase of delta activity about equally in the range from 1 to 3 Hz. The occipital cortex spontaneously generates physiological HFOs which may stand out on electrocorticography traces as prominently as pathological HFOs arising from elsewhere; this observation should be taken into consideration during presurgical evaluation. Coupling of spontaneous delta and HFOs may increase the understanding of significance of delta-oscillations during slow-wave sleep. Further studies are warranted to determine whether delta-phase coupling distinguishes physiological from pathological HFOs or simply differs across anatomical locations.
PMCID: PMC3220781  PMID: 21432945
epilepsy surgery; fast ripples; in-vivo animation of event-related gamma-oscillations; electroencephalography (EEG); memory consolidation; perceptual visual learning; slow-wave sleep
25.  How to establish causality in epilepsy surgery 
Brain & development  2013;35(8):706-720.
Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill's criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80 Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management.
PMCID: PMC3740064  PMID: 23684007
infantile spasms; pediatric epilepsy surgery; concept of the epileptogenic zone; eloquent cortex; functional brain mapping; language; in-vivo animation of event-related gamma activity; Hill's criteria for causality; high-frequency oscillations (HFOs)

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