Inroads into epilepsy through high-frequency oscillations: Achievements and benchmark areas for improvement

High-frequency oscillations (HFOs) were discovered more than 20 years ago, and since then they have been studied intensively in the context of epilepsy. HFOs encompass a broad spectrum of oscillations, typically ranging from 80 Hz to several kHz, that include both normal and pathological oscillations, documented in people with epilepsy and animal models. HFOs have drawn considerable attention due to their prominent roles in epileptogenesis, ictogenesis, and functional organization of epileptic tissue. We provide historical background on HFOs in epilepsy and summarize the current state of knowledge, synthesizing clinical and basic science content from the Third International Workshop on HFOs in Epilepsy. Over the years, the field has evolved from single-center analysis of HFOs on invasive electroencephalographic recordings to recent multicenter studies and meta-analysis, which have tempered the conviction or hope that HFOs are uniform, "one event fits all," stand-alone biomarkers. Instead, association of HFOs with other electrophysiological phenomena such as interictal spikes, seizures, and signal features like entropy have highlighted new ways to identify epileptogenic tissue. Advances in recording and analytical tools have significantly expanded their potential applications in both clinical and basic science settings. Several recent publications focus on how scalp HFOs can illuminate disease propensity, severity, and therapy responses. Moreover, it was recently discovered that HFOs are also present in experimental models of Alzheimer's disease, and research is ongoing regarding their relations to the HFOs found in epilepsy. Together, these developments highlight that HFOs represent an evolving research area, with significant inroads made over the years. Yet, key gaps in knowledge remain, and we propose five benchmark areas that warrant future research and advancement.