Abstract: Both wakeful rest and sleep are beneficial for offline memory consolidation. However, our understanding of the connections and differences in memory consolidation between these two states, particularly regarding the shared cognitive neural mechanisms, remains limited. This study will focus on “memory consolidation during wakefulness”, using declarative and procedural memory tasks to examine memory consolidation activities under natural conditions as well as during modulation by neural replay-based closed-loop Targeted Memory Reactivation (TMR) and closed-loop electrical stimulation. The aim is to investigate the roles of wakeful rest and sleep in memory consolidation and explore the underlying neural mechanisms involved.
To this end, the study will address the following key objectives: (1) Propose a unified theory of offline memory consolidation that spans both sleep and wake states, leveraging the identification of common characteristics between these states as a breakthrough to explore neural biomarkers of memory consolidation during wakeful rest. (2) Use neural replay activity as an entry point, this study will capture it to pinpoint the time window during which memory consolidation occurs and specifically identify the relevant neural features. (3) Building on sleep-state research to verify the effectiveness of the neural replay-based closed-loop TMR and provide guidance for its application during wakeful rest, while exploring the corresponding neural mechanisms. (4) Investigate the modulatory effects of direct hippocampal stimulation on memory consolidation and develop an electrical stimulation protocol for memory enhancement. (5) Conduct long-term follow-up studies to assess the effects of memory consolidation interventions over time, observing changes in memory performance across extended time scales, verifying the ecological validity of the interventions, and exploring the potential to apply laboratory findings to real-world learning contexts.
This study presents three major innovations. First, it enhances our understanding of the role of wakeful rest in facilitating memory consolidation. While sleep has been extensively studied in the context of offline memory consolidation, with its mechanisms well understood, research on memory consolidation during wakefulness remains insufficient and requires further in-depth exploration. Currently, most human studies focus on the behavioral level, with few examining the underlying neural mechanisms, which limits our understanding of offline memory consolidation during wakefulness. Therefore, this study specifically focuses on memory consolidation during wakefulness and conducts a series of experiments to broaden our understanding of offline consolidation. Second, it offers an accurate characterization of the macroscopic neural representation of offline memory consolidation during wakeful rest. Neural replay, a key mechanism in memory consolidation, is challenging to detect directly in healthy humans using non-invasive methods. However, with the aid of computational neuroscience techniques, we can capture neural replay activity using non-invasive neuroimaging techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). By focusing on neural replay activity, this study offers a more precise depiction of the neural processes involved in offline memory consolidation during wakeful rest, in contrast to traditional approaches that rely on correlation analysis to infer neural representations. Third, it provides new approaches to memory regulation. This study leverages neural replay activity to explore closed-loop TMR and closed-loop electrical stimulation as novel memory regulation techniques. By providing new insights into memory modulation, this study offers valuable directions for future research on memory intervention.
In summary, this study aims to utilize advanced techniques such as EEG, fMRI, temporal interference (TI) electrical stimulation, and computational neuroscience techniques to capture the dynamic memory consolidation activities during both waking and sleep states, uncover the core characteristics of offline memory consolidation, and explore novel pathway for memory regulation based on real-time neural feedback. The implementation of this study will be instrumental in elucidating the neural mechanisms underlying memory consolidation across different brain states and laying the foundation for regulating memory consolidation during wakeful rest. Going forward, this study aims to apply its findings to educational interventions, such as learning strategy design, and initiate translational research to unlock the full potential of these interventions in real-world applications.

Key words: memory consolidation, declarative memory, procedural memory, sleep, resting-state