Local modulation of sleep slow waves depends on timing between auditory stimuli

Conflicting evidence exists regarding the role of the targeted slow-wave phase in determining the direction and spatial specificity of slow-wave activity (SWA) modulation via phase-targeted auditory stimulation (PTAS) during sleep. To reconcile these discrepancies, we re-analyzed high-density electroencephalography (hd-EEG) data from previous studies, focusing on SWA responses to auditory stimuli presented with varying inter-stimulus intervals (ISIs). Our analysis reveals that ISI is a primary determinant of PTAS-induced SWA modulation, exceeding the influence of targeted phase alone. Specifically, auditory stimulation with longer ISIs evoked a global increase in SWA, consistent with a stereotypical auditory-evoked K-complex (KC), independent of targeted phase. Conversely, longer stimulus trains with rapid successive stimulus presentation resulted in spatially localized, phase-dependent SWA modulation, with up-PTAS enhancing and down-PTAS reducing SWA locally around the targeted area. This distinction resolves inconsistencies in prior PTAS studies by demonstrating that phase alone in insufficient in predicting slow-wave responses. Rather, it was the ISI which determined whether PTAS resulted in a global, KC-mediated response or a local, phase-specific modulation of SWA. Consequently, our findings refine the mechanistic understanding of PTAS, suggesting that ISI regulates the engagement of distinct neural circuits and thereby potentially enables the targeted manipulation of specific slow-wave subtypes and their associated functions.