Circadian phase resetting by a single short-duration light exposure

Abstract

BACKGROUND. In humans, a single light exposure of 12 minutes and multiple-millisecond light exposures can shift the phase of the circadian pacemaker. We investigated the response of the human circadian pacemaker to a single 15-second or 2-minute light pulse administered during the biological night. METHODS. Twenty-six healthy individuals participated in a 9-day inpatient protocol that included assessment of dim light melatonin onset time (DLMO time) before and after exposure to a single 15-second (n = 8) or 2-minute (n = 12) pulse of bright light (9,500 lux; 4,100 K fluorescent) or control background dim light (<3 lux; n = 6). Phase shifts were calculated as the difference in clock time between the two phase estimates. RESULTS. Both 15-second and 2-minute exposures induced phase delay shifts [median (± SD)] of -34.8 ± 47.2 minutes and -45.4 ± 28.4 minutes, respectively, that were significantly (P = 0.04) greater than the control condition (advance shift: +22.3 ± 51.3 minutes) but were not significantly different from each other. Comparisons with historic data collected under the same conditions confirmed a nonlinear relationship between exposure duration and the magnitude of phase shift. CONCLUSIONS. Our results underscore the exquisite sensitivity of the human pacemaker to even short-duration single exposures to light. These findings may have real-world implications for circadian disruption induced by exposure to brief light stimuli at night. TRIAL REGISTRATION. The study was registered as a clinical trial on www.clinicaltrials.org, NCT #01330992. FUNDING. Funding for this study was provided by NSBRI HFP02802 and NIH P01-AG09975, R01-HL114088 (EBK), RC2-HL101340-0 (EBK, SWL, SAR, REK), K02-HD045459 (EBK), K24-HL105664 (EBK), T32-HL07901 (MSH, SAR), HL094654 (CAC), and AG044416 (JFD). The project described was supported by NIH grant 1UL1 TR001102-01, 8UL1TR000170-05, UL1 RR 025758, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science.

Figure 1. CONSORT diagram for this phase I nonrandomized trial showing enrollment, allocation, and analysis.

Sixty-seven participants were assessed for eligibility; 26 completed the protocol, and 22 were included in the final analysis.

Figure 2. Study protocol and phase shift calculation.

All study events were timed according to each individual’s schedule, which was maintained for at least three weeks prior to starting the 9-day inpatient part of the study. (A) Example study raster for an individual with 2300–0700 hours habitual sleep. Black bars represent scheduled sleep (time in bed) in darkness, and white bars represent <200 lux ambient lighting while awake. Gray bars represent dim light (<3 lux). Gray hashed bars represent constant routine intervals used to assess endogenous circadian phase. The constant posture interval during light exposure is shown as gray dotted bars, and the time of bright light exposure (9,500 lux) is represented by a hashed white bar. Daily dim light melatonin onset (DLMO) times from 1 individual in the control condition is plotted across the days (●, under dim light; ○, melatonin crossing the DLMO value under 90 lux room light). (B) Daily melatonin profiles from the same individual plotted serially. The dashed square represents the constant posture interval during which light exposure occurred. All individuals in the control condition received the same dim background ambient lighting and no bright light exposure. Black horizontal lines above the melatonin profiles indicate scheduled sleep. Phase shifts were assessed as the difference in clock time between DLMO on cycles d and g.

Figure 3. Phase resetting response to short-duration pulses of light and duration response of circadian phase resetting.

Daily dim light melatonin onset (DLMOs) times for each individual are shown for (A) dim-light control and (B) 15-second and (C) 2-minute exposure conditions. Light exposure occurred on day 6 (gray arrow, dim light; black arrow, bright light). (D–F) Individual melatonin profiles across ~24 hours during the (●) first constant routine (CR1) and (○) second CR (CR2) under each of the three light exposure conditions demonstrate the phase resetting effects of bright-light exposure compared with dim light. (G) Phase shifts of the human circadian system in response to dim-light control (n = 9) and to 15-second (n = 7) and 2-minute (n = 10) high-intensity night-time light (~9,500 lux) exposure. The box and whisker plots show the median, 25th and 75th percentile (box limits), the 10th and 90th percentiles (whiskers), and the maximum and minimum points, which are represented as filled circles. *P < 0.05 by Kruskal-Wallis one-way ANOVA followed by post hoc multiple comparisons using Wilcoxon rank-sum test. All tests were 2-tailed. (H) Phase resetting response (median ± SD) to 15-second (n = 7), 2-minute (n = 10), 12-minute (n = 8), 1-hour (n = 7), 2.5-hour (n = 9), and 4-hour (n = 8) night-time light (~9,500 lux) pulses fitted with a 4-parameter logistic model. Individual phase shifts are shown as ○. The 95% CI region of the regression is shown as the shaded area.