High Frequency Oscillations Rates Research Articles

Chronobiological Spatial Clusters of Cortical Regions in the Human Brain.

We demonstrate that different regions of the cerebral cortex have different diurnal rhythms of spontaneously occurring high-frequency oscillations (HFOs). High-frequency oscillations were assessed with standard-of-care stereotactic electroencephalography in patients with drug-resistant epilepsy. To ensure generalizability of our findings beyond patients with drug-resistant epilepsy, we excluded stereotactic electroencephalography electrode contacts lying within seizure-onset zones, epileptogenic lesions, having frequent epileptiform activity, and excessive artifact. For each patient, we evaluated twenty-four 5-minute stereotactic electroencephalography epochs, sampled hourly throughout the day, and obtained the HFO rate (number of HFOs/minute) in every stereotactic electroencephalography channel. We analyzed diurnal rhythms of the HFO rates with the cosinor model and clustered neuroanatomic parcels in a standard brain space based on similarity of their cosinor parameters. Finally, we compared overlap among resting-state networks, described in the neuroimaging literature, and chronobiological spatial clusters discovered by us. We found five clusters that localized predominantly or exclusively to the left perisylvian, left perirolandic and left temporal, right perisylvian and right parietal, right frontal, and right insular-opercular cortices, respectively. These clusters were characterized by similarity of the HFO rates according to the time of the day. Also, these chronobiological spatial clusters preferentially overlapped with specific resting-state networks, particularly default mode network (clusters 1 and 3), frontoparietal network (cluster 1), visual network (cluster 1), and mesial temporal network (cluster 2). This is probably the first human study to report clusters of cortical regions with similar diurnal rhythms of electrographic activity. Overlap with resting-state networks attests to their functional significance and has implications for understanding cognitive functions and epilepsy-related mortality.

Robust compression and detection of epileptiform patterns in ECoG using a real-time spiking neural network hardware framework

Interictal Epileptiform Discharges (IED) and High Frequency Oscillations (HFO) in intraoperative electrocorticography (ECoG) may guide the surgeon by delineating the epileptogenic zone. We designed a modular spiking neural network (SNN) in a mixed-signal neuromorphic device to process the ECoG in real-time. We exploit the variability of the inhomogeneous silicon neurons to achieve efficient sparse and decorrelated temporal signal encoding. We interface the full-custom SNN device to the BCI2000 real-time framework and configure the setup to detect HFO and IED co-occurring with HFO (IED-HFO). We validate the setup on pre-recorded data and obtain HFO rates that are concordant with a previously validated offline algorithm (Spearman’s ρ = 0.75, p = 1e-4), achieving the same postsurgical seizure freedom predictions for all patients. In a remote on-line analysis, intraoperative ECoG recorded in Utrecht was compressed and transferred to Zurich for SNN processing and successful IED-HFO detection in real-time. These results further demonstrate how automated remote real-time detection may enable the use of HFO in clinical practice.

Electrode Surface Area Impacts Measurement of High Frequency Oscillations in Human Intracranial EEG.

High-frequency oscillations (HFOs) are a promising prognostic biomarker of surgical outcome in patients with epilepsy. Their rates of occurrence and morphology have been studied extensively using recordings from electrodes of various geometries. While electrode size is a potential confounding factor in HFO studies, it has largely been disregarded due to a lack of consistent evidence. Therefore, we designed an experiment to directly test the impact of electrode size on HFO measurement. We first simulated HFO measurement using a lumped model of the electrode-tissue interaction. Then eight human subjects were each implanted with a high-density 8x8 grid of subdural electrodes. After implantation, the electrode sizes were altered using a technique recently developed by our group, enabling intracranial EEG recordings for three different electrode surface areas from a static brain location. HFOs were automatically detected in the data and their characteristics were calculated. The human subject measurements were consistent with the model. Specifically, HFO rate measured per area of tissue decreased significantly as electrode surface area increased. The smallest electrodes recorded more fast ripples than ripples. Amplitude of detected HFOs also decreased as electrode surface area increased, while duration and peak frequency were unaffected. These results suggest that HFO rates measured using electrodes of different surface areas cannot be compared directly. This has significant implications for HFOs as a tool for surgical planning, particularly for individual patients implanted with electrodes of multiple sizes and comparisons of HFO rate made across patients and studies.

High frequency oscillations in relation to interictal spikes in predicting postsurgical seizure freedom

We evaluate whether interictal spikes, epileptiform HFOs and their co-occurrence (Spike + HFO) were included in the resection area with respect to seizure outcome. We also characterise the relationship between high frequency oscillations (HFOs) and propagating spikes. We analysed intracranial EEG of 20 patients that underwent resective epilepsy surgery. The co-occurrence of ripples and fast ripples was considered an HFO event; the co-occurrence of an interictal spike and HFO was considered a Spike + HFO event. HFO distribution and spike onset were compared in cases of spike propagation. Accuracy in predicting seizure outcome was 85% for HFO, 60% for Spikes, and 79% for Spike + HFO. Sensitivity was 57% for HFO, 71% for Spikes and 67% for Spikes + HFO. Specificity was 100% for HFO, 54% for Spikes and 85% for Spikes + HFO. In 2/2 patients with spike propagation, the spike onset included the HFO area. Combining interictal spikes with HFO had comparable accuracy to HFO. In patients with propagating spikes, HFO rate was maximal at the onset of spike propagation.

Scalp high-frequency oscillations differentiate neonates with seizures from healthy neonates.

We aimed to investigate (1) whether an automated detector can capture scalp high-frequency oscillations (HFO) in neonates and (2) whether scalp HFO rates can differentiate neonates with seizures from healthy neonates. We considered 20 neonates with EEG-confirmed seizures and four healthy neonates. We applied a previously validated automated HFO detector to determine scalp HFO rates in quiet sleep. Etiology in neonates with seizures included hypoxic-ischemic encephalopathy in 11 cases, structural vascular lesions in 6, and genetic causes in 3. The HFO rates were significantly higher in neonates with seizures (0.098 ± 0.091 HFO/min) than in healthy neonates (0.038 ± 0.025 HFO/min; P = 0.02) with a Hedge's g value of 0.68 indicating a medium effect size. The HFO rate of 0.1 HFO/min/ch yielded the highest Youden index in discriminating neonates with seizures from healthy neonates. In neonates with seizures, etiology, status epilepticus, EEG background activity, and seizure patterns did not significantly impact HFO rates. Neonatal scalp HFO can be detected automatically and differentiate neonates with seizures from healthy neonates. Our observations have significant implications for neuromonitoring in neonates. This is the first step in establishing neonatal HFO as a biomarker for neonatal seizures.

Interictal High-Frequency Oscillations, Spikes, and Connectivity Profiles: a Fingerprint of Epileptogenic Brain Pathologies.

Focal cortical dysplasia (FCD), hippocampal sclerosis (HS), nonspecific gliosis (NG), and normal tissue (NT) comprise the majority of histopathological results of surgically treated drug-resistant epilepsy patients. Epileptic spikes, high-frequency oscillations (HFOs), and connectivity measures are valuable biomarkers of epileptogenicity. The question remains whether they could also be utilized for pre-resective differentiation of the underlying brain pathology. This study explored spikes and HFOs together with functional connectivity in various epileptogenic pathologies. Interictal awake SEEG recordings of 33 patients with focal drug-resistant epilepsy with seizure-free postoperative outcomes were analyzed (15 FCD, 8 HS, 6 NT, and 4 NG). Interictal spikes and HFOs were automatically identified in the channels contained in the overlap of seizure onset zone (SOZ) and resected tissue. Functional connectivity measures (relative entropy, linear correlation, cross-correlation, and phase consistency) were computed for neighboring electrode pairs. Statistically significant differences were found between the individual pathologies in HFO rates, spikes, and their characteristics, together with functional connectivity measures with the highest values in the case of HS and NG/NT. A model to predict brain pathology based on all interictal measures achieved up to 84.0% prediction accuracy. The electrophysiological profile of the various epileptogenic lesions in epilepsy surgery patients was analyzed. Based on this profile, a predictive model was developed. This model offers excellent potential to identify the nature of the underlying lesion prior to resection. If validated, this model may be particularly valuable for counseling patients, as depending on the lesion type, different outcomes are achieved after epilepsy surgery.

Flexible, high-resolution cortical arrays with large coverage capture microscale high-frequency oscillations in patients with epilepsy.

Effective surgical treatment of drug-resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High-frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (μECoG) arrays, which provide high spatial resolution over large cortical surface areas. We used novel liquid crystal polymer thin-film μECoG arrays (.76-1.72-mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80-250 Hz) and fast ripple (250-600 Hz) HFOs using a common energy thresholding detection algorithm along with two stages of artifact rejection. We visualized microscale subregions of HFO activity using spatial maps of HFO rate, signal-to-noise ratio, and mean peak frequency. We quantified the spatial extent of HFO events by measuring covariance between detected HFOs and surrounding activity. We also compared HFO detection rates on microcontacts to simulated macrocontacts by spatially averaging data. We found visually delineable subregions of elevated HFO activity within each μECoG recording. Forty-seven percent of HFOs occurred on single 200-μm-diameter recording contacts, with minimal high-frequency activity on surrounding contacts. Other HFO events occurred across multiple contacts simultaneously, with covarying activity most often limited to a .95-mm radius. Through spatial averaging, we estimated that macrocontacts with 2-3-mm diameter would only capture 44% of the HFOs detected in our μECoG recordings. These results demonstrate that thin-film microcontact surface arrays with both highresolution and large coverage accurately capture microscale HFO activity and may improve the utility of HFOs to localize the EZ for treatment of drug-resistant epilepsy.

Intracranial electrophysiological recordings on a swine model of mesial temporal lobe epilepsy

To test the feasibility and reliability of intracranial electrophysiological recordings in an acute status epilepticus model on laboratory swine. Intrahippocampal injection of kainic acid (KA) was performed on 17 male Bama pigs (Sus scrofa domestica) weighing between 25 and 35 kg. Two stereoelectroencephalography (SEEG) electrodes with a total of 16 channels were implanted bilaterally along the sensorimotor cortex to the hippocampus. Brain electrical activity was recorded 2 h daily for 9-28 days. Three KA dosages were tested to evaluate the quantities capable of evoking status epilepticus. Local field potentials (LFPs) were recorded and compared before and after the KA injection. We quantified the epileptic patterns, including the interictal spikes, seizures, and high-frequency oscillations (HFOs), up to 4 weeks after the KA injection. Test-retest reliability using intraclass correlation coefficients (ICCs) were performed on interictal HFO rates to evaluate the recording stability of this model. The KA dosage test suggested that a 10 μl (1.0 μg/μl) intrahippocampal injection could successfully evoke status epilepticus lasting from 4 to 12 h. At this dosage, eight pigs (50% of total) had prolonged epileptic events (tonic-chronic seizures + interictal spikes n = 5, interictal spikes alone n = 3) in the later 4 weeks of the video-SEEG recording period. Four pigs (25% of total) had no epileptic activities, and another four (25%) had lost the cap or did not complete the experiments. Animals that showed epileptiform events were grouped as E + (n = 8) and the four animals showing no signs of epileptic events were grouped as E- (n = 4). A total of 46 electrophysiological seizures were captured in the 4-week post-KA period from 4 E + animals, with the earliest onset on day 9. The seizure durations ranged from 12 to 45 s. A significant increase of hippocampal HFOs rate (num/min) was observed in the E+ group during the post-KA period (weeks 1, 2,4, p < 0.05) compared to the baseline. But the E-showed no change or a decrease (in week 2, p = 0.43) compared to their baseline rate. The between-group comparison showed much higher HFO rates in E + vs. E - (F = 35, p < 0.01). The high ICC value [ICC (1, k) = 0.81, p < 0.05] quantified from the HFO rate suggested that this model had a stable measurement of HFOs during the four-week post-KA periods. This study measured intracranial electrophysiological activity in a swine model of KA-induced mesial temporal lobe epilepsy (mTLE). Using the clinical SEEG electrode, we distinguished abnormal EEG patterns in the swine brain. The high test-retest reliability of HFO rates in the post-KA period suggests the utility of this model for studying mechanisms of epileptogenesis. The use of swine may provide satisfactory translational value for clinical epilepsy research.

The association of magnetoencephalography high-frequency oscillations with epilepsy types and a ripple-based method with source-level connectivity for mapping epilepsy sources.

To explore the association between high-frequency oscillations (HFOs) and epilepsy types and to improve the accuracy of source localization. Magnetoencephalography (MEG) ripples of 63 drug-resistant epilepsy patients were detected. Ripple rates, distribution, spatial complexity, and the clustering coefficient of ripple channels were used for the preliminary classification of lateral temporal lobe epilepsy (LTLE), mesial temporal lobe epilepsy (MTLE), and nontemporal lobe epilepsy (NTLE), mainly frontal lobe epilepsy (FLE). Furthermore, the seizure site identification was improved using the Tucker LCMV method and source-level betweenness centrality. Ripple rates were significantly higher in MTLE than in LTLE and NTLE (p < 0.05). The LTLE and MTLE were mainly distributed in the temporal lobe, followed by the parietal lobe, occipital lobe, and frontal lobe, whereas MTLE ripples were mainly distributed in the frontal lobe, then parietal lobe and occipital lobe. Nevertheless, the NTLE ripples were primarily in the frontal lobe and partially in the occipital lobe (p < 0.05). Meanwhile, the spatial complexity of NTLE was significantly higher than that of LTLE and MTLE and was lowest in MTLE (p < 0.01). However, an opposite trend was observed for the standardized clustering coefficient compared with spatial complexity (p < 0.01). Finally, the tucker algorithm showed a higher percentage of ripples at the surgical site when the betweenness centrality was added (p < 0.01). This study demonstrated that HFO rates, distribution, spatial complexity, and clustering coefficient of ripple channels varied considerably among the three epilepsy types. Additionally, tucker MEG estimation combined with ripple rates based on the source-level functional connectivity is a promising approach for presurgical epilepsy evaluation.

Epileptogenic high-frequency oscillations present larger amplitude both in mesial temporal and neocortical regions.

High-frequency oscillations (HFO) are a promising biomarker for the identification of epileptogenic tissue. While HFO rates have been shown to predict seizure outcome, it is not yet clear whether their morphological features might improve this prediction. We validated HFO rates against seizure outcome and delineated the distribution of HFO morphological features. We collected stereo-EEG recordings from 20 patients (231 electrodes; 1,943 contacts). We computed HFO rates (the co-occurrence of ripples and fast ripples) through a validated automated detector during non-rapid eye movement sleep. Applying machine learning, we delineated HFO morphological features within and outside epileptogenic tissue across mesial temporal lobe (MTL) and Neocortex. HFO rates predicted seizure outcome with 85% accuracy, 79% specificity, 100% sensitivity, 100% negative predictive value, and 67% positive predictive value. The analysis of HFO features showed larger amplitude in the epileptogenic tissue, similar morphology for epileptogenic HFO in MTL and Neocortex, and larger amplitude for physiological HFO in MTL. We confirmed HFO rates as a reliable biomarker for epilepsy surgery and characterized the potential clinical relevance of HFO morphological features. Our results support the prospective use of HFO in epilepsy surgery and contribute to the anatomical mapping of HFO morphology.

Temporal and morphological characteristics of high-frequency oscillations in an acute in vivo model of epilepsy.

Approximately 30% of patients with epilepsy do not respond to anti-epileptogenic drugs. Surgical removal of the epileptogenic zone (EZ), the brain regions where the seizures originate and spread, can be a possible therapy for these patients, but localizing the EZ is challenging due to a variety of clinical factors. High-frequency oscillations (HFOs) in intracranial electroencephalography (EEG) are a promising biomarker of the EZ, but it is currently unknown whether HFO rates and HFO morphology modulate as pathological brain networks evolve in a way that gives rise to seizures. To address this question, we assessed the temporal evolution of the duration of HFO events, amplitude of HFO events, and rates of HFOs per minute. HFO events were quantified using the 4AP in vivo rodent model of epilepsy, inducing seizures in two different brain areas. We found that the duration and amplitude of HFO events were significantly increased for the cortex model when compared to the hippocampus model. Additionally, the duration and amplitude increased significantly between baseline and pre-ictal HFOs in both models. On the other hand, the two models did not display a consistent increasing or decreasing trend in amplitude, duration or rate when comparing ictal and postictal intervals. Clinical Relevance- We assessed the amplitude, duration, and rate of HFOs in two acute in vivo rodent models of epilepsy. The significant modulation of HFO morphology from baseline to pre-ictal periods suggests that these features may be a robust biomarker for pathological tissue involved in epileptogenesis. Moreover, the differences in HFO morphology observed between cortex and hippocampus animal models possibly indicate that different structural network characteristics of the EZ cause this modulation. In all, we found that HFO features modulate significantly with the onset of seizures, further highlighting the need to consider of HFO morphology in EZ-localizing studies.

Scalp HFO rates are higher for larger lesions.

High‐frequency oscillations (HFO) in scalp EEG are a new and promising noninvasive epilepsy biomarker, providing added prognostic value, particularly in pediatric lesional epilepsy. However, it is unclear if lesion characteristics, such as lesion volume, depth, type, and localization, impact scalp HFO rates. We analyzed scalp EEG from 13 children and adolescents with focal epilepsy associated with focal cortical dysplasia (FCD), low‐grade tumors, or hippocampal sclerosis. We applied a validated automated detector to determine HFO rates in bipolar channels. We identified the lesion characteristics in MRI. Larger lesions defined by MRI volumetric analysis corresponded to higher cumulative scalp HFO rates (P = .01) that were detectable in a higher number of channels (P = .05). Both superficial and deep lesions generated HFO detectable in the scalp EEG. Lesion type (FCD vs tumor) and lobar localization (temporal vs extratemporal) did not affect scalp HFO rates in our study. Our observations support that all lesions may generate HFO detectable in scalp EEG, irrespective of their characteristics, whereas larger epileptogenic lesions generate higher scalp HFO rates over larger areas that are thus more accessible to detection. Our study provides crucial insight into scalp HFO detectability in pediatric lesional epilepsy, facilitating their implementation as an epilepsy biomarker in a clinical setting.

Protocol for multicentre comparison of interictal high-frequency oscillations as a predictor of seizure freedom.

In drug-resistant focal epilepsy, interictal high-frequency oscillations (HFOs) recorded from intracranial EEG (iEEG) may provide clinical information for delineating epileptogenic brain tissue. The iEEG electrode contacts that contain HFO are hypothesized to delineate the epileptogenic zone; their resection should then lead to postsurgical seizure freedom. We test whether our prospective definition of clinically relevant HFO is in agreement with postsurgical seizure outcome. The algorithm is fully automated and is equally applied to all data sets. The aim is to assess the reliability of the proposed detector and analysis approach.We use an automated data-independent prospective definition of clinically relevant HFO that has been validated in data from two independent epilepsy centres. In this study, we combine retrospectively collected data sets from nine independent epilepsy centres. The analysis is blinded to clinical outcome. We use iEEG recordings during NREM sleep with a minimum of 12 epochs of 5 min of NREM sleep. We automatically detect HFO in the ripple (80–250 Hz) and in the fast ripple (250–500 Hz) band. There is no manual rejection of events in this fully automated algorithm. The type of HFO that we consider clinically relevant is defined as the simultaneous occurrence of a fast ripple and a ripple. We calculate the temporal consistency of each patient’s HFO rates over several data epochs within and between nights. Patients with temporal consistency <50% are excluded from further analysis. We determine whether all electrode contacts with high HFO rate are included in the resection volume and whether seizure freedom (ILAE 1) was achieved at ≥2 years follow-up. Applying a previously validated algorithm to a large cohort from several independent epilepsy centres may advance the clinical relevance and the generalizability of HFO analysis as essential next step for use of HFO in clinical practice.

A neuromorphic spiking neural network detects epileptic high frequency oscillations in the scalp EEG

Interictal High Frequency Oscillations (HFO) are measurable in scalp EEG. This development has aroused interest in investigating their potential as biomarkers of epileptogenesis, seizure propensity, disease severity, and treatment response. The demand for therapy monitoring in epilepsy has kindled interest in compact wearable electronic devices for long-term EEG recording. Spiking neural networks (SNN) have emerged as optimal architectures for embedding in compact low-power signal processing hardware. We analyzed 20 scalp EEG recordings from 11 pediatric focal lesional epilepsy patients. We designed a custom SNN to detect events of interest (EoI) in the 80–250 Hz ripple band and reject artifacts in the 500–900 Hz band. We identified the optimal SNN parameters to detect EoI and reject artifacts automatically. The occurrence of HFO thus detected was associated with active epilepsy with 80% accuracy. The HFO rate mirrored the decrease in seizure frequency in 8 patients (p = 0.0047). Overall, the HFO rate correlated with seizure frequency (rho = 0.90 CI [0.75 0.96], p < 0.0001, Spearman’s correlation). The fully automated SNN detected clinically relevant HFO in the scalp EEG. This study is a further step towards non-invasive epilepsy monitoring with a low-power wearable device.

Beyond rates: time-varying dynamics of high frequency oscillations as a biomarker of the seizure onset zone

Objective. High frequency oscillations (HFOs) recorded by intracranial electrodes have generated excitement for their potential to help localize epileptic tissue for surgical resection. However, the number of HFOs per minute (i.e. the HFO ‘rate’) is not stable over the duration of intracranial recordings; for example, the rate of HFOs increases during periods of slow-wave sleep. Moreover, HFOs that are predictive of epileptic tissue may occur in oscillatory patterns due to phase coupling with lower frequencies. Therefore, we sought to further characterize between-seizure (i.e. ‘interictal’) HFO dynamics both within and outside the seizure onset zone (SOZ). Approach. Using long-term intracranial EEG (mean duration 10.3 h) from 16 patients, we automatically detected HFOs using a new algorithm. We then fit a hierarchical negative binomial model to the HFO counts. To account for differences in HFO dynamics and rates between sleep and wakefulness, we also fit a mixture model to the same data that included the ability to switch between two discrete brain states that were automatically determined during the fitting process. The ability to predict the SOZ by model parameters describing HFO dynamics (i.e. clumping coefficients and coefficients of variation) was assessed using receiver operating characteristic curves. Main results. Parameters that described HFO dynamics were predictive of SOZ. In fact, these parameters were found to be more consistently predictive than HFO rate. Using concurrent scalp EEG in two patients, we show that the model-found brain states corresponded to (1) non-REM sleep and (2) awake and rapid eye movement sleep. However the brain state most likely corresponding to slow-wave sleep in the second model improved SOZ prediction compared to the first model for only some patients. Significance. This work suggests that delineation of SOZ with interictal data can be improved by the inclusion of time-varying HFO dynamics.

Scalp HFO rates decrease after successful epilepsy surgery and are not impacted by the skull defect resulting from craniotomy

Epilepsy surgery can achieve seizure freedom in selected pediatric candidates, but reliable postsurgical predictors of seizure freedom are missing. High frequency oscillations (HFO) in scalp EEG are a new and promising biomarker of treatment response. However, it is unclear if the skull defect resulting from craniotomy interferes with HFO detection in postsurgical recordings. We considered 14 children with focal lesional epilepsy who underwent presurgical evaluation, epilepsy surgery, and postsurgical follow-up of ≥ 1 year. We identified the nearest EEG electrodes to the skull defect in the postsurgical MRI. We applied a previously validated automated HFO detector to determine HFO rates in presurgical and postsurgical EEG. Overall, HFO rates showed a positive correlation with seizure frequency (p < 0.001). HFO rates in channels over the HFO area decreased following successful epilepsy surgery, irrespective of their proximity to the skull defect (p = 0.005). HFO rates in channels outside the HFO area but near the skull defect showed no increase following surgery (p = 0.091) and did not differ from their contralateral channels (p = 0.726). Our observations show that the skull defect does not interfere with postsurgical HFO detection. This supports the notion that scalp HFO can predict postsurgical seizure freedom and thus guide therapy management in focal lesional epilepsy.

Interictal high frequency background activity as a biomarker of epileptogenic tissue.

High frequency oscillations (HFOs) are very brief events that are a well-established biomarker of the epileptogenic zone (EZ) but are rare and comprise only a tiny fraction of the total recorded EEG. We hypothesize that the interictal high frequency ‘background’ data, which has received little attention but represents the majority of the EEG record, also may contain additional, novel information for identifying the EZ. We analysed intracranial EEG (30–500 Hz frequency range) acquired from 24 patients who underwent resective surgery. We computed 38 quantitative features based on all usable, interictal data (63–307 h per subject), excluding all detected HFOs. We assessed association between each feature and the seizure onset zone (SOZ) and resected volume (RV) using logistic regression. A pathology score per channel was also created via principle component analysis and logistic regression, using hold-out-one-patient cross-validation to avoid in-sample training. Association of the pathology score with the SOZ and RV was quantified using an asymmetry measure. Many features were associated with the SOZ: 23/38 features had odds ratios >1.3 or <0.7 and 17/38 had odds ratios different than zero with high significance (P < 0.001/39, logistic regression with Bonferroni Correction). The pathology score, the rate of HFOs, and their channel-wise product were each strongly associated with the SOZ [median asymmetry ≥0.44, good surgery outcome patients; median asymmetry ≥0.40, patients with other outcomes; 95% confidence interval (CI) > 0.27 in both cases]. The pathology score and the channel-wise product also had higher asymmetry with respect to the SOZ than the HFO rate alone (median difference in asymmetry ≥0.18, 95% CI >0.05). These results support that the high frequency background data contains useful information for determining the EZ, distinct and complementary to information from detected HFOs. The concordance between the high frequency activity pathology score and the rate of HFOs appears to be a better biomarker of epileptic tissue than either measure alone.

Are HFOs in the Intra-operative ECoG Related to Hippocampal Sclerosis, Volume and IQ?

Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy and is often associated with hippocampal sclerosis (HS) and cognitive disturbances. Over the last decade, high frequency oscillations (HFOs) in the intraoperative electrocorticography (ioECoG) have been proposed to be biomarkers for the delineation of epileptic tissue but hippocampal ripples have also been associated with memory consolidation. Healthy hippocampi can show prolonged ripple activity in stereo- EEG. We aimed to identify how the HFO rates [ripples (80–250 Hz, fast ripples (250–500 Hz); prolonged ripples (80–250 Hz, 200–500 ms)] in the pre-resection ioECoG over subtemporal area (hippocampus) and lateral temporal neocortex relate to presence of hippocampal sclerosis, the hippocampal volume quantified on MRI and the severity of cognitive impairment in TLE patients. Volumetric measurement of hippocampal subregions was performed in 47 patients with TLE, who underwent ioECoG. Ripples, prolonged ripples, and fast ripples were visually marked and rates of HFOs were calculated. The intellectual quotient (IQ) before resection was determined. There was a trend toward higher rates of ripples and fast ripples in subtemporal electrodes vs. the lateral neocortex (ripples: 2.1 vs. 1.3/min; fast ripples: 0.9 vs. 0.2/min). Patients with HS showed higher rates of subtemporal fast ripples than other patients (Z = −2.51, p = 0.012). Prolonged ripples were only found in the lateral temporal neocortex. The normalized ratio (smallest/largest) of hippocampal volume was correlated to pre-resection IQ (r = 0.45, p = 0.015). There was no correlation between HFO rates and hippocampal volumes or HFO rates and IQ. To conclude, intra-operative fast ripples were a marker for HS, but ripples and fast ripples were not linearly correlated with either the amount of hippocampal atrophy, nor for pre-surgical IQ.

A spiking neural network (SNN) for detecting high frequency oscillations (HFOs) in the intraoperative ECoG

To achieve seizure freedom, epilepsy surgery requires the complete resection of the epileptogenic brain tissue. In intraoperative electrocorticography (ECoG) recordings, high frequency oscillations (HFOs) generated by epileptogenic tissue can be used to tailor the resection margin. However, automatic detection of HFOs in real-time remains an open challenge. Here we present a spiking neural network (SNN) for automatic HFO detection that is optimally suited for neuromorphic hardware implementation. We trained the SNN to detect HFO signals measured from intraoperative ECoG on-line, using an independently labeled dataset (58 min, 16 recordings). We targeted the detection of HFOs in the fast ripple frequency range (250-500 Hz) and compared the network results with the labeled HFO data. We endowed the SNN with a novel artifact rejection mechanism to suppress sharp transients and demonstrate its effectiveness on the ECoG dataset. The HFO rates (median 6.6 HFO/min in pre-resection recordings) detected by this SNN are comparable to those published in the dataset (Spearman’s rho = 0.81). The postsurgical seizure outcome was “predicted” with 100% (CI [63 100%]) accuracy for all 8 patients. These results provide a further step towards the construction of a real-time portable battery-operated HFO detection system that can be used during epilepsy surgery to guide the resection of the epileptogenic zone.

Epileptic High-Frequency Oscillations in Intracranial EEG Are Not Confounded by Cognitive Tasks.

Rationale: High-frequency oscillations (HFOs) in intracranial EEG (iEEG) are used to delineate the epileptogenic zone during presurgical diagnostic assessment in patients with epilepsy. HFOs are historically divided into ripples (80–250 Hz), fast ripples (FR, >250 Hz), and their co-occurrence (FRandR). In a previous study, we had validated the rate of FRandRs during deep sleep to predict seizure outcome. Here, we ask whether epileptic FRandRs might be confounded by physiological FRandRs that are unrelated to epilepsy.Methods: We recorded iEEG in the medial temporal lobe MTL (hippocampus, entorhinal cortex, and amygdala) in 17 patients while they performed cognitive tasks. The three cognitive tasks addressed verbal working memory, visual working memory, and emotional processing. In our previous studies, these tasks activated the MTL. We re-analyzed the data of these studies with the automated detector that focuses on the co-occurrence of ripples and FRs (FRandR).Results: For each task, we identified those channels in which the HFO rate was modulated during the task condition compared to the control condition. However, the number of these channels did not exceed the chance level. Interestingly, even during wakefulness, the HFO rate was higher for channels within the seizure onset zone (SOZ) than for channels outside the SOZ.Conclusion: Our prospective definition of an epileptic HFO, the FRandR, is not confounded by physiological HFOs that might be elicited by our cognitive tasks. This is reassuring for the clinical use of FRandR as a biomarker of the EZ.