Until recently, it was widely believed that the intrinsic period of the human circadian pacemaker was 25 h. However, using a 'forced desynchrony' laboratory-based protocol in which the confounding effects of light and activity on circadian period assessment are controlled, we have found that the intrinsic period of the circadian system is close to 24 h (average 24.18 h). Similarly, we have found that blind individuals without light perception (NPL) living in society have circadian rhythms of melatonin which free-run with a period averaging approximately 24.5 h. While these data also suggest that the intrinsic circadian period is closer to 24 h than previously thought, the discrepancy between blind and sighted subjects suggests that the circadian pacemaker may be affected by unidentified factors. One likely factor is the absence of after- effects of entrainment to the 24 h light-dark cycle in non- entrained blind individuals, who may thus have a longer circadian period than sighted subjects observed upon release from entrainment. Similarly, blind subjects entrained by non-photic time cues in society may differ from sighted and non-entrained blind subjects upon release from entrainment due to differences in after-effects of photic- and non-photic synchronizers. We propose to investigate the role of after-effects of entrainment by assessing the circadian period of blind individuals under field and forced desynchrony conditions and comparing them to healthy sighted subjects who have been and will be studied. Specifically we will test the hypotheses that: 1) the endogenous circadian period of the melatonin and temperature rhythms is significantly longer in NPL subjects than sighted subjects; 2) the circadian period of NPL subjects observed in field conditions in which non-photic time cues are non-uniformly distributed is significantly longer than when assessed under controlled forced desynchrony conditions; 3) those NPL subjects who are entrained in society but who are insensitive to light will have, on average, a significantly shorter circadian period than those NPL subjects who are not entrained in society. This work has significant implications for understanding how intrinsic period relates to prior entrainment and the role of after-effects of entrainment. It will help define the limits of entrainment for non-photic synchronizers and will evaluate the efficacy of such time cues to treat circadian rhythm sleep-wake disorders in both the blind and sighted populations.
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