Millisecond flashes of light phase delay the human circadian clock during sleep

Abstract

The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.

Trial registration: ClinicalTrials.gov NCT01119365.

Keywords: circadian; electroencephalography; human; light; phase shift; sleep.

Figure 1

Protocol diagram. A protocol flow for a subject who had habitually slept from 00:00 until 08:00 during the two weeks prior to lab entry is depicted. One hour after entry, subjects had an initial constant posture (CP). For an hour, starting two hours after lights out, subjects were exposed to an experimental light exposure (ELE), consisting of either a flash sequence or darkness, during sleep. Subjects were ambulatory in the dimly lit laboratory until the start of a second CP. Phase change in salivary melatonin phase was determined between CP1 and CP2. Sleep during the ELE was compared with that which occurred during the prior hour on the same night.

Figure 2

Box chart of circadian phase changes (timing of melatonin onset) after exposure to the dark and flash stimuli. There is no significant phase change exhibited under the dark condition (P=0.95, paired t-test), while the flash condition induced a significant 30 minute phase change (P<0.01, paired t-test) that was also significantly different from that observed in the dark condition (P<0.05, t-test). Individual data are shown as stars.

Figure 3

The ERP generated from subjects exposed to the flash sequence during sleep. Each ERP represents the average 30-second EEG waveform during the one-hour exposure. Data were averaged within then between subjects for each of the four derivations (two central – C4 and C3, two occipital – O1 and O2). Data are centered on the timing of the flash (dotted line). Robust changes are observable in both the occipital (primary visual) cortex channels with lesser but still obvious changes in both the central cortical channels, confirming that the flash signal is passing through the eyelids and impacting brain firing patterns.