Racial differences in the human endogenous circadian period.

Abstract

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.

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Racial Differences in the Human Endogenous Circadian
Period
Mark R. Smith, Helen J. Burgess, Louis F. Fogg, Charmane I. Eastman*
Biological Rhythms Research Laboratory, Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, United States of America
Abstract
The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are
individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so
contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD
cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial
differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase
assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was
attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for
racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study,
subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening
each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined
with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays,
relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for
understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift
work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep
phase disorder.
Citation: Smith MR, Burgess HJ, Fogg LF, Eastman CI (2009) Racial Differences in the Human Endogenous Circadian Period. PLoS ONE 4(6): e6014. doi:10.1371/
journal.pone.0006014
Editor: Shin Yamazaki, Vanderbilt University, United States of America
Received April 29, 2009; Accepted May 26, 2009; Published June 30, 2009
Copyright: ? 2009 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Supported by R01 NR007677 and R01 HL086934. The content is solely the responsibility of the authors and does not necessarily represent the official
views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: ceastman@rush.edu
Introduction
Nearly all living organisms display circadian rhythms, which
include a diverse array of near 24-hour cycles from the subcellular
to the behavioral level. In sighted individuals the light/dark (LD)
cycle is the main time cue that entrains circadian rhythms to the
24 hour day produced by the earth’s rotation. In the absence of
these time cues, circadian rhythms persist with an endogenous
period (tau). There are inter-species differences in the length of
tau, and within a species tau is normally distributed [1]. The
averagehuman tau isslightly
[2,3,4,5,6,7,8]. Some of the differences in human tau have been
attributed to age [9,10] season [11], and sex [12], but no other
factors have been identified as mediating the individual differences
in human tau.
The phase angle of entrainment is the temporal interval
between an output of the circadian clock [(e.g. the onset of
wheel-running activity in a rodent, or in humans the time of the
onset of melatonin secretion, marked by the dim light melatonin
onset (DLMO)] and the LD cycle (e.g. lights on or sunrise). Tau
influences the phase angle of entrainment, and thus is one factor
that contributes to morningness-eveningness. For example, an
animal with a longer tau begins its daily bout of activity at a
relatively later time relative to the LD cycle than another animal of
the same species with a shorter tau [13,14], and could thus be
greaterthan24 hours
thought of as more of a ‘‘night owl’’. Duffy et al. [15] showed that
a longer tau in humans is associated with a later habitual wake
time, a later time of the minimum of the circadian rhythm of body
temperature, and more eveningness on the Owl-Lark question-
naire [16]. Tau also influences the phase angle of entrainment
between the endogenous circadian clock and the sleep schedule. In
subjects with longer taus, the temporal interval between the
DLMO and bedtime is shorter than in subjects with shorter taus
[3,17]. Thus subjects with longer taus (night owls or evening types)
go to bed at an earlier circadian phase.
We have recently reported that human tau measured in an
ultradian LD cycle averaged 24.2 hours [3], a free running period
length very similar to previous findings. Here we report racial
differences in tau. We also report racial differences in the
magnitude of circadian phase shifts in response to bright-light
pulses and a shift of the sleep/dark schedule.
Methods
Methods for Measuring Tau
Subjects (n=60, 29 male, mean age6SD 26.3365.48 years)
maintained a regular sleep schedule at home for 1 week before
coming to the laboratory for a 5-day session. The 5-day session
included a baseline phase assessment, followed by 3 days of an
ultradian light/dark cycle [3,18], and then a final phase
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assessment (Figure S1). The ultradian light/dark cycle consisted of
1.5 hour episodes of darkness for sleep alternating with 2.5 hour
episodes of wakefulness in dim room light [4,100uKelvin (K), light
exposure ,100 lux]. Subjects completed two 5-day sessions,
separated by one week. During one session they received a pill
of exogenous melatonin or a bright light pulse on each of the 3
ultradian days, and during the other session they received placebo
pills or no bright light, in counterbalanced order. Measurements of
circadian period were calculated from the placebo or no bright
light sessions only. The average circadian period for subjects that
had the placebo 5-day session first (n=33) or second (n=27) was
similar (24.2560.23 and 24.2460.21 hours, respectively). The
individual differences in human tau have previously been ascribed
to sex [12], age [9,10], and season [11]. Data from two studies also
suggests that iris color could influence sleep timing and circadian
responses [19,20]. Consequently, in addition to self-reported race
as a predictor of tau, we included sex, age, month that tau was
assessed, and iris color in a stepwise linear regression analysis.
To determine whether there were racial difference in the
magnitude of the circadian phase shift in response to bright light
exposure, we analyzed data from our recent phase advancing [21]
and phase delaying [22] studies.
Methods for the Phase Advancing Study
The protocol for the phase advancing study [21] is illustrated in
Figure S2. Subjects maintained a regular sleep schedule for 10
days before coming into the laboratory for a baseline phase
assessment. After the baseline phase assessment subjects resumed
their regular sleep schedule at home for 11 days, during which
time their baseline DLMO was determined. Subjects then slept in
the laboratory for 4 treatment days. On the first treatment day
they went to bed at their regular bedtime, were awakened 8 hours
after their baseline DLMO, and were exposed to a 2-hour phase-
advancing light pulse. Awakening time and the start time of the
light pulse was advanced by 1 hour on each successive treatment
day. Bedtime was also advanced so that the time in bed on the
2nd–4thtreatment nights was 8 hours. Following the 4 treatment
days a final phase assessment was conducted to determine the time
of the DLMO and assess the phase shift of the DLMO from the
baseline to the final phase assessment. This was a between-subjects
design in which subjects received light pulses from either
polychromatic white (4,100uK; 6,000 lux; 4.961015photons/
cm2/sec) or blue-enriched (17,000uK; 4,000 lux; 4.261015
photons/cm2/sec) fluorescent lamps contained in a desk-top light
box. Phase advances of the DLMO in response to the white and
blue-enriched light pulses were similar, and the data from the two
groups were combined for the current analysis of racial differences.
Due to heterogeneity of variance, a Wilcoxon rank sum test was
used to compare the phase advance of the DLMO in Caucasian
(n=10) and African American (n=7) subjects.
Methods for the Phase Delaying Study
The protocol for the phase delaying study is illustrated in Figure
S3. The regular sleep schedule and phase assessments in the phase
delaying study [22] were similar to the phase advancing study, but
the light pulses and sleep episodes were timed to produce a
circadian phase delay. On the first of 4 light treatment days
subjects were exposed to a 2-hour light pulse, beginning 3 hours
after their baseline DLMO. Following the light pulse subjects had
8 hours in bed in the dark. The time of the light pulse and the
sleep episode were delayed 2 hours on each successive treatment
day. This was a crossover design in which subjects were exposed to
the same polychromatic white and blue-enriched light boxes as in
the phase advancing study, in counterbalanced order, at equal
photon density (4.261015photons/cm2/sec). Phase delays in the
two light conditions were very similar, and the average phase shift
of the DLMO for the two conditions was used for the current
analysis of racial differences. The magnitude of the phase delays of
the DLMO for Caucasian (n=9) and African American (n=2)
subjects are presented in the text, but because there were only 2
African American subjects we do not present a statistical test of
their differences.
Common Methods for Assessment of Circadian Phase
Details of phase assessments have been described previously
[23]. During phase assessments subjects remained in dim light
(4,100uK lamps covered with red filters, ,3.8 mW/cm2) and
provided saliva samples every 30 minutes. The concentration of
melatonin in these saliva samples was determined by radioimmu-
noassay. The sensitivity of the assay was 0.7 pg/ml and the intra-
and inter-assay coefficients of variability were 12.1% and 13.2%,
respectively. Each melatonin profile was smoothed with a locally
weighted least squares curve (GraphPad Prism, San Diego, CA). A
threshold to determine the DLMO of each melatonin profile was
calculated by taking the average of 5 consecutive low daytime
values plus 2 standard deviations of these values [24]. The higher
of the two thresholds (from the baseline or final melatonin profile)
was applied to both profiles. The DLMO was defined as the time
that the smoothed curve exceeded and remained above the
threshold. In the phase advancing and phase delaying studies, the
phase shift was calculated by taking the difference in the time of
the DLMO between the baseline and final phase assessments.
Because there were 4 days between the baseline and final phase
assessments in the ultradian light/dark cycle, tau was calculated by
dividing the phase shift of the DLMO by 4 and adding 24 hours.
Measurements of circadian period, phase advances, and phase
delays were also calculated using a different DLMO threshold
[21], with similar results.
Protocols were approved by the Rush University Medical
Center Institutional Review Board, and all subjects provided
written informed consent before study participation commenced.
Results
Period Length (tau)
The average circadian period was 24.2460.22 (SD) hours
(Fig. 1a). The stepwise linear regression analysis indicated that a
model including race, month of assessment, and age was a
significant predictor of tau [F(4,55)=8.98, p,0.001]. Tau in
African American subjects was significantly shorter (by 12.6
minutes) than for other subjects (Fig. 1a & b) [t=23.85, p,0.001;
unstandardized coefficient B=20.21]. However, given the small
number of Asian subjects, the only clear racial difference was
betweenAfrican American
(24.3060.23 hours) subjects. Tau measured in May and June
was significantly longer than in the other months, being
lengthened by 12.5 and 16.8 minutes, respectively, relative to
other months (Fig. 1c) [May: t=2.86, p,0.01, unstandardized
coefficient B=0.21; June: t=3.03, p,0.01, unstandardized
coefficient B=0.28]. Age was also a significant independent
predictor of tau, such that older subjects had shorter taus (Fig. 1d)
[t=22.29, p=0.03,unstandardized
Although we enrolled a relatively narrow age range of subjects
(18–45 years), all 13 of the subjects age 30 or older had a tau that
was shorter than the group average, compared to 19 of 47 subjects
younger than age 30 with a shorter than average tau (Fig. 1d)
[x2(1)=14.52, p,0.001]. Tau was similar in females (24.2060.19)
(24.0960.17) andCaucasian
coefficient B=20.01].
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and males (24.2860.24 hours), and sex was not a significant
independent predictor of tau.
African American race was the strongest predictor of tau
(standardized coefficients b=20.41), followed by measurement in
June (b=0.32), and May (b=0.31), and age (b=20.24). Together
race, month of assessment, and age accounted for 40% of the
variance in tau (R2=0.40).
Phase Angle of Entrainment
In all subjects, tau was modestly associated with phase angle of
entrainment, such that a longer tau was associated with a later
DLMO relative to sunrise (r=0.34, p,0.01). However, when the
interval between the DLMO and bedtime was used as the phase
angle of entrainment, the correlation with tau was in the predicted
direction but did not reach statistical significance [r=2.23,
p=0.08].
In each of the 3 experiments described here (tau, phase-
advancing, and phase-delaying), there were no racial differences in
the bedtime, wake time, baseline DLMO, or the baseline DLMO
to bedtime phase angle.
Phase-Shifting Studies
In the phase-advancing study six of the seven African American
subjects had larger phase advances than all 11 of the Caucasian
subjects (Fig. 2a). The average phase advance for African
American subjects (1.9760.62 hours) was more than three times
as large as for Caucasian subjects (0.5661.09 hours) (Wilcoxon
W=60.00, Z=22.93, p,0.01).
The average phase delay for African American subjects
(22.2761.08 hours) was less than half as large as for Caucasian
subjects (25.2761.61 hours) (Fig. 2b). It is prudent to interpret
this difference with caution because of the small sample sizes.
Iris Color
In the portion of our sample for which we have data on eye
color, tau in subjects with brown (n=29) and blue (n=13) irises
was similar (24.2160.20 and 24.2660.27 hours, respectively), and
iris color was not a significant independent predictor of tau in the
regression analysis.
In the phase advancing study [21] Caucasians with both light
(blue and green) and dark (brown) irises were enrolled, as well as
brown-eyed African Americans, enabling a comparison of the
relative contribution of iris color versus race. While there was a
difference in the phase advance of the DLMO based on race
(described above), there was no significant difference in the phase
advance between subjects with blue and green irises (n=6) versus
brown irises (n=15) (1.161.2 and 1.361.2 hours, respectively). In
the phase delaying study [22] we could not distinguish between iris
Figure 1. Racial differences in the human endogenous circadian period. The human endogenous circadian period depends on race, season,
and age. (a) Histogram of circadian period (tau) for subjects (n=60) whose self-reported race was African American (black bars) or not African
American (white bars). (b) Circadian period by self-reported race. (c) Circadian period by 2 month bins. In (b) and (c), horizontal lines depict the mean.
(d) Circadian period by age. Black dots in (c) and (d) indicate African American subjects.
doi:10.1371/journal.pone.0006014.g001
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color and race, since all the Caucasian subjects had light irises
(blue, green, or hazel), and the two African American subjects had
dark brown irises.
Discussion
We have found that African Americans have a shorter free-
running endogenous circadian period (tau) than Caucasians. This
is the first report of racial differences in human tau. In addition, we
present evidence that there are racial differences in the amount
that the human circadian clock can be phase-shifted with bright
light exposure and a shifted sleep/dark schedule, such that African
Americans have larger phase advances, and smaller phase delays,
relative to Caucasian subjects. Racial differences in childhood
napping and nocturnal sleep as well as adult sleep architecture
between African Americans and Caucasians have previously been
reported [25,26,27,28,29,30]. Whether and how these differences
in sleep relate to differences in circadian rhythms have yet to be
elucidated.
The racial differences we found in circadian phase shifting are
consistent with what would be expected based solely on the
differences in tau, not assuming any differences in the shape of the
light phase response curves (PRCs). To illustrate why differences in
tau would produce differences in the magnitude of phase shifts
produced by our 4 day schedule of bright light pulses and shifting
sleep/dark, consider these calculations: An individual with a tau of
24.1 hours (the African American average), if allowed to free-run,
would delay 0.4 hours in 4 days, relative to the 24-hour LD cycle.
Assuming that our stimuli advanced their free-running clock
0.5 hours per day (or 2.0 hours in 4 days), the net phase advance
relative to the 24-hour LD cycle would be 2.0–0.4, or 1.6 hours.
This is close to the actual average phase advance for our small
sample of African American subjects, which was 2.0 hours. In
contrast, an individual with a tau of 24.3 hours (the Caucasian
average), if permitted to free-run, would delay 1.2 hours in 4 days.
Assuming that our stimuli advanced his or her free-running clock
the same 0.5 hours per day (or 2.0 in 4 days), the net phase
advance relative to the 24-hour LD cycle would be 2.0–1.2, or
0.8 hours. This is also close to the actual average phase advance
for our sample of Caucasians, which was 0.6 hours. Thus, based
only on the differences in tau, African American subjects would
have been expected to have larger phase advances and smaller
phase delays than Caucasian subjects.
Daan & Pittendrigh [31] showed that animals with a short tau
have a relatively enhanced delay zone of their light PRC, while
those with a long tau have a relatively enhanced advance zone of
their light PRC. These differences in PRC shape and amplitude
presumably have adaptive significance in enabling animals with
different length taus to entrain to the 24-hour LD cycle. We did
not measure tau and circadian phase shifts in the same subjects,
and it remains possible that humans with longer taus could also
have a larger amplitude advance zone of their light PRC and
advance more to the bright light stimulus than humans with
shorter taus, who in turn could have a smaller amplitude phase
advance zone of their light PRC.
We hypothesize that the racial differences in tau evolved
because of latitude, with longer taus in the Caucasian population
living at higher latitudes where there are greater seasonal changes
in photoperiod, and shorter taus in African populations living
closer to the equator where photoperiod is more constant.
Latitudinal clines have been reported for the circadian rhythm
of leaf movement in the flowering plant Arabidopsis thalinia [32] and
the eclosion rhythm of the fruitfly Drosophila auraria [33], such that
tau is longer at higher latitudes. In diurnal species with a tau
.24 hours (e.g. humans), having a longer tau enhances the ability
to track changes in photoperiod, which would be more prominent
at higher latitudes, and to maintain the normal phase angle of
entrainment between the circadian clock and the environmental
LD cycle [14].
Weitzman et al. [9] reported that the period of the core body
temperature rhythm in free-running older subjects (mean age 59.5)
was shorter than in younger subjects (mean age 25.3). More recent
data from a forced desynchrony protocol in which subjects lived
on a 28 hour day failed to replicate this age-related shortening of
tau [2]. We found that age was a significant independent but weak
predictor of tau. Contrary to the hypothesis that tau shortens with
age, a study in blind subjects reported that across a decade in mid-
life (30–54 years), the length of tau in the same subjects increased
with age [10]. Because our data and those described above [2,9]
are cross sectional, they do not exclude this latter possibility. An
alternative explanation for the apparent discrepancy between our
data and that of Kendall et al. [10] is that age-related changes in
tau may be different for sighted and blind individuals.
We observed a longer tau in May and June than in other
months. Similar seasonal effects in the period of core body
temperature rhythm have been reported in subjects free-running
in temporal isolation [11]. As stated by those authors, we do not
know whether there is an actual annual rhythm in the endogenous
circadian period, or whether the seasonal differences reflect
aftereffects of a longer summer photoperiod on tau [34].
Figure 2. Racial differences in the magnitude of phase shifts to
bright-light pulses and shifts of the sleep/dark schedule.
Circadian phase advance (a) and phase delay (b) of the DLMO by self-
reported race. By convention, phase advances are plotted as positive
numbers and phase delays are plotted as negative numbers. Lines
indicate the mean of each race.
doi:10.1371/journal.pone.0006014.g002
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Higuchi et al. [20] reported that light-induced melatonin
suppression in light-eyed Caucasian subjects was greater than in
dark-eyed Asian subjects, but they could not distinguish between
iris color and race. We did not observe differences in tau based on
iris color. In our phase advancing study, in which iris color and
race were not confounded, we observed differences in the phase
advance between African Americans and Caucasians, but not
between subjects with light or dark irises. Although these data
suggest that race influences circadian phase shifts, this does not
preclude a role of iris color as a contributing factor.
Our finding that tau was more strongly associated with the
phase angle of entrainment to the natural LD cycle than to the
behavioral LD cycle produced by the sleep/wake cycle is
consistent with a previous report that the human circadian clock
may entrain to sun time rather than clock time and the associated
social time cues [35]. Although significant, the size of the
correlation we found between tau and the phase angle of
entrainment to sun time was modest, and we observed no racial
differences in the phase angle of entrainment. One factor that
could have reduced the strength of this association was the
geographical location of our subject population (Chicago), since
living in large cities (and presumably receiving less outdoor light
exposure) has been shown to reduce the strength of the
relationship between the natural LD cycle and the phase of the
circadian clock [35].
In conclusion, we report racial differences in the endogenous
period of the human circadian clock, with concomitant racial
differences in circadian phase shifting. Because the period of the
circadian clock influences the speed with which the circadian clock
resets, our findings have broad implications for identifying the
prevalence and improving the diagnosis and treatment of
circadian-based sleep disorders, such as advanced and delayed
sleep phase disorder, shiftwork disorder, and jet lag. For example,
based upon the differences in tau, it is possible that the incidence
of advanced sleep phase disorder is higher among African
Americans, while the incidence of delayed sleep phase disorder
is higher among Caucasians. Due to their shorter tau and larger
phase advances, African American subjects might experience less
jet lag when flying east, but more severe jet lag when flying west,
compared to Caucasians. Finally, African Americans might show
smaller phase delays during a night work and day sleep schedule,
which could be associated with increased incidence of the
deleterious consequences of circadian misalignment.
Supporting Information
Figure S1
period. Subjects maintained a regular sleep schedule at home for
at least one week before coming to the laboratory for a baseline
phase assessment. This diagram shows the schedule for a subject
that slept from 00:00–8:00 on days 1–7, but sleep schedules were
tailored to each subject’s habitual sleep times. The change in the
time of the dim light melatonin onset (DLMO, indicated by the
upward arrows) from the baseline to the final phase assessment was
attributed to the free run of the endogenous circadian clock.
Found at: doi:10.1371/journal.pone.0006014.s001 (0.06 MB
PDF)
Protocol for assessing the endogenous circadian
Figure S2
were tailored to individuals’ typical sleep schedules. This shows the
protocol for a subject sleeping 00:00–8:00. The rectangle
containing the ‘‘L’’ shows the time of the 2-hour bright light
pulses. The first bright light pulse started 8 hours after the baseline
DLMO, and the start time of the light pulses occurred one hour
earlier on each successive day.
Found at: doi:10.1371/journal.pone.0006014.s002 (0.07 MB
PDF)
Protocol for the phase advancing study. Protocols
Figure S3
tailored to individuals’ typical sleep schedules. This shows the
protocol for a subject sleeping 00:00–8:00. The rectangle
containing the ‘‘L’’ shows the time of the 2-hour bright light
pulses. The first light pulse began 3 h after the baseline DLMO,
and the start time of the light pulses occurred 2 h later on each
successive day.
Found at: doi:10.1371/journal.pone.0006014.s003 (0.05 MB
PDF)
Protocol for the phase delaying study. Protocols were
Acknowledgments
We thank Dr. Shunbin Xu for constructive criticism of our data, which led
to the discovery of these racial differences, and the research assistants who
performed the data collection. In the phase-advancing and phase-delaying
studies, Phillips Lighting donated the blue-enriched light boxes, and
Enviro-Med donated the white light boxes.
Author Contributions
Conceived and designed the experiments: MRS HJB CE. Performed the
experiments: MRS HJB. Analyzed the data: MRS LFF. Wrote the paper:
MRS HJB LFF CE.
References
1. Pittendrigh CS, Daan S (1976) A functional analysis of circadian pacemakers in
nocturnal rodents. I. The stability and lability of spontaneous frequency. Journal
of Comparative Physiology 106: 223–252.
2. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, et al. (1999)
Stability, precision, and near-24-hour period of the human circadian pacemaker.
Science 284: 2177–2181.
3. Burgess HJ, Eastman CI (2008) Human tau in an ultradian light-dark cycle.
Journal of Biological Rhythms 23: 374–376.
4. Wever RA (1979) The Circadian System of Man. New York-Heidelberg-Berlin:
Springer-Verlag.
5. Campbell SS, Dawson D, Zulley J (1993) When the human circadian system is
caught napping: evidence for endogenous rhythms close to 24 hours. Sleep 16:
638–640.
6. Hiddinga AE, Beersma DGM, Van Den Hoofdakker RH (1997) Endogenous
and exogenous components in the circadian variation of core body temperature
in humans. Journal of Sleep Research 6: 156–163.
7. Carskadon MA, Labyak SE, Acebo C, Seifer R (1999) Intrinsic circadian period
of adolescent humans measured in conditions of forced desynchrony.
Neuroscience Letters 260: 129–132.
8. Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H (1992) Circadian
rhythm abnormalities in totally blind people: Incidence and clinical significance.
Journal of Clinical Endocrinology and Metabolism 75: 127–134.
9. Weitzman ED, Moline ML, Czeisler CA, Zimmerman JC (1982) Chronobiology
of aging: Temperature, sleep-wake rhythms and entrainment. Neurobiology of
Aging 3: 299–309.
10. Kendall AR, Lewy AJ, Sack RL (2001) Effects of aging on the intrinsic
circadian period of totally blind humans. Journal of Biological Rhythms 16:
87–95.
11. Wirz-Justice A, Wever RA, Aschoff J (1984) Seasonality in freerunning circadian
rhythms in man. Naturwissenschaften 71: 316–319.
12. Wever RA (1984) Sex differences in human circadian rhythms: Intrinsic periods
and sleep fractions. Experientia 40: 1226–1234.
13. Aschoff J (1965) The phase-angle difference in circadian periodicity. In:
Aschoff J, ed (1965) Circadian Clocks. Amsterdam: North-Holland Publishing
Co. pp 262–276.
14. Pittendrigh CS, Daan S (1976) A functional analysis of circadian pacemakers in
nocturnal rodents. IV. Entrainment: pacemaker as clock. Journal of Compar-
ative Physiology 106: 291–331.
15. Duffy JF, Rimmer DW, Czeisler CA (2001) Association of intrinsic circadian
period with morningness-eveningness, usual wake time, and circadian phase.
Behavioral Neuroscience 115: 895–899.
16. Horne JA, Ostberg O (1976) Self-assessment questionnaire to determine
morningness-eveningness in human circadian rhythms. International Journal
of Chronobiology 4: 97–110.
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