TY - JOUR T1 - Network mechanisms generating abnormal and normal hippocampal High Frequency Oscillations: A computational analysis JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0024-15.2015 SP - ENEURO.0024-15.2015 AU - Christian G. Fink AU - Stephen Gliske AU - Nicholas Catoni AU - William C. Stacey Y1 - 2015/06/11 UR - http://www.eneuro.org/content/early/2015/06/11/ENEURO.0024-15.2015.abstract N2 - High-frequency oscillations (HFOs) are an intriguing potential biomarker for epilepsy, typically categorized according to peak frequency as either ripples (100-250 Hz) or fast ripples (>250 Hz). In the hippocampus, fast ripples were originally thought to be more specific to epileptic tissue, but it is still very difficult to distinguish which HFOs are caused by normal versus pathological brain activity. In this study we use a computational model of hippocampus to investigate possible network mechanisms underpinning normal ripples, pathological ripples, and fast ripples. Our results unify several prior findings regarding HFO mechanisms, and also make several new predictions regarding abnormal HFOs. We show that HFOs are generic, emergent phenomena whose characteristics reflect a wide range of connectivity and network input. Although produced by different mechanisms, both normal and abnormal HFOs generate similar ripple frequencies, underscoring that peak frequency is unable to distinguish the two. Abnormal ripples are generic phenomena that arise when input to pyramidal cells overcomes network inhibition, resulting in high-frequency, uncoordinated firing. In addition, fast ripples transiently and sporadically arise from the precise conditions that produce abnormal ripples. Lastly, we show that such abnormal conditions do not require any specific network structure to produce coherent HFOs, as even completely asynchronous activity is capable of producing abnormal ripples and fast ripples in this manner. These results provide a generic, network-based explanation for the link between pathological ripples and fast ripples, and a unifying description for the entire spectrum from normal ripples to pathological fast ripples.Significance Statement: Roughly 0.25% of people throughout the world suffer from uncontrolled epilepsy, largely due to our incomplete understanding of how seizures are generated. This motivates the search for new epilepsy biomarkers, one of the most promising of which are high-frequency oscillations (HFOs): focal, brief field potential signals of 80 Hz or more. Not all HFOs are pathological, however, and despite 20 years of research, it is still unclear how to distinguish normal from pathological HFOs. We use a computational model to investigate the network properties capable of generating two types of HFOs, ripples and fast ripples. Our model indicates that a range of physiological conditions are capable of producing the full spectrum of HFOs, from normal ripples to “epileptic” fast ripples. ER -