Neurophysiological mechanisms of memory consolidation during sleep uncovered through targeted memory reactivation

Elizabeth Espinal

doi:10.17918/00011088

Memory consolidation during sleep is thought to depend on the precise temporal coordination of key electrophysiological events, including hippocampal sharp-wave ripples (SWRs), thalamocortical spindles, cortical high-frequency oscillations (HFOs), and slow oscillations. Despite progress in animal models, the mechanistic interplay between these oscillations and behavioral memory outcomes remains poorly understood in humans. Intracranial EEG (iEEG) offers a unique opportunity to observe these dynamics with high spatial and temporal resolution directly. Yet, its application in the context of targeted memory reactivation (TMR) during natural sleep has been limited. This study investigated how auditory cues delivered during sleep influence neural signatures of memory consolidation--specifically, cue-locked changes in hippocampal ripple activity, thalamo-cortical spindles, and cortical HFOs--and whether these changes predict post-sleep memory performance. We aimed to identify electrophysiological markers that index a brain state receptive to memory reactivation and stabilization. Seven epilepsy patients undergoing clinical monitoring with implanted iEEG electrodes completed a two-day TMR experiment. Participants learned auditory-object associations during wakefulness, and a subset of the sounds was replayed during non-REM sleep. Ripple rates in hippocampal contacts, spindle-HFO coupling in visually responsive cortical sites, and their relationship to post-sleep behavioral performance were analyzed. In some cases, cue delivery was manually timed to the up-state of slow oscillations to maximize alignment with memory-supportive brain states. Analyses revealed a significant increase in hippocampal ripple rates during the 500-200 ms period before cue onset in participants who demonstrated better post-sleep memory performance. This pre-cue ripple elevation may signify an "on-state" that primes the brain for memory consolidation, such that cueing during this window biases consolidation in favor of cued content. Additionally, enhanced spindle-HFO coupling in visually responsive cortical regions followed memory-relevant cues. These effects were specific to cued items and were not observed in non-visually responsive regions. Increased HFO activity post-cue, particularly when temporally coordinated with spindles and preceding ripples, was associated with better recall, supporting the role of hippocampal–cortical communication in systems consolidation. This study is among the first to combine human iEEG with TMR to investigate the spatiotemporal dynamics of memory consolidation during sleep. The observed increased ripple rate preceding--rather than following--auditory cues may reflect an "on-state" that primes the brain for memory consolidation, suggesting that cueing during this window biases consolidation in favor of cued content. Furthermore, our findings indicate that successful memory reactivation depends not only on cue presentation but also on its timing relative to endogenous hippocampal activity. Together, these findings generally support the active systems consolidation framework and highlight pre-cue ripple elevation as a potential biomarker of a brain state conducive to memory processing. They also emphasize the potential importance of temporally targeted cueing strategies. Insights from this work may inform future closed-loop neurostimulation approaches and clinical interventions for mitigating memory impairment in aging and neurological disorders.

Neurophysiological mechanisms of memory consolidation during sleep uncovered through targeted memory reactivation

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Neurophysiological mechanisms of memory consolidation during sleep uncovered through targeted memory reactivation

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