Longer Interstimulus Intervals Enhance Efficacy of Automated Phase-Targeted Auditory Stimulation on Procedural Memory Consolidation

ABSTRACT Up-phase-targeted auditory stimulation (up-PTAS) during slow-wave sleep has become a valuable tool for modulating slow oscillations and slow-oscillation-spindle-coupling in favor of overnight memory retention. Developing effective, automated protocols for translation into more naturalistic or clinical settings is an ongoing challenge, especially given that current PTAS protocols and their behavioral effects vary greatly between different studies. Here, we assessed the electrophysiological and behavioral effects of systematically varying interstimulus intervals (ISIs) in automated up-PTAS in the home setting, using a mobile PTAS device and app-based behavioral tasks. Building on studies suggesting a non-linear relationship between stimulus number and PTAS effects, we show that applying fewer stimuli with longer ISIs enhanced overnight memory consolidation of a finger-tapping sequence more effectively than applying more stimuli with shorter ISIs. The behavioral response was predicted by the number of stimuli with auditory evoked K-complexes relative to the number of stimuli without K-complexes. PTAS stimuli applied at longer ISIs (> 1.25) were associated with a higher likelihood of K-complex responses and fast spindles nesting in the K-complex up-phase. Our results suggest that up-PTAS can be optimized for overnight memory consolidation by introducing ISIs of at least 1.25s. Our study highlights the feasibility of longitudinal at-home PTAS combined with app-based behavioral tasks in healthy participants while leveraging the mechanistic insights such data can offer. Statement of Significance Phase-targeted auditory stimulation (PTAS) holds great promise for non-invasively enhancing essential functions of slow-wave sleep. However, current protocols have produced variable results and are often confined to laboratory settings. Our study demonstrates the feasibility of a mobile application of automated PTAS and provides experimental evidence that prolonging interstimulus intervals positively affects overnight procedural memory consolidation via K-complexes and coupled sleep spindles. As K-complexes may also be involved in cardiovascular function and brain waste clearance, the proposed protocol optimization may have effects beyond memory enhancement. Together, our findings lay a foundation for a broader application of PTAS in clinical longitudinal studies to improve patient care and recovery outcomes. Competing Interest Statement R.H. and W.K. are founders and shareholders of Tosoo AG, which has licensed the PTAS technology and stimulation algorithms used in this study. The remaining authors have no conflicts of interest to declare.