Melatonin administration can entrain the free-running circadian system of blind subjects

Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free-running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.

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Circadian desynchronization of core body temperature and sleep stages in the rat

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0702424104 ◽

2007 ◽

Vol 104 (18) ◽

pp. 7634-7639 ◽

Cited By ~ 74

Author(s):

Trinitat Cambras ◽

John R. Weller ◽

Montserrat Anglès-Pujoràs ◽

Michael L. Lee ◽

Andrea Christopher ◽

...

Keyword(s):

Body Temperature ◽

Circadian Rhythms ◽

Slow Wave Sleep ◽

Paradoxical Sleep ◽

Core Body Temperature ◽

The Other ◽

Sleep Stages ◽

Physical And Mental Health ◽

Free Running ◽

Core Body

Proper functioning of the human circadian timing system is crucial to physical and mental health. Much of what we know about this system is based on experimental protocols that induce the desynchronization of behavioral and physiological rhythms within individual subjects, but the neural (or extraneural) substrates for such desynchronization are unknown. We have developed an animal model of human internal desynchrony in which rats are exposed to artificially short (22-h) light–dark cycles. Under these conditions, locomotor activity, sleep–wake, and slow-wave sleep (SWS) exhibit two rhythms within individual animals, one entrained to the 22-h light–dark cycle and the other free-running with a period >24 h (τ>24 h). Whereas core body temperature showed two rhythms as well, further analysis indicates this variable oscillates more according to the τ>24 h rhythm than to the 22-h rhythm, and that this oscillation is due to an activity-independent circadian regulation. Paradoxical sleep (PS), on the other hand, shows only one free-running rhythm. Our results show that, similarly to humans, (i) circadian rhythms can be internally dissociated in a controlled and predictable manner in the rat and (ii) the circadian rhythms of sleep–wake and SWS can be desynchronized from the rhythms of PS and core body temperature within individual animals. This model now allows for a deeper understanding of the human timekeeping mechanism, for testing potential therapies for circadian dysrhythmias, and for studying the biology of PS and SWS states in a neurologically intact model.

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A relationship between heat loss and sleepiness: effects of postural change and melatonin administration

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.1.134 ◽

1997 ◽

Vol 83 (1) ◽

pp. 134-139 ◽

Cited By ~ 134

Author(s):

Kurt Kräuchi ◽

Christian Cajochen ◽

Anna Wirz-Justice

Keyword(s):

Heat Loss ◽

Core Body Temperature ◽

Circadian System ◽

Postural Change ◽

Melatonin Administration ◽

Postural Changes ◽

Subjective Sleepiness ◽

Core Body ◽

Skin Temperatures ◽

Lying Down

Kräuchi, Kurt, Christian Cajochen, and Anna Wirz-Justice. A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J. Appl. Physiol. 83(1): 134–139, 1997.—Both the pineal hormone melatonin (Mel) and postural changes have thermoregulatory sequelae. The purpose of the study was to evaluate their relationship to subjective sleepiness. Eight healthy young men were investigated under the unmasking conditions of a constant routine protocol. Heart rate, rectal temperature (Tre), skin temperatures (foot, Tfo; and stomach), and subjective sleepiness ratings were continuously recorded from 1000 to 1700. Mel (5 mg po) was administered at 1300, a time when Mel should not phase shift the circadian system. Both the postural change at 1000 from upright to a supine position (lying down in bed) and Mel administration at 1300 reduced Treand increased Tfo in parallel with increased sleepiness. These findings suggest that under comfortable ambient temperature conditions, heat loss via the distal skin regions (e.g., feet) is a key mechanism for induction of sleepiness as core body temperature declines.

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An arousing, musically enhanced bird song stimulus mediates circadian rhythm phase advances in dim light

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00550.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. R822-R827 ◽

Cited By ~ 8

Author(s):

Namni Goel

Keyword(s):

Circadian Rhythms ◽

Core Body Temperature ◽

Bird Song ◽

Circadian Phase ◽

Mediated Effects ◽

Subjective Night ◽

Total Mood Disturbance ◽

Before And After ◽

Dim Light ◽

Core Body

A musically enhanced bird song stimulus presented in the early subjective night phase delays human circadian rhythms. This study determined the phase-shifting effects of the same stimulus in the early subjective day. Eleven subjects (ages 18–63 yr; mean ± SD: 28.0 ± 16.6 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h musically enhanced bird song or control stimulus from 0600 to 0800 on the second and third mornings while awake. The 4-day sessions employing either the stimulus or control were counterbalanced. Core body temperature (CBT) was collected throughout the study, and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Dim light melatonin onset and CBT minimum circadian phase before and after stimulus or control presentation was assessed. The musically enhanced bird song stimulus produced significantly larger phase advances of the circadian melatonin (mean ± SD: 0.87 ± 0.36 vs. 0.24 ± 0.22 h) and CBT (1.08 ± 0.50 vs. 0.43 ± 0.37 h) rhythms than the control. The stimulus also decreased fatigue and total mood disturbance, suggesting arousing effects. This study shows that a musically enhanced bird song stimulus presented during the early subjective day phase advances circadian rhythms. However, it remains unclear whether the phase shifts are due directly to effects of the stimulus on the clock or are arousal- or dim light-mediated effects. This nonphotic stimulus mediates circadian resynchronization in either the phase advance or delay direction.

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Nonphotic entrainment of the human circadian pacemaker

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.4.r991 ◽

1998 ◽

Vol 274 (4) ◽

pp. R991-R996 ◽

Cited By ~ 32

Author(s):

Elizabeth B. Klerman ◽

David W. Rimmer ◽

Derk-Jan Dijk ◽

Richard E. Kronauer ◽

Joseph F. Rizzo ◽

...

Keyword(s):

Circadian Rhythms ◽

Light Exposure ◽

Core Body Temperature ◽

Biological Clock ◽

Bright Light ◽

Circadian Pacemaker ◽

Temperature Rhythms ◽

Blind Individuals ◽

Nonphotic Entrainment ◽

Core Body

In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals “free run” even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

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Ambulatory Estimation of Circadian Rhythms Shows Core Body Temperature Phase Precedes Slow Wave Sleep Phase in the Normal Elderly

Biological Psychiatry ◽

10.1016/j.biopsych.2020.02.650 ◽

2020 ◽

Vol 87 (9) ◽

pp. S251

Author(s):

Esther Blessing ◽

Ankit Paresh ◽

Arleener Turner ◽

Andrew Varga ◽

David Rapoport ◽

...

Keyword(s):

Body Temperature ◽

Circadian Rhythms ◽

Slow Wave ◽

Slow Wave Sleep ◽

Core Body Temperature ◽

Temperature Phase ◽

Sleep Phase ◽

Core Body

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Characterization of ultradian and circadian rhythms of core body temperature based on wavelet analysis

2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society ◽

10.1109/embc.2014.6944555 ◽

2014 ◽

Cited By ~ 2

Author(s):

Ming Huang ◽

Toshiyo Tamura ◽

Wenxi Chen ◽

Kei-ichiro Kitamura ◽

Tetsu Nemoto ◽

...

Keyword(s):

Body Temperature ◽

Circadian Rhythms ◽

Wavelet Analysis ◽

Core Body Temperature ◽

Core Body

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Contemporaneous melatonin administration modifies the circadian response to nocturnal bright light stimuli

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.2.r482 ◽

1997 ◽

Vol 272 (2) ◽

pp. R482-R486 ◽

Cited By ~ 3

Author(s):

A. Cagnacci ◽

R. Soldani ◽

S. S. Yen

Keyword(s):

Light Exposure ◽

Light Stimulus ◽

Core Body Temperature ◽

Bright Light ◽

Phase Shifts ◽

Double Blind ◽

Circadian Phase ◽

Melatonin Administration ◽

Baseline Evaluation ◽

Light Stimuli

We investigated whether the contemporaneous administration of melatonin can modify circadian phase shifts induced by bright light stimuli. After a baseline evaluation, 10 women were exposed for three consecutive nights to a 4-h bright light stimulus (>3,000 lx) initiated at the time of the estimated core body temperature (BT(c)) nadir. Along with light, each woman orally received, randomly and in a double-blind fashion, placebo (n = 5) or melatonin (n = 5; 1 mg 30 min before and 0.75 mg 120 min after the start of light exposure). Daily rhythms were reevaluated at the end of treatment. Bright light phase advanced, by about 90-120 min, BT(c) (P < 0.01), cortisol (P < 0.05), and melatonin (P < 0.01) rhythms. Contemporaneous administration of melatonin antagonized the phase advances of the cortisol and BT(c) rhythms, as well as the melatonin peak and melatonin offset. The phase advance of the melatonin onset was instead enhanced (P < 0.05). Contemporaneous melatonin administration modifies the capability of light to induce circadian phase shifts.

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Maternal-fetal communication of circadian phase in a precocious rodent, the spiny mouse

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.4.e401 ◽

1987 ◽

Vol 253 (4) ◽

pp. E401-E409

Author(s):

D. R. Weaver ◽

S. M. Reppert

Keyword(s):

Circadian Rhythms ◽

Postnatal Period ◽

Spiny Mouse ◽

Constant Darkness ◽

Suprachiasmatic Nuclei ◽

Maternal Influences ◽

Circadian Phase ◽

Environmental Light ◽

Running Activity ◽

Free Running

The development of circadian rhythms was examined in a precocious rodent species, the spiny mouse. Spiny mouse pups born and reared in constant darkness expressed robust circadian rhythms in locomotor activity as early as day 5 of life. Free-running activity rhythms of pups born and reared in constant darkness were coordinated with the dam on the day of birth. Postnatal maternal influences on pup rhythmicity are minimal in this species, as pups fostered on the day of birth to dams whose circadian phases were opposite to the pups' original dams were coordinated with their original dams on the day of birth. Studies using 2-deoxy-D-[1-14C]-glucose autoradiography showed that there were synchronous (coordinated) rhythms in metabolic activity in the maternal and fetal suprachiasmatic nuclei, directly demonstrating prenatal coordination of maternal and fetal rhythmicity. Maternal-fetal coordination of circadian phase was not the result of direct entrainment of the fetuses to the environmental light-dark cycle. These results demonstrate that there is prenatal communication of circadian phase in this precocious species, without demonstrable postnatal maternal influences on pup circadian rhythmicity. Spiny mice therefore represent an important animal model in which circadian rhythms in the postnatal period can be used to precisely assess prenatal influences on circadian phase.

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Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients

Interface Focus ◽

10.1098/rsfs.2010.0012 ◽

2010 ◽

Vol 1 (1) ◽

pp. 48-60 ◽

Cited By ~ 28

Author(s):

Christopher G. Scully ◽

Abdoulaye Karaboué ◽

Wei-Min Liu ◽

Joseph Meyer ◽

Pasquale F. Innominato ◽

...

Keyword(s):

Circadian Rhythms ◽

Skin Temperature ◽

Cancer Patients ◽

Infrared Imaging ◽

Core Body Temperature ◽

Dynamic Assessment ◽

Invasive Approach ◽

Circadian Timing ◽

Circadian Phase ◽

Temperature Rhythms

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2–6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.

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