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.
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.