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Pupil size reveals arousal level fluctuations in human sleep

Carro-Domínguez, Manuel, Huwiler, Stephanie, Oberlin, Stella, Oesch, Timona Leandra, Badii, Gabriela, Lüthi, Anita, Wenderoth, Nicole, Meissner, Sarah Nadine, Lustenberger, Caroline·2025·Nature Communications
DOI 10.1038/s41467-025-57289-5PMC PMC11871316

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Abstract

Recent animal research has revealed the intricate dynamics of arousal levels that are important for maintaining proper sleep resilience and memory consolidation. In humans, changes in arousal level are believed to be a determining characteristic of healthy and pathological sleep but tracking arousal level fluctuations has been methodologically challenging. Here we measured pupil size, an established indicator of arousal levels, by safely taping the right eye open during overnight sleep and tested whether pupil size affects cortical response to auditory stimulation. We show that pupil size dynamics change as a function of important sleep events across different temporal scales. In particular, our results show pupil size to be inversely related to the occurrence of sleep spindle clusters, a marker of sleep resilience. Additionally, we found pupil size prior to auditory stimulation to influence the evoked response, most notably in delta power, a marker of several restorative and regenerative functions of sleep. Recording pupil size dynamics provides insights into the interplay between arousal levels and sleep oscillations.

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Fig. 1 Experimental procedures. A Overall sleep protocol: Auditory stimulation was applied during non-rapid eye movement (NREM) sleep, whereas pupil size was measured only for up to 4 h. B Pupillometry protocol: The eye was taped open and protected with a transparent bandage while tracked with a camera. Eye features were extracted from the videos: pupil and eyelid centroids (red markers), fitted ellipse around pupil circumference (black ellipse), major and minor axis of pupil ellipse (cyan and green line), iris points connected to pupil centroid (center black lines). C–J W: Wakefulness (yellow); N1: NREM1 (gray); N2: NREM2 (green); N3: NREM3 (blue); R: REM (orange). Consent was obtained for the publication of this image. C–E Hypnogram while pupil size was recorded and accompanying time series from a representative participant. The displayed time period refers to the first 3.5 h of a recording, as shown in (A). C Pupil size fluctuations during sleep. D 30-s segments of the spectral slope without artifacts. E Heart rate (HR) in beats per minute (BPM). The gray box is the time period plotted in the bottom plot of Fig. 2A. F Average pupil size (F(4, 57.43) = 168.90, p < 0.001), G spectral slope (F(4, 68) = 41.37, p < 0.001), and H HR (F(4, 55.52) = 7.623, p < 0.001) for wake, N1, N2, N3, and REM sleep. The data of each participant is depicted in gray. Statistical differences between sleep stages are depicted (see supplementary Tables 1–3 for more detailed information). I Repeated measures correlation within sleep stages where pupil data was aggregated in 30-s segments to match the segment lengths of the spectral slope data. “All” refers to all sleep stages together (All: n = 17, W: n = 16, N1: n = 17, N2: n = 17, N3: n = 3, R: n = 12). J Repeated measures correlation within sleep stages where HR was aggregated in 30 s segments to match the segment lengths of the spectral slope data (All: n = 17, W: n = 16, N1: n = 17, N2: n = 17, N3: n = 3, R: n = 12). 30-s segments where auditory stimulation had been applied were excluded. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. Data are presented as mean values +/− 95% confidence intervals. All statistical results are based on two-sided tests.
Fig. 1 Experimental procedures. A Overall sleep protocol: Auditory stimulation was applied during non-rapid eye movement (NREM) sleep, whereas pupil size was measured only for up to 4 h. B Pupillometry protocol: The eye was taped open and protected with a transparent bandage while tracked with a camera. Eye features were extracted from the videos: pupil and eyelid centroids (red markers), fitted ellipse around pupil circumference (black ellipse), major and minor axis of pupil ellipse (cyan and green line), iris points connected to pupil centroid (center black lines). C–J W: Wakefulness (yellow); N1: NREM1 (gray); N2: NREM2 (green); N3: NREM3 (blue); R: REM (orange). Consent was obtained for the publication of this image. C–E Hypnogram while pupil size was recorded and accompanying time series from a representative participant. The displayed time period refers to the first 3.5 h of a recording, as shown in (A). C Pupil size fluctuations during sleep. D 30-s segments of the spectral slope without artifacts. E Heart rate (HR) in beats per minute (BPM). The gray box is the time period plotted in the bottom plot of Fig. 2A. F Average pupil size (F(4, 57.43) = 168.90, p < 0.001), G spectral slope (F(4, 68) = 41.37, p < 0.001), and H HR (F(4, 55.52) = 7.623, p < 0.001) for wake, N1, N2, N3, and REM sleep. The data of each participant is depicted in gray. Statistical differences between sleep stages are depicted (see supplementary Tables 1–3 for more detailed information). I Repeated measures correlation within sleep stages where pupil data was aggregated in 30-s segments to match the segment lengths of the spectral slope data. “All” refers to all sleep stages together (All: n = 17, W: n = 16, N1: n = 17, N2: n = 17, N3: n = 3, R: n = 12). J Repeated measures correlation within sleep stages where HR was aggregated in 30 s segments to match the segment lengths of the spectral slope data (All: n = 17, W: n = 16, N1: n = 17, N2: n = 17, N3: n = 3, R: n = 12). 30-s segments where auditory stimulation had been applied were excluded. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. Data are presented as mean values +/− 95% confidence intervals. All statistical results are based on two-sided tests.CC BY · PubMed Central
Fig. 2 Relationship between sigma power, pupil size, heart rate, and K-complexes. A–C Individual example of sigma power fluctuations alongside the corresponding pupil size, HR in beats per minute (BPM), and K-complexes (green dots in C), respectively. The example window corresponds to the time in the gray boxes in the sleep recording from Fig. 1C and E. D–F Sigma power (black & right axis) with pupil size (blue & left axis in D), heart rate (red & left axis in E), and K-complex likelihood (green & left axis in F). All metrics are normalized to the timing of the troughs of detected spindle infraslow fluctuations (ISF). The time between troughs was renormalized in terms of cycle percentage. Centerline plots represent the mean across participants, and shadings around center lines represent the standard error of the mean (SEM). G Average pupil size (F(3, 48.00) = 10.853, p < 0.001), H heart rate (F(3, 48.00) = 16.062, p < 0.001), and I K-complex likelihood (F(3, 48.00) = 17.602, p < 0.001) for the rise, peak, fall, and trough of the normalized sigma power fluctuations. The data of each participant is depicted in gray. Statistical differences between the rise, peak, fall, and trough of sigma power ISFs are depicted, p-values are based on post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.
Fig. 2 Relationship between sigma power, pupil size, heart rate, and K-complexes. A–C Individual example of sigma power fluctuations alongside the corresponding pupil size, HR in beats per minute (BPM), and K-complexes (green dots in C), respectively. The example window corresponds to the time in the gray boxes in the sleep recording from Fig. 1C and E. D–F Sigma power (black & right axis) with pupil size (blue & left axis in D), heart rate (red & left axis in E), and K-complex likelihood (green & left axis in F). All metrics are normalized to the timing of the troughs of detected spindle infraslow fluctuations (ISF). The time between troughs was renormalized in terms of cycle percentage. Centerline plots represent the mean across participants, and shadings around center lines represent the standard error of the mean (SEM). G Average pupil size (F(3, 48.00) = 10.853, p < 0.001), H heart rate (F(3, 48.00) = 16.062, p < 0.001), and I K-complex likelihood (F(3, 48.00) = 17.602, p < 0.001) for the rise, peak, fall, and trough of the normalized sigma power fluctuations. The data of each participant is depicted in gray. Statistical differences between the rise, peak, fall, and trough of sigma power ISFs are depicted, p-values are based on post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.CC BY · PubMed Central
Fig. 3 Pupil size and instantaneous heart rate dynamics of N2 events. A–C Pupil size color-coded in blue and normalized to the 5 s prior the detected event: K-complexes, sleep arousals, and spindle trains (respectively).D–F Heart rate color-coded in orange and normalized to the 5 s prior to the detected event: K-Complexes, spindle trains, and sleep arousals (respectively). C, F Green vertical shading in top panels reflects the mean ± 1 SEM of the median spindle train end across participants. The center lines represent the group mean, and shading around the center lines is the SEM. Gray lines are the mean response of each participant. Black horizontal lines mark significant differences from the 5 s baseline prior to each event (p < 0.05). p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.
Fig. 3 Pupil size and instantaneous heart rate dynamics of N2 events. A–C Pupil size color-coded in blue and normalized to the 5 s prior the detected event: K-complexes, sleep arousals, and spindle trains (respectively).D–F Heart rate color-coded in orange and normalized to the 5 s prior to the detected event: K-Complexes, spindle trains, and sleep arousals (respectively). C, F Green vertical shading in top panels reflects the mean ± 1 SEM of the median spindle train end across participants. The center lines represent the group mean, and shading around the center lines is the SEM. Gray lines are the mean response of each participant. Black horizontal lines mark significant differences from the 5 s baseline prior to each event (p < 0.05). p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.CC BY · PubMed Central
Fig. 4 Pupil and EEG responses to auditory stimulation. We applied a 10-s stimulation condition of 1 Hz rhythmic auditory stimulation at 45 dB (verum) at varying arousal levels and a control condition where no stimuli were applied (sham). A–C Pupil size, sigma power, and delta power relative to the 5 s prior to the detection of verum (blue) and sham (green) stimulation windows. Center lines represent the mean, and shading around center lines represent SEM. Time zero is the start of the stimulation window. The stimulation window start times were marked by the stimulation-algorithm independent of whether sham or verum followed. They only differ in terms of whether real tones were played or not. D–F Pupil size, sigma power, and delta power of A–C, respectively, during verum (blue) and sham (green) averaged every 5 s from time zero onwards for each participant. Black stars highlight significant differences (p < 0.05) between verum and sham for a given 5 s region. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. D Pupil in verum condition was significantly larger than sham during Stimearly (13.77 ± 4.81%, p = 0.046) and Stimlate (34.87 ± 12.90%, p = 0.046). E Sigma power in verum condition was significantly larger during Stimearly relative to sham (3.52 ± 1.30 µV2, p = 0.036) and significantly lower during Stimpost relative to sham (−2.55 ± 0.46 µV2, p = 0.001). F Delta power in verum condition increased during Stimearly (1’353 ± 271.54µV2, p = 0.002) and Stimlate (265.95 ± 78.29 µV2, p = 0.001) when compared to sham and then during Stimpost returned then back to Stimpre values (−165.23 ± 135.99 µV2, p = 0.255). See Supplementary Table 8 for a list of participants of the participants used in this analysis. All statistical results are based on two-sided tests.
Fig. 4 Pupil and EEG responses to auditory stimulation. We applied a 10-s stimulation condition of 1 Hz rhythmic auditory stimulation at 45 dB (verum) at varying arousal levels and a control condition where no stimuli were applied (sham). A–C Pupil size, sigma power, and delta power relative to the 5 s prior to the detection of verum (blue) and sham (green) stimulation windows. Center lines represent the mean, and shading around center lines represent SEM. Time zero is the start of the stimulation window. The stimulation window start times were marked by the stimulation-algorithm independent of whether sham or verum followed. They only differ in terms of whether real tones were played or not. D–F Pupil size, sigma power, and delta power of A–C, respectively, during verum (blue) and sham (green) averaged every 5 s from time zero onwards for each participant. Black stars highlight significant differences (p < 0.05) between verum and sham for a given 5 s region. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. D Pupil in verum condition was significantly larger than sham during Stimearly (13.77 ± 4.81%, p = 0.046) and Stimlate (34.87 ± 12.90%, p = 0.046). E Sigma power in verum condition was significantly larger during Stimearly relative to sham (3.52 ± 1.30 µV2, p = 0.036) and significantly lower during Stimpost relative to sham (−2.55 ± 0.46 µV2, p = 0.001). F Delta power in verum condition increased during Stimearly (1’353 ± 271.54µV2, p = 0.002) and Stimlate (265.95 ± 78.29 µV2, p = 0.001) when compared to sham and then during Stimpost returned then back to Stimpre values (−165.23 ± 135.99 µV2, p = 0.255). See Supplementary Table 8 for a list of participants of the participants used in this analysis. All statistical results are based on two-sided tests.CC BY · PubMed Central
Fig. 5 EEG responses to auditory stimulation at small and large pupil size baselines. A Sigma power 5 s before (Stimpre) and during the first 5 s (Stimearly) of verum stimulation of trials with large (highest quartile) and small pupil baselines (lowest quartile) to group into high and low arousal level trials. We found an interaction effect indicating increased sigma power from Stimpre to Stimearly in the small pupil baseline condition (5.53 ± 2.04 µV2) but not in the large pupil baseline condition (0.08 ± 2.17 µV2), FsigmaXpupilrange(1, 21) = 5.66, p = 0.027, post-hoc comparison Stimpre to Stimearly with small pupil baseline: F(1, 7) = 8.60, p = 0.044, post-hoc comparison Stimpre to Stimearly with large pupil baseline: F(1, 7) = 0.002, p = 0.97. B Delta power during Stimpre and during Stimearly of verum stimulation of trials with large (highest quartile) and small pupil baselines (lowest quartile) to group into high and low arousal level trials. We found an interaction effect indicating increased delta power from Stimpre to Stimearly in the small pupil baseline condition but not in the large pupil baseline condition FdeltaXpupilrange(1, 28) = 6.77, p = 0.015, post-hoc comparison Stimpre to Stimearly with small pupil baseline: F(1, 14) = 7.58, p = 0.031, post-hoc comparison Stimpre to Stimearly with large pupil baseline: F(1, 14) = 0.25, p = 0.623. The numbers next to the gray lines correspond to the participant number. The stimulation protocol V0 was used in 2 and 4, and V1 for the rest. The horizontal black lines connecting pupil size ranges are the interaction effects between pupil size range and Stimpre-Stimearly power values. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.
Fig. 5 EEG responses to auditory stimulation at small and large pupil size baselines. A Sigma power 5 s before (Stimpre) and during the first 5 s (Stimearly) of verum stimulation of trials with large (highest quartile) and small pupil baselines (lowest quartile) to group into high and low arousal level trials. We found an interaction effect indicating increased sigma power from Stimpre to Stimearly in the small pupil baseline condition (5.53 ± 2.04 µV2) but not in the large pupil baseline condition (0.08 ± 2.17 µV2), FsigmaXpupilrange(1, 21) = 5.66, p = 0.027, post-hoc comparison Stimpre to Stimearly with small pupil baseline: F(1, 7) = 8.60, p = 0.044, post-hoc comparison Stimpre to Stimearly with large pupil baseline: F(1, 7) = 0.002, p = 0.97. B Delta power during Stimpre and during Stimearly of verum stimulation of trials with large (highest quartile) and small pupil baselines (lowest quartile) to group into high and low arousal level trials. We found an interaction effect indicating increased delta power from Stimpre to Stimearly in the small pupil baseline condition but not in the large pupil baseline condition FdeltaXpupilrange(1, 28) = 6.77, p = 0.015, post-hoc comparison Stimpre to Stimearly with small pupil baseline: F(1, 14) = 7.58, p = 0.031, post-hoc comparison Stimpre to Stimearly with large pupil baseline: F(1, 14) = 0.25, p = 0.623. The numbers next to the gray lines correspond to the participant number. The stimulation protocol V0 was used in 2 and 4, and V1 for the rest. The horizontal black lines connecting pupil size ranges are the interaction effects between pupil size range and Stimpre-Stimearly power values. p-values are based on a post hoc t-test and are adjusted for multiple comparisons using Benjamini-Hochberg correction. All statistical results are based on two-sided tests.CC BY · PubMed Central

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Metadata

Authors
Carro-Domínguez, M., Huwiler, S., Oberlin, S., Oesch, T. L., Badii, G., Lüthi, A., Wenderoth, N., Meissner, S. N., & Lustenberger, C.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-28
Volume
16
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-025-57289-5
PMC
PMC11871316
Cited by
41
References
10
Language
en
Licence

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