Saliva samples were spun and immediately frozen. Saliva samples were obtained every 30 minutes, immediately before or midway between snacks, using untreated Salivettes (Sarstedt, Newton NC). Instead of receiving dinner, subjects were given hourly equicaloric aliquots of food and isovolumetric (90 mL) water ( Mifflin et al., 1990) in order to minimize any possible effects of meals on metabolism and subsequent effects on circadian rhythms. For 9 hours prior to bedtime, subjects lay in bed in a constant, semirecumbent posture ( Deacon and Arendt, 1994 Duffy and Dijk, 2002). Low illuminance is necessary to unmask the endogenous rhythm of melatonin ( Zeitzer et al., 2000). In the laboratory, subjects were exposed to <10 lux during scheduled wake and complete darkness (<0.05 lux) during scheduled sleep. All events were timed relative to their at-home sleep pattern ( Zeitzer et al., 2011). Subjects stayed in the laboratory for a 35-hour protocol starting seven hours after habitual waketime ( Figure 1). Bringing these two streams of evidence together, we examined whether a train of millisecond flashes of light during sleep had the capacity to change the phase of the circadian system and to do so without affecting sleep. We have recently demonstrated that a train of millisecond flashes of light presented to subjects who are awake has the capacity to elicit phase delays of the human circadian system ( Zeitzer et al., 2011). Continuous bright light or long duration light pulses delivered during this most sensitive phase would, however, disrupt sleep as these would be likely to either cause or sustain awakenings ( Cajochen et al., 2000). Administration of light during sleep is plausible, given the penetrance of light through closed eyelids (which act as a red-pass filter with approximately twice as much of the longer wavelengths passing through as the shorter wavelengths) ( Moseley et al., 1988 Robinson et al., 1991), and preliminary evidence indicates that such treatment is effective in shifting circadian rhythms ( Cole et al., 2002 Figueiro and Rea, 2012). While bright light is a useful tool for maintaining proper alignment, the human circadian timing system is most sensitive to light during times at which people are normally asleep ( St Hilaire et al., 2012). A number of sleep disorders (advanced and delayed sleep phase disorder, non-24-sleep-wake disorder, shift work sleep disorder) are also directly attributable to an improper alignment between the circadian system and an individual’s social schedule ( Morgenthaler et al., 2007). Circadian misalignment can lead to health disruptions from mundane (e.g., jet lag) to serious (e.g., cancer) ( Stevens, 2005). The primary manner by which the internal circadian system remains entrained with the external day is through regular exposure to light and dark ( Duffy and Czeisler, 2009). Proper alignment of the circadian system with the external day is important for good health ( Vogel et al., 2012). The human circadian system controls the timing of most physiological systems including the endocrine, immune, and neurologic. While a greater number of matched subjects and more research will be necessary to ascertain whether there is an effect of these light flashes on sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. Exposing sleeping individuals to 0.24 seconds of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm as compared to the control dark condition (P0.30) during the flash stimulus. Changes in circadian timing (phase), micro- and macroarchitecture of sleep were all assessed.
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 seconds (n=6) from hours 2–3 after habitual bed time. Healthy volunteers participated in a two-week circadian stabilization protocol followed by a two-night laboratory stay. 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. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. 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. 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.
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