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•Auditory stimuli were presented at specific phases of slow waves during sleep.•Inter-stimulus interval (ISI) determines global vs. local modulation of slow waves.•Short ISIs in stimulus trains enable local, phase-specific modulation of slow waves.•Long ISIs evoke a global K-complex response irrespective of the targeted phase.•Different EEG responses suggest the engagement of distinct neural circuits. 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 is 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.

Over the past decade, phase-targeted auditory stimulation (PTAS), a neuromodulation approach which presents auditory stimuli locked to the ongoing phase of slow waves during sleep, has shown potential to enhance specific aspects of sleep functions. However, the complexity of PTAS responses complicates the establishment of causality between specific electroencephalographic events and observed benefits. Here, we used down-PTAS during sleep to specifically evoke the early, K-complex (KC)-like response following PTAS without leading to a sustained increase in slow-wave activity throughout the stimulation window. Over the course of two nights, one with down-PTAS, the other without, high-density electroencephalography (hd-EEG) was recorded from 14 young healthy adults. The early response exhibited striking similarities to evoked KCs and was associated with improved verbal memory consolidation via stimulus-evoked spindle events nested into the up-phase of ongoing 1 Hz waves in a central region. These findings suggest that the early, KC-like response is sufficient to boost memory, potentially by orchestrating aspects of the hippocampal-neocortical dialogue.

Sufficient recovery during sleep is the basis of physical and psychological well-being. Understanding the physiological mechanisms underlying this restorative function is essential for developing novel approaches to promote recovery during sleep. Phase-targeted auditory stimulation (PTAS) is an increasingly popular technique for boosting the key electrophysiological marker of recovery during sleep, slow-wave activity (SWA, 1–4 Hz EEG power). However, it is unknown whether PTAS induces physiological sleep. In this study, we demonstrate that, when applied during deep sleep, PTAS accelerates SWA decline across the night which is associated with an overnight improvement in attentional performance. Thus, we provide evidence that PTAS enhances physiological sleep and demonstrate under which conditions this occurs most efficiently. These findings will be important for future translation into clinical populations suffering from insufficient recovery during sleep.

Abstract The propagating pattern of sleep slow waves (high-amplitude oscillations < 4.5 Hz) serves as a blueprint of cortical excitability and brain connectivity. Phase-locked auditory stimulation is a promising tool for the modulation of ongoing brain activity during sleep; however, its underlying mechanisms remain unknown. Here, eighteen healthy young adults were measured with high-density electroencephalography in three experimental conditions; one with no stimulation, one with up- and one with down-phase stimulation; ten participants were included in the analysis. We show that up-phase auditory stimulation on a right prefrontal area locally enhances cortical involvement and promotes traveling by increasing the propagating distance and duration of targeted small-amplitude waves. On the contrary, down-phase stimulation proves more efficient at perturbing large-amplitude waves and interferes with ongoing traveling by disengaging cortical regions and interrupting high synchronicity in the target area as indicated by increased traveling speed. These results point out different underlying mechanisms mediating the effects of up- and down-phase stimulation and highlight the strength of traveling wave analysis as a sensitive and informative method for the study of connectivity and cortical excitability alterations.

Freezing of gait (FoG) is a motor impairment among patients with advanced Parkinson's disease which is associated with falls and has a negative impact on a patient's quality of life. Wearable systems have been developed to detect FoG and to help patients resume walking by means of rhythmical cueing. A step further is to predict the FoG and start cueing a few seconds before it happens, which might help patients avoid the gait freeze entirely. We characterize the gait parameters continuously with up to 10-12 seconds prior to FoG, observe if and how they change before subjects enter FoG, and compare them with the gait before turns. Moreover, we introduce and discuss new frequency-based features to describe gait and motor anomalies prior to FoG. Using inertial units mounted on the ankles of 5 subjects, we show specific changes in the stride duration and length with up to four seconds prior to FoG on all subjects, compared with turns. Moreover, the dominant frequency migrates towards [3, 8] Hz band with up to six seconds prior to FoG on 3 subjects. These findings open the path to real-time prediction of FoG from inertial measurement units.

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 and clinical settings is an ongoing challenge, especially because current PTAS protocols and their behavioral effects vary greatly between studies. Our study contributes to ongoing efforts in characterizing parameter choices in PTAS and compares two up-PTAS protocols with systematic variations of the interstimulus intervals (ISIs) and their effect on the consolidation of a finger-tapping sequence using a mobile PTAS device and an app-based behavioral task in a home setting. Participants tolerated both protocols well and showed high adherence to the study procedures. Electrophysiological stimulus responses and learning trajectories in the finger-tapping task replicated lab-based findings. We extend studies suggesting a nonlinear relationship between stimulus number and PTAS effects by showing that applying fewer stimuli with longer ISIs enhances overnight consolidation of a finger-tapping sequence more effectively than applying more stimuli with shorter ISIs. Exploratory electrophysiological analyses revealed that the behavioral response was positively correlated with the number of stimuli with auditory evoked K-complexes relative to the number of stimuli without K-complexes. PTAS stimuli with longer ISIs (>1.25) were associated with a higher likelihood of K-complex responses and increased spindle power. Our findings demonstrate the feasibility of mobile, at-home PTAS combined with app-delivered behavioral tasks in healthy participants and can inform the development of more effective memory enhancement protocols. 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 an at-home application of automated PTAS and provides experimental evidence that prolonging interstimulus intervals may positively affect overnight procedural memory consolidation via K-complexes and sleep spindles. Together, our findings lay a foundation for a broader application of PTAS in longitudinal clinical studies to improve patient care and recovery outcomes.

Auditory stimulation of EEG slow waves (SW) during non-rapid eye movement (NREM) sleep has shown to improve cognitive function when it is delivered at the up-phase of SW. SW enhancement is particularly desirable in subjects with low-amplitude SW such as older adults or patients suffering from neurodegeneration such as Parkinson disease (PD). However, existing algorithms to estimate the up-phase suffer from a poor phase accuracy at low EEG amplitudes and when SW frequencies are not constant. We introduce two novel algorithms for real-time EEG phase estimation on autonomous wearable devices. The algorithms were based on a phase-locked loop (PLL) and, for the first time, a phase vocoder (PV). We compared these phase tracking algorithms with a simple amplitude threshold approach. The optimized algorithms were benchmarked for phase accuracy, the capacity to estimate phase at SW amplitudes between 20 and 60 microV, and SW frequencies above 1 Hz on 324 recordings from healthy older adults and PD patients. Furthermore, the algorithms were implemented on a wearable device and the computational efficiency and the performance was evaluated on simulated sleep EEG, as well as prospectively during a recording with a PD patient. All three algorithms delivered more than 70% of the stimulation triggers during the SW up-phase. The PV showed the highest capacity on targeting low-amplitude SW and SW with frequencies above 1 Hz. The testing on real-time hardware revealed that both PV and PLL have marginal impact on microcontroller load, while the efficiency of the PV was 4% lower than the PLL. Active auditory stimulation did not influence the phase tracking. This work demonstrated that phase-accurate auditory stimulation can be delivered during home-based sleep interventions with a wearable device also in populations with low-amplitude SW.

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.Competing Interest StatementR.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.

Over the past decade, phase-targeted auditory stimulation (PTAS), a neuromodulation approach which presents auditory stimuli locked to the ongoing phase of slow waves during sleep, has shown potential to enhance specific aspects of sleep functions. However, the complexity of PTAS responses complicates the establishment of causality between specific electroencephalographic events and observed benefits. Here, we used down-PTAS during sleep to specifically evoke the early, K-complex (KC)-like response following PTAS without leading to a sustained increase in slow-wave activity throughout the stimulation window. Over the course of two nights, one with down-PTAS, the other without, high-density electroencephalography (hd-EEG) was recorded from 14 young healthy adults. The early response exhibited striking similarities to evoked KCs and was associated with improved verbal memory consolidation via stimulus-evoked spindle events nested into the up-phase of ongoing 1 Hz waves in a central region. These findings suggest that the early, KC-like response is sufficient to boost memory, potentially by orchestrating aspects of the hippocampal-neocortical dialogue.