Neurophysiological effects of targeting sleep spindles with closed-loop auditory stimulation

Abstract

Sleep spindles are neural events unique to nonrapid eye movement sleep that play key roles in memory reactivation and consolidation. However, much of the evidence for their function remains correlational rather than causal. Closed-loop brain stimulation uses real-time monitoring of neural events (often via electroencephalography; EEG) to deliver precise auditory, magnetic, or electrical stimulation for research or therapeutic purposes. Automated online algorithms to detect and stimulate sleep spindles have recently been validated, but the time- and frequency-resolved physiological responses generated by them have not yet been documented. Building on the recent findings that sleep spindles do not block the transmission of sound to cortex, the present work investigates the neurophysiological responses to closed-loop auditory stimulation of sleep spindles. EEG data were collected from 10 healthy human adults (6 nights each), whilst sleep spindles were detected and in half the nights, targeted with auditory stimulation. Spindles were successfully stimulated before their offset in 97.6% of detections and did not disturb sleep. Comparing stimulation with sham, we observed that stimulation resulted in increased sigma activity (11-16 Hz) at about 1 second poststimulation but that stimulation occurring at the beginning of the spindle also resulted in early termination of the spindle. Finally, we observed that stimulating an evoked spindle did not elicit additional sigma activity. Our results validate the use of closed-loop auditory stimulation targeting sleep spindles, and document its neural effects, as a basis for future causal investigations concerning spindles' roles in memory consolidation.

Keywords: audition memory; brain stimulation; causal manipulation; closed-loop auditory stimulation; sleep; sleep spindles; slow oscillations.

Graphical Abstract

Figure 1.

Successful real-time detection of sleep spindles. (A) Mean time–frequency plot shows a clear burst of sigma activity at the time of detection. (B) Comparison of the envelope of the sigma activity (11–16 Hz) 1 second prior to the detection (Baseline) and at the time of the detection suggests the presence of a spindle. “***” indicates significance at p < .001, FDR-corrected.

Figure 2.

Effects of closed-loop auditory simulations of sleep spindles (detected at Cz). (A) Position of the three electrode sites. (B) Event-related spectral perturbation following closed-loop auditory stimulation of sleep spindles as compared with sham. Black contours highlight the significant differences between conditions (for visualization purposes, only significant clusters bigger than a single time–frequency bin are represented). The overlaid line represents the broadband (0.5–30 Hz) mean evoked response potential (shaded area: standard error of the mean). (C) Slow wave-filtered evoked responses. (D) Spindle-band activity. In C and D, solid lines indicate that group mean and shaded lines represent standard error of the mean. Statistical differences (STIM vs SHAM) are represented in the bottom panels. Gray areas represent uncorrected p-values and black areas represent corrected p-values.

Figure 3.

Timing relative to the ongoing sigma activity impacts the neurophysiological response to stimulation. (A) Top: Comparison of the envelope of the sigma activity (11–16 Hz) for both STIM and SHAM conditions when stimulation occurred before the peak of the detected spindle. Bottom: Cumulative sigma power in the 15 seconds following stimulation. (B) Top: Comparison of the envelope of the sigma activity for both STIM and SHAM conditions when stimulation occurred after the peak of the detected spindle. Bottom: Cumulative sigma power in the 15 seconds following stimulation. Dashed vertical line represent timing of auditory stimulation. Gray areas represent uncorrected p-values and black areas represent corrected p-values.

Figure 4.

Effect of trains of spindle stimulation showing that stimulating evoked spindles (i.e. two stimulations in a row) does not appear to elicit additional sigma activity (A) as observed in the envelope amplitude timecourse and (B) confirmed statistically within a window 1.5–2.5 seconds (gray shading in A) following the first sound onset. Dashed vertical lines represent timing of auditory stimulations. Gray areas represent uncorrected p-values and black areas represent corrected p-values.