Fast-ripples are emergent properties of neuronal networks

Fast-ripples have been proposed as a promising biomarker in epilepsy, but their specificity remains unclear. In particular, it is uncertain whether they reflect chance coincident neural activity or distinctly generated pathological entities. We combined in silico simulations, neuronal cultures, a rodent model of hippocampal epilepsy, and human microwire recordings to investigate whether fast-ripples occur more frequently than expected by the chance aggregation of action potentials. Our simulations showed that chance aggregation can generate fast-ripples and predicted higher occurrence during wakefulness, which was confirmed in rodent recordings. The likelihood of exceeding chance depended on biological system complexity and vigilance state: fast-ripples in neuronal cultures did not surpass chance, whereas those in awake – but not sleeping – rodents did. Similarly, the frequency of fast-ripples in awake human recordings was ∼30% greater than expected by chance. As such, our findings suggest that most fast-ripples reflect stochastic network activity rather than distinctly generated pathological entities, challenging prevailing assumptions about their pathogenesis and biomarker specificity.