Examining the optimal timing for closed-loop auditory stimulation of slow-wave sleep in young and older adults

Miguel Navarrete, Jules Schneider, Hong-Viet V Ngo, Mario Valderrama, Alexander J Casson, Penelope A Lewis, Miguel Navarrete, Jules Schneider, Hong-Viet V Ngo, Mario Valderrama, Alexander J Casson, Penelope A Lewis

Abstract

Study objectives: Closed-loop auditory stimulation (CLAS) is a method for enhancing slow oscillations (SOs) through the presentation of auditory clicks during sleep. CLAS boosts SOs amplitude and sleep spindle power, but the optimal timing for click delivery remains unclear. Here, we determine the optimal time to present auditory clicks to maximize the enhancement of SO amplitude and spindle likelihood.

Methods: We examined the main factors predicting SO amplitude and sleep spindles in a dataset of 21 young and 17 older subjects. The participants received CLAS during slow-wave-sleep in two experimental conditions: sham and auditory stimulation. Post-stimulus SOs and spindles were evaluated according to the click phase on the SOs and compared between and within conditions.

Results: We revealed that auditory clicks applied anywhere on the positive portion of the SO increased SO amplitudes and spindle likelihood, although the interval of opportunity was shorter in the older group. For both groups, analyses showed that the optimal timing for click delivery is close to the SO peak phase. Click phase on the SO wave was the main factor determining the impact of auditory stimulation on spindle likelihood for young subjects, whereas for older participants, the temporal lag since the last spindle was a better predictor of spindle likelihood.

Conclusions: Our data suggest that CLAS can more effectively boost SOs during specific phase windows, and these differ between young and older participants. It is possible that this is due to the fluctuation of sensory inputs modulated by the thalamocortical networks during the SO.

Keywords: age; closed-loop auditory stimulation; memory; sleep; slow oscillation.

© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society.

Figures

Figure 1.
Figure 1.
Description of datasets and analysis methods. (a) Stimulation protocols were similar in all datasets. Two clicks marked by the vertical arrow lines were presented in the predicted up-state. All datasets presented similar ERPs with increased SOs amplitude for the STIM condition. (b) The delay from the zero-crossing to the click time (vertical arrow line) and the corresponding click phase were obtained and used as reference points for further analysis. For SO wave phase, 0° states the negative to positive zero-crossing (ZC), −90° and 270° represent the SO troughs and 90° the SO peak of the trace. (c) Detection of sleep spindles (SS) as well as SO and SS measurements used in the analysis. Only SS that start in the detection interval were analyzed (yellow shadow). (d) For the detected and stimulated SOs, the trough-to-trough interval in both phase and time was divided into 50 bins. For instance, in the phase analysis, trials in which the stimulation was applied 45° around the bin centre were selected and comprise the events of each bin. Here we show 30 events of one young subject around the 45° bin (J) and 135° bin (K). (e) Histograms of detected events for all datasets. As CLAS targets SO peaks, the distribution of events is not even across all bins, 45° bin (J) and 135° bin (K) are also depicted for reference. Shaded areas represent subject mean ± SD.
Figure 2.
Figure 2.
Slow-wave amplitudes after CLAS in young and old subjects. (a) Distribution of the post-stimulus absolute trough amplitude of SOs during SHAM (white bars) and STIM (blue bars) in young subjects. (b) Size of the difference between STIM and SHAM for post-stimulus SO amplitudes for clicks applied at different phase/delay-bins for young people. Dotted line represents the significance threshold for p < .05 after FDR correction. Yellow shadow indicates intervals for which a significant increasing of >100 µV amplitudes was found. Click delay was evaluated from the negative to positive zero-crossing (zc). For reference, the gray shading on top of the axes displays the morphology of the average SO wave. (c) Distribution of the post-stimulus trough amplitude of slow waves during SHAM and STIM conditions for older subjects. (d) Size of the difference between STIM and SHAM for post-stimulus trough amplitudes for clicks applied at different phase/delay-bins for older people. (e) Absolute distance (mean ± 95% CI) of post-stimulus trough amplitudes to spontaneous activity over different phase bins for SHAM vs. Monte Carlo (SHAM—MC) and STIM vs. Monte Carlo (STIM—MC). Thick black bars show phase intervals in which significant differences were observed at p < .05 after FDR correction. Red squares remark maximal significant distance for each subject after corrected p < .05. (*) p < .05 and (**) p < .01 after FDR correction; (n.s.) for nonsignificant.
Figure 3.
Figure 3.
Pairwise comparison for SO trough amplitude in STIM condition. (a, b) Pairwise comparison matrix for post-stimulus trough amplitude events evaluated in click phase and click delay bins for young (a) and older subjects (b). X and Y axis represent the same bins comparing each point to every other point. Matrix values correspond to the mean size of the difference (t-values) of bin pairwise comparisons significant after FDR correction. (c, d) Pairwise response index (mean ± 95% CI) for click phases for young (c) and older subjects (d). Thick black bars show phase intervals in which significant differences were observed at p < .05 after FDR correction.
Figure 4.
Figure 4.
Sleep spindle response to CLAS. (a) sleep spindles (SS) likelihood (mean ± 95% CI) modulated for the click phase for STIM and SHAM conditions for young subjects. (b) Pairwise comparison matrix for post-stimulus SS likelihood for young subjects. Matrix values correspond to the mean size of the difference (t-values) of bin pairwise comparisons significant after FDR correction. (c) Modulation of SS features depending on the click phase for STIM and SHAM conditions for young subjects. (d) Size of the difference between STIM and SHAM conditions for significant t-values after FDR correction indicating SS likelihood as a joint function of the click phase and the SS lag for young subjects. (e) SS likelihood (mean ± 95% CI) modulated for the click phase for STIM and SHAM conditions for older subjects. (f) Modulation of SS features depending on the click phase for STIM and SHAM conditions for older subjects. Thick horizontal lines on the top display phase intervals in which conditions differed at p < .05 after FDR correction.

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