Temporal integration of light flashes by the human circadian system
Raymond P. Najjar, Jamie M. Zeitzer
Raymond P. Najjar, Jamie M. Zeitzer
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):938-947. https://doi.org/10.1172/JCI82306.
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Clinical Research and Public Health Neuroscience

Temporal integration of light flashes by the human circadian system

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.

Authors

Raymond P. Najjar, Jamie M. Zeitzer

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Figure 2

In-lab protocol design.

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In-lab protocol design. From day 1 to day 14, participants maintained a ...
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.