Closed-Loop Acoustic Stimulation During Sleep in Children With Epilepsy: A Hypothesis-Driven Novel Approach to Interact With Spike-Wave Activity and Pilot Data Assessing Feasibility

Sara Fattinger, Bigna Bölsterli Heinzle, Georgia Ramantani, Lucia Abela, Bernhard Schmitt, Reto Huber, Sara Fattinger, Bigna Bölsterli Heinzle, Georgia Ramantani, Lucia Abela, Bernhard Schmitt, Reto Huber

Abstract

Slow waves, the electroencephalographic (EEG) hallmark of deep sleep, can be systematically manipulated by acoustic stimulation: stimulation time-locked to the down phase of slow waves reduces, whereas stimulation time-locked to the up phase increases slow waves. Spike-waves during sleep seem to be related to slow waves, raising the question of whether spike-waves can be systematically influenced by such acoustic stimulation. In five pediatric patients, all-night EEG was recorded, combined with real-time slow wave detection. Throughout the night, acoustic stimulation was performed in a 3 × 5-min-block design (no stimulation-stimulation-no stimulation). Tones were applied time-locked either to the up or to the down phase of the detected slow waves in an alternating pattern. All patients tolerated the acoustic stimulation during sleep well. They showed high sleep quality and no signs of clinical or non-convulsive electrographic seizures. Our preliminary analysis shows no systematic effect of acoustic stimulation on spike-wave activity. Moreover, with our stimulation approach tones were distributed over a rather broad phase-range during the DOWN or UP stimulation and showed inter-individual differences in their distribution. In this study, we applied for the first time an acoustic closed-loop slow wave stimulation tool for a non-invasive manipulation of spike-wave activity. Thus, our pilot data show that closed-loop acoustic stimulation is feasible and well tolerated in children with spike wave activity during sleep. Improved precision in phase targeting and personalized stimulation parameters in a larger sample of subjects might be needed to show systematic effects.

Keywords: development; electrical status epilepticus during slow wave sleep; high-density EEG; interictal activity; neurostimulation.

Figures

Figure 1
Figure 1
Graphical illustration of the acoustic stimulation. During the night, slow waves were detected online in real time and tones were presented according to a 3 × 5-min-block design. One stimulation cycle consisted of 5 min no stimulation (NoStimpre), 5 min stimulation (DOWN or UP) followed by 5 min no stimulation [(NoStimafter), shown for DOWN (left) and UP stimulation (right) enlarged on the bottom]. In patients diagnosed with benign epilepsy with centro-temporal spikes (BECTS) or generalized spike waves in sleep (n = 3) tones onset during the stimulation blocks were played precisely time-locked either to the down-phase (DOWN, reddish color) or up-phase (UP, bluish color) of the detected slow wave, alternately in every other stimulation cycle (top panel). In patients diagnosed with ESES (n = 2), only the DOWN stimulation (reddish color) was applied (middle panel). Stimulation was applied throughout the night when subjects were in deep sleep (i.e., N2 and N3, for further details see “Materials and Methods” section).
Figure 2
Figure 2
Effects on the spike-wave index (SWI) of the acoustic stimulation during the up-phase (A) or the down-phase (B) of slow waves for each patient. Boxplot: the middle red line indicates the median, the black cross indicates the mean, the bottom and top of the box indicate the first (Q1 = 25th percentile) and third quartiles (Q3 = 75th percentile), whiskers extend to indicate 1.5 × the IQR (IQR = Q3 − Q1), red crosses correspond to values outside the whisker range. The dashed blue line indicates the mean SWI over all blocks [i.e., for ESES NoSTIMpre&after, STIMdown; for BECTS and generalized spike waves in sleep electroencephalographic (EEG): NoSTIMpre&after, STIMdown&UP]; G, generalized spike waves in sleep EEG; B, BECTS; E, ESES.
Figure 3
Figure 3
Distribution of tone onset relative to the slow wave oscillation of each subject presented separately for the UP stimulation (A) and the DOWN stimulation (B). The phase of the slow wave oscillation was subdivided into 12 30° phase-bins (see graphical illustration in the upper right corner, red: phase-bin 1–6 corresponding to the down-phase, blue: phase-bin 7–12 corresponding to the up-phase). The mean percentage of tone onset allocated during each 30° phase-bin is shown. Note the variability of tone onset allocation across subjects (G, generalized spike waves in sleep EEG; B, BECTS; E, ESES).
Figure 4
Figure 4
Relationship between phase-timing of tone onset relative to the slow wave oscillation and changes in SWI after stimulation (ΔSWI [%] = (SWIStim − SWIafter)/SWIpre)* 100. A positive ΔSWI value indicates that SWI was higher during stimulation, whereas a negative value indicates that SWI was lower during stimulation than after the stimulation block). The phase of the slow wave oscillation was subdivided into 12 30° phase-bins (see graphical illustration). The mean percentage of tone onsets allocated during each 30° phase-bin was calculated. (A) Data points for each patient are shown for the UP and DOWN stimulation separately for the 5th phase-bin (i.e., the onset of the EEG positive trend). The distribution of the individual data points might indicate that the more tones were played during the 5th phase-bin, the more the SWI was increased during stimulation. (B) Data points for each patient are shown for the UP and DOWN stimulation separately for the 11th phase-bin (i.e., the onset of the EEG negative trend). The distribution of the individual data points might indicate that the more tones were played during the 11th phase-bin the more the SWI was reduced during stimulation (G, generalized spike waves in sleep EEG; B, BECTS; E, ESES).
Figure 5
Figure 5
Relationship between spike-wave index (ΔSWI) and Δlow-slow wave activity (low-SWA) for DOWN (red dots) and UP (blue dots) stimulation pooled. Data points for each patient are shown for the UP and DOWN stimulation separately (ΔSWI [%] = (SWIStim − SWIafter)/SWIpre)* 100; Δlow-SWA [%] = (low-SWAafter − low-SWASTIM)/low-SWApre)* 100. A positive ΔSWI/Δlow-SWA value indicates that SWI/low-SWA was higher during stimulation, whereas a negative value indicates that SWI/low-SWA was lower during stimulation than after the stimulation block. G, generalized spike waves in sleep EEG; B, BECTS; E, ESES.

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