Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2016 Mar 1;126(3):938-47.
doi: 10.1172/JCI82306. Epub 2016 Feb 8.

Temporal integration of light flashes by the human circadian system

Raymond P Najjar, Jamie M Zeitzer
Clinical Trial

Temporal integration of light flashes by the human circadian system

Raymond P Najjar et al. J Clin Invest. .

Abstract

Background: Beyond image formation, the light that is detected by retinal photoreceptors influences subcortical functions, including circadian timing, sleep, and arousal. The physiology of nonimage-forming (NIF) photoresponses in humans is not well understood; therefore, the development of therapeutic interventions based on this physiology, such as bright light therapy to treat chronobiological disorders, remains challenging.

Methods: Thirty-nine participants were exposed to 60 minutes of either continuous light (n = 8) or sequences of 2-millisecond light flashes (n = 31) with different interstimulus intervals (ISIs; ranging from 2.5 to 240 seconds). Melatonin phase shift and suppression, along with changes in alertness and sleepiness, were assessed.

Results: We determined that the human circadian system integrates flash sequences in a nonlinear fashion with a linear rise to a peak response (ISI = 7.6 ± 0.53 seconds) and a power function decrease following the peak of responsivity. At peak ISI, flashes were at least 2-fold more effective in phase delaying the circadian system as compared with exposure to equiluminous continuous light 3,800 times the duration. Flashes did not change melatonin concentrations or alertness in an ISI-dependent manner.

Conclusion: We have demonstrated that intermittent light is more effective than continuous light at eliciting circadian changes. These findings cast light on the phenomenology of photic integration and suggest a dichotomous retinohypothalamic network leading to circadian phase shifting and other NIF photoresponses. Further clinical trials are required to judge the practicality of light flash protocols.

Trial registration: Clinicaltrials.gov NCT01119365.

Funding: National Heart, Lung, and Blood Institute (1R01HL108441-01A1) and Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center.

PubMed Disclaimer

Figures

Figure 1
Figure 1. CONSORT flow diagram showing enrollment, allocation, and analysis.
Seventy-seven participants were assessed for eligibility. Thirty-five participants were excluded from participation for either not meeting the criteria (n = 4) or declining to participate (n = 31). Forty-two participants participated in the study and were randomized to either a flash sequence or continuous light exposure protocol. Of the 34 participants who were allocated randomly to the different flash sequence light exposures, 3 failed to comply with the prelaboratory sleep schedule and were excluded and 31 were randomly assigned to different sequences of light flashes. Eight participants were allocated to the continuous light exposure. All 39 participants were analyzed. Melatonin suppression values in 3 participants from the flash allocated group were aberrant and had to be excluded.
Figure 2
Figure 2. In-lab protocol design.
From day 1 to day 14, participants maintained a regular at-home sleep-wake schedule. The approximate clock times in the case of a participant who maintained a regular sleep schedule between 0:00 hours and 08:00 hours from day 1 to day 14 prior to coming to the lab are shown. On day 15, participants came to the sleep lab (blue arrow) and underwent a first CP procedure (CP1) that included multiple assessments of saliva, SSS, and an auditory psychomotor vigilance task (aPVT) in dim light (0.6–1.9 lux). All procedures were timed based on an individual’s average MSP from day 1 to day 14. Lights were turned off 4 hours prior to MSP on day 15, and subjects were allowed to sleep (recorded with polysomnography [PSG]). Two hours and fifteen minutes prior to MSP participants were awoken for scheduled light exposure (LE). LE ended 1 hour prior to MSP and consisted of either 60 minutes of continuous light or 60 minutes of a sequence of ultrashort flashes. On day 16, participants were awoken at habitual wake time, provided breakfast and lunch, and then underwent a second CP procedure (CP2) similar to CP1. After CP2, participants were discharged (red arrow) and were offered a taxi ride home.
Figure 3
Figure 3. Change in melatonin phase shift as a function of the ISI.
An initial linear rise to peak circadian phase change (~1.85 hours phase delay) was observed when flashes were separated by 2.5 to 7.6 seconds of darkness. Thereafter, light-evoked phase shifts dropped following an exponential decay curve as ISI increased (n = 31). Responses of individuals (black circles) are plotted with the modeled curve (red line) and 95% CIs (dotted red lines). The average circadian phase delay of –0.60 ± 0.34 hours to a continuous 60-minute white light exposure is represented a dark gray horizontal bar, while the individual phase shift to continuous light is represented by yellow diamonds. Average phase shift induced by a similar protocol without light administration (data previously published in Zeitzer et al., ref. 44) is represented by a gray diamond with error bars (mean ± SD). In some participants, flashes separated by an ISI of 5 and 10 seconds induced over 2 hours of circadian phase shift. Negative values on the y scale indicate a phase delay.
Figure 4
Figure 4. Effect of flashes and continuous light on melatonin suppression, objective alertness, and subjective sleepiness.
There was no systematic ISI-dependent change in (A) melatonin suppression (n = 28), (B and C) objective alertness (n = 31), or (D) subjective sleepiness (n = 31). Continuous light significantly suppressed melatonin (W = 35, Z = 2.31, P = 0.016, Wilcoxon signed-rank test), reduced RT (t = 4.49, df = 7, P = 0.002, paired t test), and number of lapses (W = 34, Z = 2.18, P = 0.02, Wilcoxon signed-rank test) but did not decrease subjective sleepiness, as assessed by the SSS (W = 13.5, Z = 1.5, P = 0.19, Wilcoxon signed-rank test). (A–C) Average and (D) median changes induced by continuous light are represented as gray horizontal bars; yellow diamonds represent individual data. (D) Overlapping yellow diamonds are represented next to each other separated by a vertical red bar. Descending arrows or negative values indicate less melatonin suppression, faster RTs, fewer lapses, and decreased sleepiness.
Figure 5
Figure 5. Melatonin suppression and median RT changes associated with a similar circadian phase shift.
(A) Melatonin concentrations (n = 8, W = 35, Z = 2.31, *P < 0.05, Wilcoxon signed-rank test) and (B) median RT (n = 8, t = 4.49, df = 7, **P < 0.01, paired t test) are significantly decreased under continuous light exposure. (C) Participants exposed to flashes who exhibit a similar circadian phase shift as those exposed to continuous light (i.e., within the 95% CI) do not exhibit a significant decrease in melatonin concentrations (n = 7, W = 12, Z = –0.25, P = 0.81, Wilcoxon signed-rank test) or (D) median RT (n = 10, t = –0.02, df = 9, P = 0.98, paired t test) after the different flash exposures. Individual data before and after light exposure are represented as white circles connected with gray bars. (A and C) Median and (B and D) average data are represented as red circles connected by black bars.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Czeisler CA, Wright KP Jr. Influence of light on circadian rhythmicity in humans. In: Turek FW, Zee PC, eds. Regulation of Sleep and Circadian Rhythms. New York, New York, USA: Marcel Dekker; 1999:149–180.
    1. Duffy JF, Kronauer RE, Czeisler CA. Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure. J Physiol. 1996;495(pt 1):289–297. - PMC - PubMed
    1. Skene DJ, Lockley SW, Thapan K, Arendt J. Effects of light on human circadian rhythms. Reprod Nutr Dev. 1999;39(3):295–304. doi: 10.1051/rnd:19990302. - DOI - PubMed
    1. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995;15(5 pt 1):3526–3538. - PMC - PubMed
    1. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunization. JAMA. 2002;288(12):1471–1472. - PubMed

Publication types

Associated data