Search

In medication-resistant epilepsy, the goal of epilepsy surgery is to make a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure-onset zone and incorporation of neuroimaging findings from MRI, PET, single-photon emission CT and magnetoencephalography modalities. Resecting cortical tissue generating high-frequency oscillations has been investigated as a more efficacious alternative to targeting the seizure-onset zone. In this study, we used a support vector machine (SVM), with four distinct fast ripple (FR: 350-600 Hz on oscillations, 200-600 Hz on spikes) metrics as factors. These metrics included the FR resection ratio, a spatial FR network measure and two temporal FR network measures. The SVM was trained by the value of these four factors with respect to the actual resection boundaries and actual seizure-free labels of 18 patients with medically refractory focal epilepsy. Leave-one-out cross-validation of the trained SVM in this training set had an accuracy of 0.78. We next used a simulated iterative virtual resection targeting the FR sites that were of highest rate and showed most temporal autonomy. The trained SVM utilized the four virtual FR metrics to predict virtual seizure freedom. In all but one of the nine patients who were seizure free after surgery, we found that the virtual resections sufficient for virtual seizure freedom were larger in volume (P < 0.05). In nine patients who were not seizure free, a larger virtual resection made five virtually seizure free. We also examined 10 medically refractory focal epilepsy patients implanted with the responsive neurostimulator system and virtually targeted the responsive neurostimulator system stimulation contacts proximal to sites generating FR at highest rates to determine if the simulated value of the stimulated seizure-onset zone and stimulated FR metrics would trend towards those patients with a better seizure outcome. Our results suggest the following: (i) FR measures can accurately predict whether a resection, defined by the standard of care, will result in seizure freedom; (ii) utilizing FR alone for planning an efficacious surgery can be associated with larger resections; (iii) when FR metrics predict the standard-of-care resection will fail, amending the boundaries of the planned resection with certain FR-generating sites may improve outcome and (iv) more work is required to determine whether targeting responsive neurostimulator system stimulation contact proximal to FR generating sites will improve seizure outcome.

Fast ripples (FR) are a biomarker of epileptogenic brain, but when larger portions of FR generating regions are resected seizure freedom is not always achieved. To evaluate and improve the diagnostic accuracy of FR resection for predicting seizure freedom we compared the FR resection ratio (RR) with FR network graph theoretical measures. In 23 patients FR were semi-automatically detected and quantified in stereo EEG recordings during sleep. MRI normalization and co-registration localized contacts and relation to resection margins. The number of FR, and graph theoretical measures, which were spatial (i.e., FR rate-distance radius) or temporal correlational (i.e., FR mutual information), were compared with the resection margins and with seizure outcome We found that the FR RR did not correlate with seizure-outcome (p > 0.05). In contrast, the FR rate-distance radius resected difference and the FR MI mean characteristic path length RR did correlate with seizure-outcome (p

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200-600 Hz), but not ripples (80-200 Hz), frequently occur

ObjectiveAiming to improve the feasibility and reliability of using high-frequency oscillations (HFOs) for translational studies of epilepsy, we present a pipeline with features specifically designed to reject false positives for HFOs to improve the automatic HFO detector.MethodsWe presented an integrated, multi-layered procedure capable of automatically rejecting HFOs from a variety of common false positives, such as motion, background signals, and sharp transients. This method utilizes a time-frequency contour approach that embeds three different layers including peak constraints, power thresholds, and morphological identification to discard false positives. Four experts were involved in rating detected HFO events that were randomly selected from different posttraumatic epilepsy (PTE) animals for a comprehensive evaluation.ResultsThe algorithm was run on 768-h recordings of intracranial electrodes in 48 PTE animals. A total of 453 917 HFOs were identified by initial HFO detection, of which 450 917 were implemented for HFO refinement and 203 531 events were retained. Random sampling was used to evaluate the performance of the detector. The HFO detection yielded an overall accuracy of 0.95±0.03 , with precision, recall, and F1 scores of 0.92±0.05 , 0.99±0.01 , and 0.94±0.03 , respectively. For the HFO classification, our algorithm obtained an accuracy of 0.97±0.02 . For the inter-rater reliability of algorithm evaluation, the agreement among four experts was 0.94±0.03 for HFO detection and 0.85±0.04 for HFO classification.SignificanceOur approach shows that a segregated pipeline design with a focus on false-positive rejection can improve the detection efficiency and provide reliable results. This pipeline does not require customization and uses fixed parameters, making it highly feasible and translatable for basic and clinical applications of epilepsy.

The epileptic network hypothesis and epileptogenic zone hypothesis are two theories of ictogenesis. The network hypothesis posits that coordinated activity among interconnected nodes produces seizures. The epileptogenic zone hypothesis posits that distinct regions are necessary and sufficient for seizure generation. High-frequency oscillations, and particularly fast ripples, are thought to be biomarkers of the epileptogenic zone. We sought to test these theories by comparing high-frequency oscillation rates and networks in surgical responders and non-responders, with no appreciable change in seizure frequency or severity, within a retrospective cohort of 48 patients implanted with stereo-EEG electrodes. We recorded inter-ictal activity during non-rapid eye movement sleep and semi-automatically detected and quantified high-frequency oscillations. Each electrode contact was localized in normalized coordinates. We found that the accuracy of seizure onset zone electrode contact classification using high-frequency oscillation rates was not significantly different in surgical responders and non-responders, suggesting that in non-responders the epileptogenic zone partially encompassed the seizure onset zone(s) (P > 0.05). We also found that in the responders, fast ripple on oscillations exhibited a higher spectral content in the seizure onset zone compared with the non-seizure onset zone (P 350 Hz. The first was a rate-distance network that multiplied the Euclidian distance between fast ripple-generating contacts by the average rate of fast ripple in the two contacts. The radius of the rate-distance network, which excluded seizure onset zone nodes, discriminated non-responders, including patients not offered resection or responsive neurostimulation due to diffuse multifocal onsets, with an accuracy of 0.77 [95% confidence interval (CI) 0.56-0.98]. The second fast ripple network was constructed using the mutual information between the timing of the events to measure functional connectivity. For most non-responders, this network had a longer characteristic path length, lower mean local efficiency in the non-seizure onset zone, and a higher nodal strength among non-seizure onset zone nodes relative to seizure onset zone nodes. The graphical theoretical measures from the rate-distance and mutual information networks of 22 non- responsive neurostimulation treated patients was used to train a support vector machine, which when tested on 13 distinct patients classified non-responders with an accuracy of 0.92 (95% CI 0.75-1). These results indicate patients who do not respond to surgery or those not selected for resection or responsive neurostimulation can be explained by the epileptic network hypothesis that is a decentralized network consisting of widely distributed, hyperexcitable fast ripple-generating nodes.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

We studied the role of temporal and spatial changes in high-frequency oscillation (HFO, 80-500 Hz) generation in epileptogenesis following traumatic brain injury (TBI). Experiments were conducted on adult male Sprague Dawley rats. For the TBI group, fluid percussion injury (FPI) on the left sensorimotor area was performed to induce posttraumatic epileptogenesis. For the sham control group, only the craniotomy was performed. After TBI, 8 bipolar micro-electrodes were implanted bilaterally in the prefrontal cortex, perilesional area and homotopic contralateral site, striatum, and hippocampus. Long-term video/local field potential (LFP) recordings were performed for up to 21 weeks to identify and characterize seizures and capture HFOs. The electrode tip locations and the volume of post TBI brain lesions were further estimated by ex-vivo MRI scans. HFOs were detected during slow-wave sleep and categorized as ripple (80-200 Hz) and fast ripple (FR, 250-500 Hz) events. HFO rates and the HFO peak frequencies were compared in the 8 recording locations and across 8-weeks following TBI. Data from 48 rats (8 sham controls and 40 TBI rats) were analyzed. Within the TBI group, 22 rats (55%) developed recurrent spontaneous seizures (E+ group), at an average of 62.2 (+17.1) days, while 18 rats (45%) did not (E- group). We observed that the HFOs in the E+ group had a higher mean peak frequency than the E- group and the sham group (P

To see whether acute intraoperative recordings using stereo EEG (SEEG) electrodes can replace prolonged interictal intracranial EEG (iEEG) recording, making the process more efficient and safer, 10 min of iEEG were recorded following electrode implantation in 16 anesthetized patients, and 1-2 days later during non-rapid eye movement (REM) sleep. Ripples on oscillations (RonO, 80-250 Hz), ripples on spikes (RonS), sharp-spikes, fast RonO (fRonO, 250-600 Hz), and fast RonS (fRonS) were semi-automatically detected. HFO power and frequency were compared between the conditions using a generalized linear mixed-effects model. HFO rates were compared using a two-way repeated measures ANOVA with anesthesia type and SOZ as factors. A receiver-operating characteristic (ROC) curve analysis quantified seizure onset zone (SOZ) classification accuracy, and the scalar product was used to assess spatial reliability. Resection of contacts with the highest rate of events was compared with outcome. During sleep, all HFOs, except fRonO, were larger in amplitude compared to intraoperatively (p

BackgroundWhile deep brain stimulation has been successful in treating movement disorders, such as in Parkinson's disease, its potential application in alleviating memory disorders is inconclusive.Objective/hypothesisWe investigated the role of the location of the stimulating electrode on memory improvement and hypothesized that entorhinal white versus gray matter stimulation would have differential effects on memory.MethodsIntracranial electrical stimulation was applied to the entorhinal area of twenty-two participants with already implanted electrodes as they completed visual memory tasks.ResultsWe found that stimulation of right entorhinal white matter during learning had a beneficial effect on subsequent memory, while stimulation of adjacent gray matter or left-sided stimulation was ineffective. This finding was consistent across three different visually guided memory tasks.ConclusionsOur results highlight the importance of precise stimulation site on modulation of human hippocampal-dependent memory and suggest that stimulation of afferent input into the right hippocampus may be an especially promising target for enhancement of visual memory.

Ripple oscillations (80-200 Hz) in the normal hippocampus are involved in memory consolidation during rest and sleep. In the epileptic brain, increased ripple and fast ripple (200-600 Hz) rates serve as a biomarker of epileptogenic brain. We report that both ripples and fast ripples exhibit a preferred phase angle of coupling with the trough-peak (or On-Off) state transition of the sleep slow wave in the hippocampal seizure onset zone (SOZ). Ripples on slow waves in the hippocampal SOZ also had a lower power, greater spectral frequency, and shorter duration than those in the non-SOZ. Slow waves in the mesial temporal lobe modulated the baseline firing rate of excitatory neurons, but did not significantly influence the increased firing rate associated with ripples. In summary, pathological ripples and fast ripples occur preferentially during the On-Off state transition of the slow wave in the epileptogenic hippocampus, and ripples do not require the increased recruitment of excitatory neurons.

Pathological high frequency oscillations (HFOs) are putative neurophysiological biomarkers of epileptogenic brain tissue. Utilizing HFOs for epilepsy surgery planning offers the promise of improved seizure outcomes for patients with medically refractory epilepsy. This review discusses possible machine learning strategies that can be applied to HFO biomarkers to better identify epileptogenic regions. We discuss the role of HFO rate, and utilizing features such as explicit HFO properties (spectral content, duration, and power) and phase-amplitude coupling for distinguishing pathological HFO (pHFO) events from physiological HFO events. In addition, the review highlights the importance of neuroanatomical localization in machine learning strategies.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

ObjectiveIntracellular recordings from cells in entorhinal cortex tissue slices show that low-voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial-temporal LVF seizures recorded in patients.MethodsThe seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single-unit activity during the onset of LVF seizures recorded from microelectrodes in mesial-temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K-means clustering.ResultsFrom a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial-temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p

ObjectiveTo develop a reliable software method using a topographic analysis of time-frequency plots to distinguish ripple (80-200 Hz) oscillations that are often associated with EEG sharp waves or spikes (RonS) from sinusoid-like waveforms that appear as ripples but correspond with digital filtering of sharp transients contained in the wide bandwidth EEG.MethodsA custom algorithm distinguished true from false ripples in one second intracranial EEG (iEEG) recordings using wavelet convolution, identifying contours of isopower, and categorizing these contours into sets of open or closed loop groups. The spectral and temporal features of candidate groups were used to classify the ripple, and determine its duration, frequency, and power. Verification of detector accuracy was performed on the basis of simulations, and visual inspection of the original and band-pass filtered signals.ResultsThe detector could distinguish simulated true from false ripple on spikes (RonS). Among 2934 visually verified trials of iEEG recordings and spectrograms exhibiting RonS the accuracy of the detector was 88.5% with a sensitivity of 81.8% and a specificity of 95.2%. The precision was 94.5% and the negative predictive value was 84.0% (N = 12). Among, 1,370 trials of iEEG recording exhibiting RonS that were reviewed blindly without spectrograms the accuracy of the detector was 68.0%, with kappa equal to 0.01 ± 0.03. The detector successfully distinguished ripple from high spectral frequency 'fast ripple' oscillations (200-600 Hz), and characterize ripple duration and spectral frequency and power. The detector was confounded by brief bursts of gamma (30-80 Hz) activity in 7.31 ± 6.09% of trials, and in 30.2 ± 14.4% of the true RonS detections ripple duration was underestimated.ConclusionsCharacterizing the topographic features of a time-frequency plot generated by wavelet convolution is useful for distinguishing true oscillations from false oscillations generated by filter ringing.SignificanceCategorizing ripple oscillations and characterizing their properties can improve the clinical utility of the biomarker.

ObjectiveTo develop and validate a detector that identifies ripple (80-200 Hz) events in intracranial EEG (iEEG) recordings in a referential montage and utilizes independent component analysis (ICA) to eliminate or reduce high-frequency artifact contamination. Also, investigate the correspondence of detected ripples and the seizure onset zone (SOZ).MethodsiEEG recordings from 16 patients were first band-pass filtered (80-600 Hz) and Infomax ICA was next applied to derive the first independent component (IC1). IC1 was subsequently pruned, and an artifact index was derived to reduce the identification of high-frequency events introduced by the reference electrode signal. A Hilbert detector identified ripple events in the processed iEEG recordings using amplitude and duration criteria. The identified ripple events were further classified and characterized as true or false ripple on spikes, or ripples on oscillations by utilizing a topographical analysis to their time-frequency plot, and confirmed by visual inspection.ResultsThe signal to noise ratio was improved by pruning IC1. The precision of the detector for ripple events was 91.27 ± 4.3%, and the sensitivity of the detector was 79.4 ± 3.0% (N = 16 patients, 5842 ripple events). The sensitivity and precision of the detector was equivalent in iEEG recordings obtained during sleep or intra-operatively. Across all the patients, true ripple on spike rates and also the rates of false ripple on spikes, that were generated due to filter ringing, classified the seizure onset zone (SOZ) with an area under the receiver operating curve (AUROC) of >76%. The magnitude and spectral content of true ripple on spikes generated in the SOZ was distinct as compared with the ripples generated in the NSOZ (p

OBJECTIVE:Differentiating pathologic and physiologic high-frequency oscillations (HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone (SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. METHODS:Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography (iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. RESULTS:We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p

ObjectiveRipples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event.MethodsWe quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ).ResultsBoth the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05).SignificanceGeneration of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

High-frequency oscillations (HFOs) encompass ripples (80 Hz–200 Hz) and fast ripples (200 Hz–600 Hz), serving as a promising biomarker for localizing the epileptogenic zone in epilepsy. Spontaneous fast ripples are always pathological, while ripples may be physiological or pathological. Distinguishing physiological from pathological ripples is important not only for designating epileptogenic brain regions, but also for investigations that study ripples in the context of memory encoding, consolidation, and recall in patients with epilepsy. Many studies have sought to identify distinguishing features between pathological and physiological ripples over the past two decades. Physiological and pathological ripples differ with respect to their spatial location, cellular mechanisms, morphology, and coupling with background electroencephalographic activity. Retrospective studies have demonstrated that differentiating between pathological and physiological ripples can improve surgical outcome prediction. In this review, we summarize the characteristics, differences, and applications of pathological and physiological HFOs and discuss strategies for their clinical translation. [ABSTRACT FROM AUTHOR]

This article discusses the objective of epilepsy surgery, which is to render a patient seizure-free with minimal resection/ablation to minimize morbidity. The current standard of care involves electroclinical delineation of the seizure onset zone (SOZ) using various diagnostic tools. However, this process is time-consuming, costly, and often inconclusive. The article explores the use of interictal high-frequency oscillations (HFOs) as biomarkers to improve the planning of epilepsy surgery. While some studies have shown strong correlations between HFOs and post-operative seizure outcomes, there are concerns about the reliability of using HFO metrics alone to define resection boundaries. The authors encourage further research and propose a clinical trial to compare the efficacy of the standard resection with resection boundaries amended by HFO metrics. [Extracted from the article]

Objective: To confirm and investigate why pathological high‐frequency oscillations (pHFOs), including ripples (80–200 Hz) and fast ripples (200–600 Hz), are generated during the UP‐DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure‐onset zone (SOZ). Methods: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact‐hours of synchronized macro‐ and microelectrode recordings from 6 patients. Sleep slow oscillation (.1–2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP‐DOWN transition. We also examined ripple temporal correlations using cross‐correlograms. Results: At the group level in the SOZ, HFO and HFO‐associated AP probability was highest during the UP‐DOWN transition of slow wave excitability (p < <.001). In the non‐SOZ, HFO and HFO‐associated AP was highest during the DOWN‐UP transition (p < <.001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d =.11–.83) and fast ripples (d =.36–.90) at the UP‐DOWN transition (p <.05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d =.14–.30) and 8.5% (d =.33–.41) of units had significantly less firing during ripples and fast ripples at the UP‐DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non‐SOZ (N = 3). Significance: The UP‐DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation. [ABSTRACT FROM AUTHOR]