Stability, precision, and near-24-hour period of the human circadian pacemaker

Science

Volumn 284, Issue 5423, 1999, Pages 2177-2181

  Czeisler, Charles A ^a   Duffy, Jeanne F ^a   Shanahan, Theresa L ^a   Brown, Emery N ^b   Mitchell, Jude F ^a   Rimmer, David W ^a   Ronda, Joseph M ^a   Silva, Edward J ^a   Allan, James S ^a   Emens, Jonathan S ^a   Dijk, Derk Jan ^a   Kronauer, Richard E ^c  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROCORTISONE; MELATONIN;

ACCURACY; ADULT; AGE; AGED; ARTICLE; CIRCADIAN RHYTHM; CORE TEMPERATURE; FEMALE; HUMAN; HUMAN EXPERIMENT; HYDROCORTISONE BLOOD LEVEL; LIGHT DARK CYCLE; MALE; NORMAL HUMAN; PRIORITY JOURNAL; SLEEP DISORDER; SLEEP WAKING CYCLE; TIME;

NASA DISCIPLINE REGULATORY PHYSIOLOGY; NON-NASA CENTER;

ADULT; AGED; AGING; BIOLOGICAL CLOCKS; BODY TEMPERATURE; CIRCADIAN RHYTHM; DARKNESS; FEMALE; HUMANS; HYDROCORTISONE; LIGHT; MALE; MELATONIN; MIDDLE AGED; SLEEP;

EID: 0033603542     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.284.5423.2177     Document Type: Article

References (92)

1. D. P. King et al., Cell 89, 641 (1997).
2. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
3. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
4. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
5. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
6. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
7. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
8. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
9. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
10. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
11. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
12. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
13. Z. S. Sun et al., ibid. 90, 1003 (1997); H. Tei et al., Nature 389, 512 (1997); L. P. Shearman, M. J. Zylka, D. R. Weaver, L. F. Kolakowski, S. M. Reppert, Neuron 19, 1261 (1997); N. Gekakis et al., Science 280, 1564 (1998); M. J. Zylka, L. P. Shearman, D. R. Weaver, S. M. Reppert, Neuron 20, 1103 (1998); S. K. Crosthwaite, J. C. Dunlap, J. J. Loros, Science 276, 763 (1997): T. K. Darlington et al., ibid. 280, 1599 (1998); H. Hao, D. L. Allen, P. E. Hardin, Mol. Cell. Biol. 17, 3687 (1997); C. Liu, D. R. Weaver, S. H. Strogatz, S. M. Reppert. Cell 91, 855 (1997); J. E. Rutila et al., ibid. 93, 805 (1998); S. M. Reppert, Neuron 21, 1 (1998); J. C. Dunlap, Science 280, 1548 (1998).
14. M. R. Ralph and M. Menaker, Science 241, 1225 (1988).
15. M. H. Vitaterna et al., ibid. 264, 719 (1994).
16. R. J. Konopka and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68, 2112 (1971); J. J. Loros, S. A. Denome, J. C. Dunlap, Science 243, 385 (1989); J. C. Dunlap, Annu. Rev. Physiol. 55, 683 (1993); T. Kondo et al., Science 266, 1233 (1994); A. J. Millar, I. A. Carré, C. A. Strayer, N.-H. Chua, S. A. Kay, ibid, 267, 1161 (1995).
17. R. J. Konopka and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68, 2112 (1971); J. J. Loros, S. A. Denome, J. C. Dunlap, Science 243, 385 (1989); J. C. Dunlap, Annu. Rev. Physiol. 55, 683 (1993); T. Kondo et al., Science 266, 1233 (1994); A. J. Millar, I. A. Carré, C. A. Strayer, N.-H. Chua, S. A. Kay, ibid, 267, 1161 (1995).
18. R. J. Konopka and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68, 2112 (1971); J. J. Loros, S. A. Denome, J. C. Dunlap, Science 243, 385 (1989); J. C. Dunlap, Annu. Rev. Physiol. 55, 683 (1993); T. Kondo et al., Science 266, 1233 (1994); A. J. Millar, I. A. Carré, C. A. Strayer, N.-H. Chua, S. A. Kay, ibid, 267, 1161 (1995).
19. R. J. Konopka and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68, 2112 (1971); J. J. Loros, S. A. Denome, J. C. Dunlap, Science 243, 385 (1989); J. C. Dunlap, Annu. Rev. Physiol. 55, 683 (1993); T. Kondo et al., Science 266, 1233 (1994); A. J. Millar, I. A. Carré, C. A. Strayer, N.-H. Chua, S. A. Kay, ibid, 267, 1161 (1995).
20. R. J. Konopka and S. Benzer, Proc. Natl. Acad. Sci. U.S.A. 68, 2112 (1971); J. J. Loros, S. A. Denome, J. C. Dunlap, Science 243, 385 (1989); J. C. Dunlap, Annu. Rev. Physiol. 55, 683 (1993); T. Kondo et al., Science 266, 1233 (1994); A. J. Millar, I. A. Carré, C. A. Strayer, N.-H. Chua, S. A. Kay, ibid, 267, 1161 (1995).
21. C. H. Lowe, D. S. Hinds, P. J. Lardner, K. E. Justice, Science 156, 531 (1967).
22. C. S. Pittendrigh and S. Daan, ibid. 186, 548 (1974); L P. Morin, J. Biol. Rhythms 3, 237 (1988).
23. C. S. Pittendrigh and S. Daan, ibid. 186, 548 (1974); L P. Morin, J. Biol. Rhythms 3, 237 (1988).
24. E. D. Weitzman, M. L. Moline, C. A. Czeisler, J. C. Zimmerman, Neurobiol. Aging 3, 299 (1982).
25. W. C. Dement et al., in The Biology of Aging, C. E. Finch and E. L. Schneider, Eds. (Van Nostrand Reinhold, New York, 1985), pp. 692-717; B. L. Myers and P. Badia, Neurosci. Biobehav. Rev. 19, 553 (1995).
26. W. C. Dement et al., in The Biology of Aging, C. E. Finch and E. L. Schneider, Eds. (Van Nostrand Reinhold, New York, 1985), pp. 692-717; B. L. Myers and P. Badia, Neurosci. Biobehav. Rev. 19, 553 (1995).
27. C. A. Czeisler et al., Science 233, 667 (1986).
28. C. A. Czeisler et al., Lancet 340, 933 (1992).
29. J. Aschoff and R. Wever, Naturwissenschaften 49, 337 (1962).
30. R. A. Wever, The Circadian System of Man: Results of Experiments Under Temporal Isolation (Springer-Verlag, New York, 1979); Experientia 40, 1226 (1984).
31. R. A. Wever, The Circadian System of Man: Results of Experiments Under Temporal Isolation (Springer-Verlag, New York, 1979); Experientia 40, 1226 (1984).
32. S. S. Campbell, D. Dawson, J. Zulley, Sleep 16, 638 (1993).
33. B. Middleton, J. Arendt, B. M. Stone, J. Sleep Res. 5, 69 (1996).
34. O. M. Buxton et al., Am. J. Physiol. 273, E536 (1997); R. Leproult, O. Van Reeth, M. M. Byrne, J. Sturis, E. Van Cauter, J. Biol. Rhythms 12, 245 (1997).
35. O. M. Buxton et al., Am. J. Physiol. 273, E536 (1997); R. Leproult, O. Van Reeth, M. M. Byrne, J. Sturis, E. Van Cauter, J. Biol. Rhythms 12, 245 (1997).
36. O. Van Reeth et al., Am. J. Physiol. 266, E964 (1994); C. I. Eastman, E. K. Hoese, S. D. Youngstedt, L. Liu, Physiol. Behav. 58, 1287 (1995).
37. O. Van Reeth et al., Am. J. Physiol. 266, E964 (1994); C. I. Eastman, E. K. Hoese, S. D. Youngstedt, L. Liu, Physiol. Behav. 58, 1287 (1995).
38. J. N. Mills, J. Physiol. (London) 174, 217 (1964).
39. D. B. Boivin, J. F. Duffy, R. E. Kronauer, C. A. Czeisler, Nature 379, 540 (1996); D. B. Boivin and C. A. Czeisler, Neuroreport 9, 779 (1998).
40. D. B. Boivin, J. F. Duffy, R. E. Kronauer, C. A. Czeisler, Nature 379, 540 (1996); D. B. Boivin and C. A. Czeisler, Neuroreport 9, 779 (1998).
41. J. Waterhouse et al., Neurosci. Lett. 245, 97 (1998).
42. C. A. Czeisler, J. S. Allan, R. E. Kronauer, Sleep Res. 15, 266 (1986); in Sleep and Biological Rhythms: Basic Mechanisms and Applications to Psychiatry, J. Montplaisir and R. Codbout, Eds. (Oxford Univ. Press, New York, 1990), pp. 87-98.
43. C. A. Czeisler, J. S. Allan, R. E. Kronauer, Sleep Res. 15, 266 (1986); in Sleep and Biological Rhythms: Basic Mechanisms and Applications to Psychiatry, J. Montplaisir and R. Codbout, Eds. (Oxford Univ. Press, New York, 1990), pp. 87-98.
44. N. Kleitman, Sleep and Wakefulness (Univ. of Chicago Press, Chicago, 1939).
45. J. F. Duffy, D.-J. Dijk, E. B. Klerman, C A. Czeisler, Am. J. Physiol 275, R1478 (1998); D.-J. Dijk, J. F. Duffy, E. Riel, T. L. Shanahan, C. A. Czeisler, J. Physiol. (London) 516.2, 611 (1999).
46. J. F. Duffy, D.-J. Dijk, E. B. Klerman, C A. Czeisler, Am. J. Physiol 275, R1478 (1998); D.-J. Dijk, J. F. Duffy, E. Riel, T. L. Shanahan, C. A. Czeisler, J. Physiol. (London) 516.2, 611 (1999).
47. Subjects had no medical, psychiatric, or sleep disorders, as determined by history, physical examination, electrocardiogram, clinical laboratory screening tests, psychological questionnaires, interview with a clinical psychologist, and, for older subjects, chest radiograph and diagnostic sleep recording. None reported regular night or rotating shift work within the prior 3 years, or crossing more than one time zone within the prior 3 months. Urinary toxicological screening was used to verify that all subjects were drug-free at the time of study. The experimental procedures were reviewed and approved by the Human Research Committee at Brigham and Women's Hospital, and each subject gave written informed consent [23).
48. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
49. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
50. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
51. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
52. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
53. D. M. Edgar, C. E. Martin, W. C. Dement, J. Biol. Rhythms 6, 185 (1991); O. Van Reeth and F. W. Turek, Nature 339, 49 (1989); D. Janik and N. Mrosovsky, Physiol. Behav. 53, 431 (1993); N. Mrosovsky, S. G. Reebs, G. I. Honrado, P. A. Salmon, Experientia 45, 696 (1989); E. Van Cauter et al., J. Biol. Rhythms 8, S99 (1993); S. Amir and J. Stewart, Nature 379, 542 (1996).
54. E. B. Klerman et al., Am. J. Physiol. 43, R991 (1998).
55. R. E. Kronauer, J. E. Fookson, S. H. Strogatz, Steep Res. 15, 274 (1986).
56. R. E. Kronauer and C. A. Czeisler, in Light and Biological Rhythms in Man, L. Wetterberg, Ed. (Pergamon, Oxford, 1993), pp. 217-236; C. A. Czeisler et al., Science 244, 1328 (1989); E. B. Klerman, D.-J. Dijk, R. E. Kronauer, C. A. Czeisler, Am. J. Physiol. 270, R271 (1996).
57. R. E. Kronauer and C. A. Czeisler, in Light and Biological Rhythms in Man, L. Wetterberg, Ed. (Pergamon, Oxford, 1993), pp. 217-236; C. A. Czeisler et al., Science 244, 1328 (1989); E. B. Klerman, D.-J. Dijk, R. E. Kronauer, C. A. Czeisler, Am. J. Physiol. 270, R271 (1996).
58. R. E. Kronauer and C. A. Czeisler, in Light and Biological Rhythms in Man, L. Wetterberg, Ed. (Pergamon, Oxford, 1993), pp. 217-236; C. A. Czeisler et al., Science 244, 1328 (1989); E. B. Klerman, D.-J. Dijk, R. E. Kronauer, C. A. Czeisler, Am. J. Physiol. 270, R271 (1996).
59. P. H. Gander, R. E. Kronauer, C. A. Czeisler, M. C. Moore-Ede, Am. J. Physiol. 247, R427 (1984).
60. Two young subjects (1111 and 1105) returned for a classical free-running study in which they self-selected their light-dark cycle (12, 13) (Fig. 1, center panel). Two subjects (1111 and 1507) later returned for a 20-hour forced desynchrony protocol (Fig. 1, left panel). One of those subjects (1507) also returned for yet another forced desynchrony protocol with a 42.85-hour imposed day length. The ratio of scheduled bedtime to scheduled wake time was maintained at 1:2 for each forced desynchrony protocol.
61. t. We have explored such additional terms and identified those that rise above the level of noise in the temperature data. However, when these are included, the effect on the average endogenous period reported here is minimal (< 1 min) and not statistically significant. We therefore report the endogenous periods estimated without interaction periodicities, which can be used to investigate related nonlinear processes that are beyond the scope of this report
62. t. We have explored such additional terms and identified those that rise above the level of noise in the temperature data. However, when these are included, the effect on the average endogenous period reported here is minimal (< 1 min) and not statistically significant. We therefore report the endogenous periods estimated without interaction periodicities, which can be used to investigate related nonlinear processes that are beyond the scope of this report
63. E. N. Brown and C. A. Czeisler, J. Biol. Rhythms 7, 177 (1992).
64. T. L. Shanahan and C. A. Czeisler, Sleep Res. 20A, 557 (1991); T. L. Shanahan, thesis, Harvard Medical School (1995).
65. T. L. Shanahan and C. A. Czeisler, Sleep Res. 20A, 557 (1991); T. L. Shanahan, thesis, Harvard Medical School (1995).
66. J. K. Wyatt et al., Sleep Res. 26, 759 (1997); D. W. Rimmer, D. J. Dijk, J. K. Wyatt, D. F. Dinges, C. A. Czeisler, Med. Sci. Sports Exercise 30, 5 (1997).
67. J. K. Wyatt et al., Sleep Res. 26, 759 (1997); D. W. Rimmer, D. J. Dijk, J. K. Wyatt, D. F. Dinges, C. A. Czeisler, Med. Sci. Sports Exercise 30, 5 (1997).
68. Free-running subjects, who self-selected the timing of their sleep-wake and light-dark schedule while living in an environment free of time cues, chose sleep episode fractions averaging 29 to 33% (8, 12, 13, 36, 37, 39), comparable to the sleep fraction imposed in the forced desynchrony reported herein.
69. C. A. Czeisler, E. D. Weitzman, M. C. Moore-Ede, J. C. Zimmerman, R. S. Knauer, Science 210, 1264 (1980).
70. J. Zulley, R. Wever, J. Aschoff, Pfluegers Arch. 391, 314 (1981).
71. This same mechanism by which free-running subjects exhibit a longer observed period than their actual intrinsic circadian period may underlie some clinical cases of non-24-hour sleep-wake schedule disorder in which subjects exhibit an average sleep-wake cycle duration of ≥25 hours, even though their actual intrinsic circadian period may be much closer to 24 hours [J. S. Emens, D. J. Brotman, C. A. Czeisler, Sleep Res. 23, 256 (1994)]. Thus, their disorder may be behaviorally self-induced via self-selected exposure to artificial light, rather than being the result of an aberrant intrinsic circadian period.
72. C. A. Czeisler, thesis, Stanford University (1978).
73. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
74. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
75. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
76. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
77. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
78. L. P. Morin, K. M. Fitzgerald, I. Zucker, Science 196, 305 (1977); K.-I. Honma, S. Honma, T. Hiroshige, Jpn. J. Physiol. 35, 643 (1985); D. M. Edgar and W. C. Dement, Am. J. Physiol. 261, R928 (1991); P. J. Shiromani and D. Overstreet, Biol. Psychiatry 36, 622 (1994); R. E. Kronauer, C A. Czeisler, S. F. Pilato, M. C. Moore-Ede, Am. J. Physiol. 242, R3 (1982); A. Gundet and M. B. Spencer, Chronobiol. Int. 9, 148 (1992).
79. A. E. Hiddinga, D. C. M. Beersma, R. H. van den Hoofdakker, J. Sleep Res. 6, 156 (1997).
80. J. Zulley and S. S. Campbell, Hum. Neurobiol. 4, 123 (1985); N. Mrosovsky, Nature 319, 536 (1986).
81. J. Zulley and S. S. Campbell, Hum. Neurobiol. 4, 123 (1985); N. Mrosovsky, Nature 319, 536 (1986).
82. 3 (31).
83. D. Minors et al., Chronobiol. Int. 13, 179 (1996).
84. T. L. Kelly et al., J. Biol. Rhythms 14, 190 (1999).
85. R. L. Sack, A. J. Lewy, M. L. Blood, L. D. Keith, H. Nakagawa J. Clin. Endocrinol. Metab. 75, 127 (1992); D. N. Orth, C. M. Besser, P. H. King, W. E. Nicholson, Clin. Enodocrinol. 10, 603 (1979); S. W. Lockley et al., J. Clin. Endocrinol. Metab. 82, 3763 (1997).
86. R. L. Sack, A. J. Lewy, M. L. Blood, L. D. Keith, H. Nakagawa J. Clin. Endocrinol. Metab. 75, 127 (1992); D. N. Orth, C. M. Besser, P. H. King, W. E. Nicholson, Clin. Enodocrinol. 10, 603 (1979); S. W. Lockley et al., J. Clin. Endocrinol. Metab. 82, 3763 (1997).
87. R. L. Sack, A. J. Lewy, M. L. Blood, L. D. Keith, H. Nakagawa J. Clin. Endocrinol. Metab. 75, 127 (1992); D. N. Orth, C. M. Besser, P. H. King, W. E. Nicholson, Clin. Enodocrinol. 10, 603 (1979); S. W. Lockley et al., J. Clin. Endocrinol. Metab. 82, 3763 (1997).
88. A. Eskin, in Biochronometry, M. Menaker, Ed. (National Academy of Sciences, Washington, DC, 1971), pp. 55-80.
89. F. C. Davis and N. Viswanathan, Am. J. Physiol. 275, R960 (1998); J. F. Duffy, thesis, Northeastern University (1998).
90. F. C. Davis and N. Viswanathan, Am. J. Physiol. 275, R960 (1998); J. F. Duffy, thesis, Northeastern University (1998).
91. M. A. Carskadon, S. E. Labyak, C. Acebo, R. Seifer, Neurosci. Lett. 260, 129 (1999).
92. We thank the subject volunteers; research technicians; senior research technicians A. Fergus, K. Foote, G. Jayne, E. Martin, and A. Ward; S. Driscoll and the staff of the General Clinical Research Center (GCRC) of Brigham and Women's Hospital; subject recruiters J. Daley, J. Kao, D. Margolis, and R. McCarley, research assistants D. Chen and J. Whittemore Jr.; the Clinical Core Laboratory of the GCRC and Elias USA Inc. for hormonal assays; T. Ding for analytic software; W. Freitag for management of bioengineering systems; L Rosenthal for illustrations; J. Zeitzer for comments; J. K. Wyatt for provision of comparative data; and G. H. Williams for overall support Supported by the U.S. Public Health Service National Institute on Aging Award PO1-AG09975 (C.A.C.), National Institute of General Medical Sciences Award R01-GM53559 (E.N.B.), and NASA Cooperative Agreement NCC9-58 with the National Space Biomedical Research Institute. The studies were performed in a GCRC supported by MO1-RR02635. This paper is dedicated to the memory of Professor Jürgen Aschoff (1913-1998), who pioneered the modern science of circadian biology and established the first continuously operational laboratory shielded from external time cues to study human circadian physiology.