In the previous grant, 'After-effects of entrainment of the human circadian pacemaker', we were able to demonstrate that non-photic time cues elicited a phase-shifting effect on circadian rhythms in totally blind subjects that, while unable to entrain non-24-hour circadian rhythms in society, was able to modify phase to a greater extent than previously thought. We also discovered that the prevalence of intact circadian photoreception (i.e., maintenance of the melatonin suppression response following ocular exposure to white light) in the absence of light perception was greater than prior studies suggested. In the current renewal application, we propose to further investigate these initial findings. Following screening to test for the presence or absence of an intact circadian photoreception response, subjects will enter one of two studies. ? Study 1 will study those with an intact circadian response to light and examine the spectral sensitivity of circadian photoreception in the absence of photopic and scotopic photoreception. These results will be compared with similar studies that have already been completed in sighted subjects who maintain both circadian and photopic/scotopic photoreception to assess the relative contributions of these photoreceptor systems to circadian responses. Study 2 will study those who are not affected by light and will determine the limits of entrainment for non-photic time cues (sleep-wake, rest-activity, meals, showers, social contact) in order that the strength of such time cues can be determined for therapeutic use. Specifically we will test the hypotheses that: Study 1) exposure to monochromatic light of 460 nm for 6.5 h in the early biological night will cause a 3 h delay in circadian phase and a 85 percent suppression in pineal melatonin production whereas exposure to the same photon density of 555 nm will have no effect on circadian phase or melatonin suppression (compared to 1.7 h delay and 37 percent suppression in sighted subjects); Study 2) Exposure to a non-photic schedule advanced by 0.4 h relative to baseline intrinsic period will cause a phase advance of period of 0.4 h. This work has significant implications for understanding the novel photoreceptor system(s) underlying circadian and non-image-forming effects of light in humans and for further understanding the impact of non-photic time cues on the human circadian pacemaker by defining the limits of entrainment for non-photic synchronizers in order to potentially evaluate the efficacy of such time cues for treatment of circadian rhythm sleep-wake disorders in both the blind and sighted populations ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (02))
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Mitler, Merrill
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Brigham and Women's Hospital
United States
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Vandewalle, Gilles; Collignon, Olivier; Hull, Joseph T et al. (2013) Blue light stimulates cognitive brain activity in visually blind individuals. J Cogn Neurosci 25:2072-85
Klerman, Hadassa; St Hilaire, Melissa A; Kronauer, Richard E et al. (2012) Analysis method and experimental conditions affect computed circadian phase from melatonin data. PLoS One 7:e33836
Zaidi, Farhan H; Hull, Joseph T; Peirson, Stuart N et al. (2007) Short-wavelength light sensitivity of circadian, pupillary, and visual awareness in humans lacking an outer retina. Curr Biol 17:2122-8
Lockley, Steven W; Arendt, Josephine; Skene, Debra J (2007) Visual impairment and circadian rhythm disorders. Dialogues Clin Neurosci 9:301-14