Short-Wavelength Sensitivity of the Human Circadian System to Phase-Advancing Light

The light-dark cycle is the most important environmental stimulus for entraining the human circadian system (reviewed in Czeisler and Wright, 1999; Mistlberger and Skene, 2004). In mice, all nonvisual light responses are maximally sensitive to wavelengths around 480 nm (Hattar et al., 2003), and in humans, a range of nonvisual light responses has been shown to short wavelengths (Brainard et al., 2001; Thapan et al., 2001; Wright and Lack, 2001; Lockley et al., 2003; Warman et al., 2003; Cajochen et al., 2004; Wright et al., 2004). However, the peak sensitivity of the human phase-shifting response has yet to be determined; in particular, the phase-shifting ability of wavelengths less than 460 nm needs to be assessed. The aim of the present study was to compare the ability of 3 short-wavelength monochromatic light pulses (420, 440, and 470 nm light) to phase advance the human circadian system in comparison to 600 nm light. Arepresentation of the protocol used is shown in Figure 1. The overall mean times of melatonin onset (Melon50%) and melatonin acrophase on night 1 (N1) were 23.3 0.4 h (n = 12) and 3.4 0.4 h (n = 12), respectively. The CT of light administration was 3.9 0.4 (n = 12). Figure 2 shows the mean phase shifts in all the phase markers under the 3 high-photon density light conditions. There was a significant difference in the phase advances observed in the SynOff (F = 4.24, df = 18, p = 0.03); phase advances with 470-nm light exposure (74.4 14.8 min) were larger than with 600 nm (–1.3 17.7 min; p < 0.05). The 440-nm light exposure gave an insignificant SynOff advance (–2.4 25.8 min; p = 0.07), but the error was too large to distinguish its lack of effect from the clear advance with 470 nm. The remaining markers also showed a greater advance at 470 nm compared to those seen using 440 nm or 600 nm, but the differences were not statistically significant. In general, phase shifts were small and variable, and there were essentially no phase shifts at 440 or 600 nm (Fig. 2). With low-photon density, there were, at best, paltry phase shifts, inconsistent in direction, and no significant differences with wavelength (data not shown). Our results indicate that the 470-nm light is more effective than the 600-nm and, perhaps, the 440-nm light in phase advancing the offset of the human melatonin rhythm. This is the 1st time that wavelengths shorter than 460 nm have been assessed for their phase-shifting ability. The results of the current study, combined with previous work (Wright et al., 2004), suggest that the phase-advancing response exhibits a similar spectral sensitivity to that observed for light-induced melatonin suppression (Brainard et al., 2001; Thapan et al., 2001), with a maximal sensitivity between 460 and 480 nm, and may involve the same proposed novel opsin-based photopigment (Hankins and Lucas, 2002). The clarity of the results from this study was likely limited by the small sample size and by the unequal impact of each subject on the data set. Furthermore, before final conclusions can be drawn, it will be necessary to complete a full-action spectrum using the same subjects for each wavelength tested. The melatonin onset and offset responded differentially to the morning light exposure, as was observed in our previous study (Warman et al., 2003), and this may reflect the putative morning and evening oscillators (Pittendrigh and Daan, 1976). However, the phase advances observed in the Meloff50% are smaller (approximately half) than those observed in our previous study (Warman et al., 2003). This is likely due to the intermittent rather than continuous exposure and the use of monochromatic light rather than a broader range of wavelengths (432-462 nm; Warman et al.,