Totally blind people with no light perception cannot synchronize (entrain) their circadian rhythms to the light/dark cycle. Nevertheless, about half of these people are entrained to the 24- hour day. The time cues for entrainment are not known and may include social interactions. Those who are not naturally entrained free-run, usually with a circadian period slightly longer than 24 hours, resulting in their endogenous rhythms drifting a little later each day. We have found that all free-running blind people shift their circadian rhythms in response to these time cues in the same way: they drift later ( delay) at a faster rate when the onset of endogenous melatonin production is drifting across the day than when it is drifting across the night, which in animal experiments is termed relative coordination. Because the confounding effect of light has been naturally removed in totally blind people, we have also been able to precisely quantify their amplitude (amount) of relative coordination, the greater the amplitude, the greater the sensitivity. Remarkably, free-running adult females have a greater amplitude than adult males. Consistent with this finding is that more adult females appear to be naturally entrained to these time cues than males, a difference that appears to occur after puberty;in fact, it may be reversed before puberty, in that in the small number of subjects studied thus far, there may be a higher proportion of pre-pubertal males than pre- or post-pubertal females. We think these findings may be preliminary evidence for greater sensitivity to these time cues in females compared to post-pubertal males, whereas pre-pubertal males may possibly be more sensitive than pre- and post-pubertal females. We now propose to physiologically survey blind children and older adolescents (ages 5-8 and 17-20) across the nation to assess the proportion of naturally entrained males and females using actigraphy devices worn continuously on the wrist (as well as collecting salivary melatonin samples in some highly motivated subjects), which will lead to studies to identify these as of yet unknown non-photic time cues, as well as hormonal and other factors that affect sensitivity to them, thus leading to new treatment modalities for circadian disorders of both blind and sighted people. In a future grant application, we will assess feasibility of a large-scale, multi-center study of melatonin safety and efficacy, which may also be of benefit sighted people with circadian rhythm sleep and mood disorders

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Freund, Lisa S
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Oregon Health and Science University
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Emens, Jonathan; Lewy, Alfred J; Laurie, Amber L et al. (2010) Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods. J Biol Rhythms 25:381-4
Emens, Jonathan; Lewy, Alfred; Kinzie, John Mark et al. (2009) Circadian misalignment in major depressive disorder. Psychiatry Res 168:259-61
Boudreau, Eilis A; Johnson, Kyle P; Jackman, Angela R et al. (2009) Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am J Med Genet A 149A:1382-91
Lewy, Alfred J; Emens, Jonathan S; Songer, Jeannie B et al. (2009) Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model. Sleep Med Clin 4:285-299
Emens, Jonathan S; Yuhas, Krista; Rough, Jennifer et al. (2009) Phase angle of entrainment in morning- and evening-types under naturalistic conditions. Chronobiol Int 26:474-93
Lewy, A J (2007) Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol 72:623-36
Lewy, Alfred J (2007) Current understanding and future implications of the circadian uses of melatonin, a neurohormone discovered by Aaron B. Lerner. J Invest Dermatol 127:2082-5
Lewy, Alfred J; Emens, Jonathan; Jackman, Angela et al. (2006) Circadian uses of melatonin in humans. Chronobiol Int 23:403-12
Lewy, Alfred J; Lefler, Bryan J; Emens, Jonathan S et al. (2006) The circadian basis of winter depression. Proc Natl Acad Sci U S A 103:7414-9
Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J et al. (2005) Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 22:1093-106

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