Hippocampal ripples evoke a stereotyped cortical response followed by spindle-mediated network synchronization.
Hippocampal sharp-wave ripples (SWRs) are thought to play a key role in systems memory consolidation by broadcasting reactivated memory content to distributed cortical networks while we sleep. Elucidating how this hippocampal-cortical dialogue unfolds at the brain-wide level is therefore essential to understanding how sleep transforms new experiences into lasting memories. Here we combined simultaneous hippocampal intracranial EEG and 21-channel scalp EEG during overnight sleep to characterize the large-scale cortical impact of hippocampal ripple events. We found that individual hippocampal ripples elicited a decodable, phase-locked cortical response at the scalp level. This cortical response was followed by increases in cortico-cortical synchronization and network density in the spindle-band. Mediation analyses revealed a sequential pathway in which ripple magnitude predicted large-scale cortical connectivity through this intermediate cortical response and subsequent spindle activity. These findings demonstrate that hippocampal ripples trigger a two-step cascade, i.e., an early stereotyped cortical response followed by spindle-mediated network synchronization, consistent with the view that SWRs co-activate distributed cortical nodes and potentiate the cortical-cortical connections that support memory consolidation. By demonstrating that ripple-related cortical responses are decodable noninvasively, our results moreover suggest a new strategy for inferring hippocampal ripple activity from scalp electrophysiology. Significance StatementHippocampal sharp-wave ripples are brief bursts of coordinated neural activity believed to support memory consolidation by coordinating communication between the hippocampus and the cortex during sleep. Although animal studies show that ripples influence widespread cortical activity, their large-scale cortical effects in humans have previously only been measurable through invasive brain recordings. By combining hippocampal intracranial recordings with scalp EEG, we show that hippocampal ripples evoke a cortical response decodable noninvasively, followed by widespread spindle-mediated synchronization across cortical networks. These findings reveal a temporally structured cascade linking hippocampal activity to large-scale cortical coordination during sleep and suggest that ripple-driven brain-wide responses can be monitored using non-invasive EEG recordings.