title: Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology.
abstract: Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.
authors.affiliation: Division of Sleep Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ajphillips@partners.org
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Phillips
authors.forename: Charles A
authors.initials: CA
authors.lastname: Czeisler
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Klerman
mesh_terms: D001683:Biological Clocks / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D008954:Models, Biological; D012890:Sleep / Q000502:physiology*; D014851:Wakefulness / Q000502:physiology*