How Can I Disentangle Physiological and Pathological High-Frequency Oscillations?

High-frequency oscillations (HFOs) consist of ripples (80–250 Hz) and fast ripples (>250 Hz). Ripples are attributed an important role in cognition, sleep, and task-related processes and have been reported in many cortical areas of the healthy brain, with large variations in rates depending on anatomical localization. HFOs are also a promising interictal biomarker of epilepsy. HFOs were shown to be more specific to localize the epileptogenic zone than interictal epileptiform discharges. One emerging area in HFO research is the nontrivial task of separating physiological from pathological HFOs. Attempts to differentiate between both entities consist of considering their coupling with epileptic spikes, the background EEG activity, their relation to tasks, the anatomical localization of implanted electrodes, more classical neurophysiological features such as amplitude and frequency, as well as their interaction with sleep and distinct pharmacological modulation. This chapter provides an overview of the current state of evidence, discusses unresolved challenges, and finally shows how to improve the yield of HFOs for prediction of the epileptogenic zone and isolating physiological HFOs for cognitive research. Accounting for the distinct properties of physiological and pathological HFOs could be critical for the interpretation of HFO findings for clinical use or neurocognitive research.