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The search for valid biomarkers to aid in epilepsy diagnosis and management is a major goal of the Epilepsy Research Benchmarks. Many papers and grants answer this call by searching for new biomarkers from a wide range of disciplines. However, the academic use of the word "biomarker" is often imprecise. Without proper definition, such work is not well-prepared to progress to the next step of translating these biomarkers into clinical use. In 2016, the Food and Drug Administration and National Institutes of Health collaborated to develop the BEST (Biomarkers, EndpointS, and other Tools) Resource as a guide to adopt formal definitions that aid in pushing successful biomarkers toward regulatory approval. Using the vignette of high-frequency oscillations, which have been proposed as a potential biomarker of several potential aspects of epilepsy, we demonstrate how improper use of the term "biomarker," and lack of a clear context of use, can lead to confusion and difficulty obtaining regulatory approval. Similar conditions are likely in many areas of biomarker research. This Resource should be adopted by all researchers developing epilepsy biomarkers. Adopting the BEST guidelines will improve reproducibility, guide research objectives toward translation, and better target the Epilepsy Benchmarks. [ABSTRACT FROM AUTHOR]

Motivation: There is an ongoing search for definitive and reliable biomarkers to forecast or predict imminent seizure onset, but to date most research has been limited to EEG with sampling rates <1,000 Hz. High-frequency oscillations (HFOs) have gained acceptance as an indicator of epileptic tissue, but few have investigated the temporal properties of HFOs or their potential role as a predictor in seizure prediction. Here we evaluate time-varying trends in preictal HFO rates as a potential biomarker of seizure prediction. Methods: HFOs were identified for all interictal and preictal periods with a validated automated detector in 27 patients who underwent intracranial EEG monitoring. We used LASSO logistic regression with several features of the HFO rate to distinguish preictal from interictal periods in each individual. We then tested these models with held-out data and evaluated their performance with the area-under-the-curve (AUC) of their receiver-operating curve (ROC). Finally, we assessed the significance of these results using non-parametric statistical tests. Results: There was variability in the ability of HFOs to discern preictal from interictal states across our cohort. We identified a subset of 10 patients in whom the presence of the preictal state could be successfully predicted better than chance. For some of these individuals, average AUC in the held-out data reached higher than 0.80, which suggests that HFO rates can significantly differentiate preictal and interictal periods for certain patients. Significance: These findings show that temporal trends in HFO rate can predict the preictal state better than random chance in some individuals. Such promising results indicate that future prediction efforts would benefit from the inclusion of high-frequency information in their predictive models and technological architecture. [ABSTRACT FROM AUTHOR]

Objective: High‐frequency oscillations (HFOs) have shown promising utility in the spatial localization of the seizure onset zone for patients with focal refractory epilepsy. Comparatively few studies have addressed potential temporal variations in HFOs, or their role in the preictal period. Here, we introduce a novel evaluation of the instantaneous HFO rate through interictal and peri‐ictal epochs to assess their usefulness in identifying imminent seizure onset. Methods: Utilizing an automated HFO detector, we analyzed intracranial electroencephalographic data from 30 patients with refractory epilepsy undergoing long‐term presurgical evaluation. We evaluated HFO rates both as a 30‐minute average and as a continuous function of time and used nonparametric statistical methods to compare individual and population‐level differences in rate during peri‐ictal and interictal periods. Results: Mean HFO rate was significantly higher for all epochs in seizure onset zone channels versus other channels. Across the 30 patients of our cohort, we found no statistically significant differences in mean HFO rate during preictal and interictal epochs. For continuous HFO rates in seizure onset zone channels, however, we found significant population‐wide increases in preictal trends relative to interictal periods. Using a data‐driven analysis, we identified a subset of 11 patients in whom either preictal HFO rates or their continuous trends were significantly increased relative to those of interictal baseline and the rest of the population. Significance: These results corroborate existing findings that HFO rates within epileptic tissue are higher during interictal periods. We show this finding is also present in preictal, ictal, and postictal data, and identify a novel biomarker of preictal state: an upward trend in HFO rate leading into seizures in some patients. Overall, our findings provide preliminary evidence that HFOs can function as a temporal biomarker of seizure onset. [ABSTRACT FROM AUTHOR]

High-frequency (100-500 Hz) oscillations (HFOs) recorded from intracranial electrodes are a potential biomarker for epileptogenic brain. HFOs are commonly categorized as ripples (100-250 Hz) or fast ripples (250-500 Hz), and a third class of mixed frequency events has also been identified. We hypothesize that temporal changes in HFOs may identify periods of increased the likelihood of seizure onset. HFOs (86,151) from five patients with neocortical epilepsy implanted with hybrid (micro + macro) intracranial electrodes were detected using a previously validated automated algorithm run over all channels of each patient's entire recording. HFOs were characterized by extracting quantitative morphologic features and divided into four time epochs (interictal, preictal, ictal, and postictal) and three HFO clusters (ripples, fast ripples, and mixed events). We used supervised classification and nonparametric statistical tests to explore quantitative changes in HFO features before, during, and after seizures. We also analyzed temporal changes in the rates and proportions of events from each HFO cluster during these periods. We observed patient-specific changes in HFO morphology linked to fluctuation in the relative rates of ripples, fast ripples, and mixed frequency events. These changes in relative rate occurred in pre- and postictal periods up to thirty min before and after seizures. We also found evidence that the distribution of HFOs during these different time periods varied greatly between individual patients. These results suggest that temporal analysis of HFO features has potential for designing custom seizure prediction algorithms and for exploring the relationship between HFOs and seizure generation. [ABSTRACT FROM AUTHOR]

• Epileptogenicity Index and Slow Polarizing Shift index are higher for electrode contacts inside the seizure onset zone. • Performance of these indices varies based on the pattern of seizure onset. • Recognition of the pattern of seizure onset may improve the performance of quantitative biomarkers of the seizure onset zone. To compare the performance of different ictal quantitative biomarkers of the seizure onset zone (SOZ) across many seizures in a cohort of consecutive patients with a variety of seizure onset patterns. The Epileptogenicity Index (EI, a measure of fast activity) and Slow Polarizing Shift index (SPS, a measure of infraslow activity) were calculated for 212 seizures (22 patients). After stratification by onset pattern, median index values inside and outside the SOZ were compared in aggregate and for each of the onset patterns. Receiver Operating Characteristic (ROC) curves were constructed to compare the performance of each index. Median values of EI (0.056 vs 0.0087), SPS (0.27 vs 0.19), and CI (0.21 vs 0.12) were significantly higher for contacts inside the SOZ, all p < 0.0001. Analysis of AUC showed variable performance of these indices across seizure types, although AUC for EI and SPS was generally greatest for seizures with fast activity at onset. All indices were significantly higher for contacts inside the SOZ; however, the performance of these indices varied depending on the pattern of seizure onset. These findings suggest that future studies of quantitative biomarkers of the SOZ should account for seizure onset pattern. [ABSTRACT FROM AUTHOR]

Objective High Frequency Oscillations (HFOs) are being studied as a biomarker of epilepsy, yet it is unknown how various acquisition parameters at different centers affect detection and analysis of HFOs. This paper specifically quantifies effects of sampling rate (FS) and anti-aliasing filter (AAF) positions on automated HFO detection. Methods HFOs were detected on intracranial EEG recordings (17 patients) with 5 kHz FS. HFO detection was repeated on downsampled and/or filtered copies of the EEG data, mimicking sampling rates and low-pass filter settings of various acquisition equipment. For each setting, we compared the HFO detection sensitivity, HFO features, and ability to identify the ictal onset zone. Results The relative sensitivity remained above 80% for either FS ⩾2 kHz or AAF ⩾500 Hz. HFO feature distributions were consistent (AUROC < 0.7) down to 1 kHz FS or 200 Hz AAF. HFO rate successfully identified ictal onset zone over most settings. HFO peak frequency was highly variable under most parameters (Spearman correlation < 0.5). Conclusions We recommend at least FS ⩾2 kHz and AAF ⩾500 Hz to detect HFOs. Additionally, HFO peak frequency is not robust at any setting: the same HFO event can be variably classified either as a ripple (<200 Hz) or fast ripple (>250 Hz) under different acquisition settings. Significance These results inform clinical centers on requirements to analyze HFO rates and features. [ABSTRACT FROM AUTHOR]

Objective Interictal high frequency oscillations (HFOs) in intracranial EEG are a potential biomarker of epilepsy, but current automated HFO detectors require human review to remove artifacts. Our objective is to automatically redact false HFO detections, facilitating clinical use of interictal HFOs. Methods Intracranial EEG data from 23 patients were processed with automated detectors of HFOs and artifacts. HFOs not concurrent with artifacts were labeled quality HFOs (qHFOs). Methods were validated by human review on a subset of 2000 events. The correlation of qHFO rates with the seizure onset zone (SOZ) was assessed via (1) a retrospective asymmetry measure and (2) a novel quasi-prospective algorithm to identify SOZ. Results Human review estimated that less than 12% of qHFOs are artifacts, whereas 78.5% of redacted HFOs are artifacts. The qHFO rate was more correlated with SOZ ( p = 0.020, Wilcoxon signed rank test) and resected volume ( p = 0.0037) than baseline detections. Using qHFOs, our algorithm was able to determine SOZ in 60% of the ILAE Class I patients, with all algorithmically-determined SOZs fully within the resected volumes. Conclusions The algorithm reduced false-positive HFO detections, improving the precision of the HFO-biomarker. Significance These methods provide a feasible strategy for HFO detection in real-time, continuous EEG with minimal human monitoring of data quality. [ABSTRACT FROM AUTHOR]