A train of blue light pulses delivered through closed eyelids suppresses melatonin and phase shifts the human circadian system

Abstract

A model of circadian phototransduction was published in 2005 to predict the spectral sensitivity of the human circadian system to narrow-band and polychromatic light sources by combining responses to light from the spectral-opponent "blue" versus "yellow" cone bipolar pathway with direct responses to light by the intrinsically photosensitive retinal ganglion cells. In the model, depolarizing "blue" responses, but not hyperpolarizing "yellow" responses, from the "blue" versus "yellow" pathway are combined with the intrinsically photosensitive retinal ganglion cell responses. Intrinsically photosensitive retinal ganglion cell neurons are known to be much slower to respond to light than the cone pathway, so an implication of the model is that periodic flashes of "blue" light, but not "yellow" light, would be effective for stimulating the circadian system. A within-subjects study was designed to test the implications of the model regarding retinal exposures to brief flashes of light. The study was also aimed at broadening the foundation for clinical treatment of circadian sleep disorders by delivering flashing light through closed eyelids while people were asleep. In addition to a dark control night, the eyelids of 16 subjects were exposed to three light-stimulus conditions in the phase delay portion of the phase response curve while they were asleep: (1) 2-second flashes of 111 W/m(2) of blue (λmax ≈ 480 nm) light once every minute for 1 hour, (2) 131 W/m(2) of green (λmax ≈ 527 nm) light, continuously on for 1 hour, and (3) 2-second flashes of the same green light once every minute for 1 hour. Inferential statistics showed that the blue flash light-stimulus condition significantly delayed circadian phase and significantly suppressed nocturnal melatonin. The results of this study further our basic understanding of circadian phototransduction and broaden the technical foundations for delivering light through closed eyelids during sleep for treating circadian sleep disorders.

Keywords: circadian rhythms; dim light melatonin onset; eyelids; flashing blue light; melatonin; sleep.

Figures

Figure 1

Experimental protocol for each 30-hour session. Notes: Each of four 30 hour sessions began at 6.30 pm. Subjects were given a sleep opportunity at 11.30 pm; otherwise they were awake in dim red light (<1 lx at cornea). Saliva samples for DLMO calculations were taken during both evenings (E1 and E2) of each session every 20 minutes, starting both evenings at 7 pm and ending at 11.20 pm during the first evening (E1) and midnight during the second evening (E2). Each session was associated with a single lighting condition: dark, continuous green light, flashing green light, and flashing blue light. All lighting conditions, including dark, were presented 90–120 minutes after the sleep opportunity period began (large arrow). One blood sample was collected immediately prior to light exposure and another blood sample was collected immediately after. Abbreviation: DLMO, dim light melatonin onset.

Figure 2

Individual phase shifts in minutes (ordinate) for 16 subjects who completed the four 30-hour experimental sessions (filled diamonds). Notes: A negative value means that dim light melatonin onset (DLMO) on the second evening occurred later than DLMO on the first evening. The mean ± standard error of the mean are also shown (filled circles). *Represents phase shifts significantly greater than zero (P < 0.05). When DLMO phase shift was adjusted to account for the natural drift that occurs in the dark (control) night, phase shift was significantly greater than zero (P < 0.05) only after exposure to flashing blue light. Abbreviation: DLMO, dim light melatonin onset.

Figure 3

Mean ± standard error of the mean adjusted melatonin suppression for the three lighting conditions. Note: Melatonin suppression significantly greater than zero (*P < 0.05 or **P < 0.01).