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Variation of length of circadian rhythm in humans in absense of time reference

Variation of length of circadian rhythm in humans in absense of time reference


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Are there any studies which show the range of the length of circadian rhythms for people that are removed from actual time, (Eg no sunset/ sunrise, no clocks or other reference of time)?

For example, what proportion of people tend to have a natural 30 hour rhythm or greater?

I ask because I would like to know if it is a possible cause of insomnia, how likely insomnia is caused by this, and if this knowledge might in some way lead to solutions for insomnia


This might be the study to which you refer in your answer, the people tested averaged a daily cycle of 24 hours and 11 minutes with a surprisingly small variation in their rhythms:

The variation between our subjects, with a 95 percent level of confidence, was no more than plus or minus 16 minutes, a remarkably small range.

Worth noting they were all healthy and so it doesn't tell us much about insomnia.

This study about insomnia in adults with ADHD shows that circadian rhythms of insomnia sufferers aren't so much longer as delayed (for sleep-onset insomnia anyway). Figure 2 might be of interest, showing that insomnia sufferers have significantly delayed melatonin production.


Apparently, in one(?) study, it was shown that the natural period for humans is actually a bit greater than 24 hours.

I only know this by what Jessa Gamble said in her TED talk:

http://www.ted.com/talks/jessa_gamble_how_to_sleep?

She goes into a lot more detail, and apparently we wouldn't just have one continuous sleep each day, so that makes answering the part of the question relating to length of sleep more complicated.

But interestingly, she gets to the core of how sense of reference disturbs sleep. To quote:

The people in these studies report feeling so awake during the daytime that they realise they're experiencing true wakefulness for the first time in their lives.

Unfortunately it is sparse of detail, short, and lacks any references!


Humans Found Closer Yet to Animals

For over three decades, basic texts in biology and psychology have informed their readers that humans' internal clock works differently from other animals'.

But a report by Harvard University researchers in today's issue of the journal Science indicates that the textbooks are wrong. Humans, it turns out, keep time the same way other animals do.

''Regardless of other differences between us, our clocks are extremely similar and our timing is first rate,'' Dr. Robert Y. Moore, chairman of the department of neurology at the University of Pittsburgh, writes in a commentary accompanying the article.

Like every other living creature, humans adapt their daily cycle of sleep and wakefulness, rest and activity, to the 24-hour solar cycle of darkness and daylight. But while many other animals, in the absence of light and other environmental cues, maintain an intrinsic circadian rhythm that approximates 24 hours in length and varies little from individual to individual, previous studies suggested that humans varied widely in their intrinsic rhythms. Some people seemed to have a natural cycle as short as 13 hours others required up to 65 hours for their sleep-wake cycle.

The average human cycle, scientists believed, was 25 hours, and the cycle's length appeared to shorten with age, perhaps accounting for why older people often woke up earlier and had trouble sleeping through the night.

In the new study, however, Dr. Charles Czeisler and his colleagues at the Harvard-affiliated Brigham and Women's Hospital in Boston undercut past findings, demonstrating that humans' intrinsic cycle in fact averages 24.18 hours -- about 24 hours 11 minutes -- and differs little from person to person. The length of the circadian cycle also appears to remain unchanged with age, Dr. Czeisler's team found.

The results, sleep researchers say, have implications for the understanding of basic sleep physiology, as well as for the treatment of many sleep disorders, including problems caused by jet lag and shift work and the sleep difficulties of the elderly.

Previous studies, Dr. Czeisler said, came up with inaccurate measurements of intrinsic circadian rhythms because researchers did not realize that ordinary room lights and other factors, like activity level, could have an impact on the body's clock, shifting it earlier or later.

Dr. Czeisler, professor of medicine at Harvard Medical School, and his colleagues overcame these problems by turning to a methodology pioneered six decades ago by a University of Chicago researcher, Dr. Nathaniel Kleitman, who carried out an experiment on circadian rhythms in Mammoth Cave in southwest Kentucky. Dr. Kleitman put his two human subjects, who lived for a month in the cave, on a 28-hour sleep-wake schedule, their bedtime shifting four hours later each day. He then compared fluctuations in the subjects' core body temperatures with readings taken when the same subjects were living in a university laboratory on a normal 24-hour schedule.

In that 1938 study, Dr. Kleitman found that in the cave, one subject's body temperature rhythm '⟞synchronized,'' passing through seven full cycles per week, even though, on the 28-hour schedule, only six '⟚ys'' of sleep and waking elapsed. In the years since, however, the Kleitman study was all but forgotten.

Dr. Czeisler and his fellow researchers adopted a similar 'ɿorced desynchrony'' strategy for their 24 subjects (11 young men, and 13 men and women in their 60's and 70's), who lived in the laboratory for three and a half to four weeks on a 28-hour schedule, the timing of sleep, activity, showers and meals shifting four hours later each day. Light levels were kept low, and the laboratory staff was trained not to give any hint of what time it was.

Under these conditions, the subjects' internal clocks, unable to synchronize with external cues, oscillated freely, offering the researchers a much more accurate indicator of how long the intrinsic cycles might be. All the subjects had cycles close to 24 hours -- the shortest was 23 hours 53 minutes, the longest 24 hours 28 minutes -- and the rhythms did not differ significantly between younger and older subjects.

Scientists studying the brain have determined that the body's circadian clock is situated in the suprachiasmatic nucleus, or SCN, a tiny structure in the hypothalamus. The clock receives input from the retina, and also from other brain structures. Through a complicated series of molecular processes, it serves as a pacemaker for a variety of cyclical functions, including sleep-wake cycles, body temperature and the secretion of hormones like melatonin.

The new study suggests that as in other animals, some humans may have genetic variations that cause their intrinsic cycles to be longer or shorter and perhaps predispose some people to sleep disorders.

Dr. Andrew Monjan, chief of neurobiology at the National Institute on Aging, which provided financing for the Harvard study, said the findings had practical implications for the treatment of sleep difficulties in the elderly.

'ɼzeisler's paper says there's no problem with the clock -- it's working fine,'' Dr. Monjan said. Instead, researchers must look to other influences, like exposure to room light, or perhaps an increased sensitivity of older people to internal alerting signals from the body clock.

For shift workers and transcontinental travelers, the new findings support the use of bright light to help push sleep-wake cycles earlier or later, depending on when the exposure occurs. And for the average working person, the study removes a convenient excuse that leads to sleep deprivation: that going to sleep later on weekends, simply because one does not feel like getting to bed, is nothing more than a reversion to the clock's natural rhythm. In fact, Dr. Czeisler said, people unwittingly shift their clocks by leaving room lights on until late at night.

The study's findings, he said, mean ''we're not being dragged by our physiology to go to bed later, we're dragging ourselves by our self-selected exposure to light.''


Overview of Adolescent Sleep Patterns in Humans

A recent poll by the National Sleep Foundation found that over 45% of adolescents in the United States obtain inadequate sleep [1]. At the root of this chronic sleep deprivation is the adolescent tendency to stay up late. Teenagers maintain later bedtimes than younger adolescents, even when wake up times are constrained by school or work [2,3,4,5,6]. This delayed timing of sleep is popularly attributed to many external influences, ranging from evening work to social opportunities [7]. Current evidence demonstrates, however, that social factors cannot completely account for the adolescent delayed sleep onset typical of an evening chronotype.

The developmental timing of the adolescent transition into a more evening chronotype suggests physiological underpinnings. Girls begin to show a delay in the timing of sleep 1 year earlier than boys, paralleling their younger pubertal onset. Maximum delay also occurs earlier in girls (19.5 vs. 20.9 years), and the magnitude of the peak delay is sexually differentiated [5]. In other cultures, similar developmental timing is observed, although the peak delay may occur as early as 15� years of age [1,2,3,4,5,6]. Importantly, a delay in the timing of sleep during the second decade of life has been observed in over 16 countries on 6 continents, in cultures ranging from pre-industrial to modern (as reviewed in [8]). Although most studies have been cross-sectional, retrospective longitudinal measures confirm that the timing of sleep is delayed during adolescence [5].

Adolescents continue to show a delayed circadian (or internal clock) phase as indicated by daily endocrine rhythms even after several weeks of regulated schedules that allow for sufficient sleep. This delay is maintained under controlled laboratory conditions in which there is limited possibility for social influence [7, 9]. Moreover, both home-based and laboratory studies of adolescents show that delayed circadian phase correlates with secondary-sex development [7, 10, 11]. This correlation holds true for subjective ratings of chronotype and puberty even when grade level in school is held constant [11]. If we assume that teenagers attending the same grade in school are exposed to a similar social environment, this evidence suggests that a biological component drives adolescent changes in sleep patterns.


Results

Division of labor and circadian rhythms in colonies foraging in the field

There was a clear division of labor between B. terrestris workers. Some workers specialized in nursing activities, whereas others specialized in foraging activities. In each of the three colonies we observed bees that cared for brood but did not forage during the observation sessions. By contrast, all bees that performed foraging activities also performed nursing activities. Division of labor was strongly correlated with body size. Large bees were more likely to perform foraging activities (linear regression analysis sessions A and B in colonies 2 and 3, R 2 =0.25–0.51, N=20–50, P<0.001 Fig. 1A). Bees that were classified as nurses were smaller than those classified as foragers or intermediates (see Materials and methods for classifications one-way ANOVA, P<0.001, followed by Bonferroni multiple comparison, P<0.05, in both sessions in colonies 2 and 3). In a sample of 64 workers we found that 92% of the bees that were classified as nurses in session A were also classified as nurses in session B(Fig. 1B). By contrast, only half of the bees classified as foragers in session A fit this classification in session B the rest were classified as intermediates. Intermediates constituted the most flexible group, with only 25% of those classified as intermediates in session A fitting this definition in session B, where 50%were classified as foragers and 25% as nurses(Fig. 1B). Intermediates were younger than both foragers and nurses (one-way ANOVA, P<0.001Bonferroni, P<0.005 for both sessions in all three colonies, with the exception of session B in colony 2). In Colony 3, in which we used an automatic motion-detection based video recording system, we found that large bees performed their first pollen foraging earlier than small individuals(Fig. 1C). This analysis revealed that some bumblebees performed successful foraging trips as early as 2 days of age (Fig. 1C).

Division of labor was associated with variation in diurnal rhythms. The proportion of bees with activity rhythms in the 19–29 h range was significantly higher for foragers as compared to nurses in session B in all three colonies (Fisher's Exact Test P<0.05, two-tailed, Fig. 2A–C), and in session A (in which colonies contained fewer bees) in colony 2(P<0.001). A similar trend was obtained in colonies 1 and 3(P=0.58, P=0.095, respectively), and the proportion was significantly higher in a pooled analysis of all three colonies (Fisher's combined P-values, P<0.005). An increase in overall activity in the hive typically started approximately 1 h before sunrise,consistent with the premise that the endogenous clock influences diurnal activity rhythms. To determine whether bees develop circadian rhythms with age, we compared the proportion of rhythmic bees in sessions A and B in a group of bees that were observed for both sessions (only included are bees<3 days of age on the first day of session A). We found no changes for nurses (Fisher's Exact Test, P>0.37, two-tailed in all three colonies, data not shown) but in a group that included all bees classified as foragers and intermediates in session A (both were typically large, see above), there was an increase in the proportion of bees with a circadian rhythm in session B (Fig. 2D, N=13, P<0.05). Worker size was positively correlated with power in both sessions of colonies 2 and 3 (in which we measured worker size, Fig. 2E, Linear regression analysis, R 2 =0.22–0.34, P<0.05).


Acknowledgements

The authors acknowledge support from Innovation and the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Science. S.C. receives support from the Jacob Jongbloed Talent Society Grant (Circulatory Health, University Medical Centre Utrecht). J.P.G.S. receives support from Horizon2020 ERC-2016-COG EVICARE (725229).

Reviewer information

Nature Reviews Cardiology thanks G. Cornelissen, R. Manfredini and K. Otsuka for their contribution to the peer review of this work.


Human Health Issues

The medical implications of circadian rhythms are immense and can be broadly classified into the following three groups (based on Ref. 114).

Effects imposed by external conditions on otherwise healthy individuals.

This group can be further divided into symptoms that arise from acute changes in external time cues, such as transmeridian flight (jet lag), and those that result from continual changes in light-dark cycles, most notably arising from shift work. Technological advances, from the invention of the light bulb to dramatic increases in the speed of air travel to highly integrated world wide communication systems, have permitted individuals and societies to escape the temporal constraints otherwise imposed by the natural environment. However, this “escapement” has a price tag, because human physiology has not undergone comparable changes and remains firmly interconnected with the internal pacemakers we all carry. Performing tasks during times in the day when psychomotor capabilities are suboptimal is associated with many serious consequences. For example, nurses on a repetitive shift work schedule are two- to threefold more likely to misdiagnose and wrongly treat patients than their daytime counterparts (53). More extreme examples of accidents related to the ill effects of “unnatural” work schedules include the Chernobyl nuclear plant in 1986, the chemical explosion of the Union Carbide plant in Bhopal, India, in 1984 and the grounding of the oil tanker Exxon Valdez in 1989 (92).

The effects of transmeridian flight and shift work on the human circadian timing system likely occur at two levels. For many years it was believed that the primary circadian pacemaker in mammals is located in the suprachiasmatic nucleus (SCN) in the brain (reviewed in Ref. 191). Although this idea remains relatively intact, more recent studies have shown that similar to Drosophila (49, 50, 60, 130), independent circadian pacemakers are present in many tissues in vertebrates such as zebrafish (193, 194) and mammals (7, 180). The emerging picture is that in intact mammals, much of the photic input to the circadian timing system is transduced via the retinohypothalamic tract (RHT) to the SCN (reviewed in Refs. 44 and 104), which in turn conveys time-of-day information to peripheral clocks that have tissue-specific regulatory features (e.g., 157, 212). Desynchronization not only occurs between the external environment and the SCN rhythm generator but also affects phase alignments between the different peripheral clocks (201). Different rates of resynchronization amongst the cellular clocks in the SCN and those found in the various tissues likely contribute to the dysfunction associated with jet lag and other abrupt changes in light-dark cycles (201).

Melatonin, a naturally produced hormone that is under circadian regulation, has been used to alleviate disorders associated with jet lag and shift work (reviewed in Ref. 13). Numerous lines of evidence suggest that the administration of melatonin can elicit phase shifts (e.g., 99), although other roles for this “wonder drug”, such as beneficial effects on longevity, combating cancer, and mounting immune responses remain controversial (138). Another successful approach for treating jet lag and shift work has been the use of phototherapy (11, 32, 33). The rationale for this noninvasive treatment is based on earlier work in model organisms showing that depending on when during the night a short pulse of light is administered, it can evoke either a delay or advance in the phase of the clock. Ideally, by correctly timing the phototherapeutic treatment, the rate of resynchronization to local time can be accelerated.

It is estimated that more than 20% of the U.S. work force is subjected to shifting work schedules (201). This includes a wide variety of occupations where suboptimal psychomotor capabilities could have disastrous consequences for many people, such as medical personnel, pilots (16), air traffic controllers and other systems administrators (26, 106), security and military personnel (52), and commercial truck drivers (57). More attention needs to be placed on the physiological, behavioral, social, and economic consequences of maintaining societies that are active round the clock. Indeed, a growing number of private and public entities have emerged that use circadian principles to recommend ways of minimizing the malaise associated with abrupt changes in light-dark schedules.

Issues related to diagnosis and treatment.

Many physiological and behavioral variables change in a rhythmic manner over the course of a day. Whether the lack of accounting for circadian variations in medically relevant variables has had a significant negative impact on diagnosis and treatment plans is not clear. Sampling at different times of day and knowing the natural rhythm of the variable in question would enable physicians a more precise account of the status of the patient. However, in addition to the inherent problem of feasibility in round-the-clock sampling, other factors such as exposure to “unnatural” light conditions or patients with malfunctions in their circadian timing system might lead to rhythms that are altered, rendering the variable unreliable as a diagnostic indicator.

For many years it has been known that the efficacy of certain drugs is dependent on time of delivery. Some well-studied examples are in the treatment of cancer (reviewed in Ref. 97). It is possible to increase the therapeutic potential and minimize toxic side effects by optimizing schedules for administering drugs. Many drugs used in chemotherapy affect the function and replication of normal and malignant cells. By targeting times when normal cells are less likely to be undergoing DNA synthesis, higher levels of chemotherapeutic drugs can be tolerated, increasing the effectiveness of the treatment (84, 160). In general, it is not surprising that there is circadian variation in the efficacy of certain drugs or agents. Rates of absorption, metabolism, target susceptibility, and excretion vary throughout the day, contributing to time-of-day differences in the beneficial and toxic effects of drugs.

Disorders or disease states that appear to be causally linked to malfunctions in the circadian timing system.

Malfunctions in the circadian timing system are associated with several disorders such as chronic sleep disturbances, manic-depression and seasonal affective disorders (SAD, or winter depression) (reviewed in Ref. 23). This is a very active area of research. The extent to which circadian disturbances are causally linked to the manifestation of the disorder or are secondary downstream events of the diseased state are not clear. Nonetheless, many of the symptoms associated with certain chronic sleep problems and affective disorders can be alleviated by alterations in light-dark schedules (e.g., 176). With recent advances in molecular genetics, it will be possible to determine whether polymorphisms in clock genes are causally linked to disorders that show a strong circadian component. Whether this line of investigation will also explain the basis for “night owls” and “early birds” remains to be seen (78). The recent demonstration that rest in D. melanogaster has physiological and behavioral correlates with sleep in mammals should provide interesting insights into understanding the role of circadian factors on regulating sleep and its substrates (66, 155).


Abstract

Background— Stroke onset shows a pattern of diurnal variation, with a peak in morning hours. Rhythmic changes in blood pressure, hormones, and other parameters have been suggested as underlying mechanisms, but exogenous factors such as increasing physical activity after awakening may also be of relevance. To characterize the impact of external clock changes on the rhythmic variation in stroke onset, this parameter was recorded in patients during transition periods into and out of Daylight Saving Time (DST).

Methods and Results— The present study was based on a prospective stroke registry in Germany that contains time points of stroke onset from 44 251 patients admitted between 2000 and 2005. To achieve a uniform timeline, time points of stroke onset were set back from Central European Summer Time (CEST) to Central European Time (CET) for patients admitted during DST periods. Compared with the last week before the clock change, transition to or from DST resulted in an immediate shift of stroke onset time points within the first week after the clock change in reference to the uniform timeline (transition from CET to CEST −60 minutes for the time points in both the 25th and 50th percentiles of the diurnal pattern, P<0.001 transition from CEST to CET +60 minutes for the time points in both the 25th and 50th percentiles, P<0.001 patients pooled on a weekly basis). A significant shift was already present the first and second day after the transitions (ie, Monday and Tuesday).

Conclusions— Transition to or from DST is coupled with an immediate shift in the time pattern of stroke onset. This strengthens the idea that exogenous factors associated with awakening are important determinants of the pattern of diurnal variation of stroke onset, because entrainment of the human circadian clock within hours is unlikely.

Stroke onset shows a characteristic pattern of diurnal (day/night) variation, with a peak occurring during morning hours. 1–3 A large number of publications have focused on identifying the underlying pathophysiological mechanisms and have reported rhythmic variation in blood pressure, vascular tone, platelet function, blood viscosity, fibrinolysis, cerebral vasomotor activity, and concentrations of hormones and coagulation factors to be of relevance in this context. 3–13 Furthermore, time-of-day–dependent variations in neuronal vulnerability to cerebral ischemia may also provide an explanation for temporal differences in stroke onset. 14,15 Most of these rhythms are governed by the circadian clock, which generates an endogenous rhythm via clock genes that interact in transcriptional/translational feedback loops. 16–21 The rhythmic variation in stroke onset may thus reflect the impact of the circadian clock. In addition, exogenous factors such as increasing physical activity after awakening in combination with gaining an upright body position have been discussed as factors that influence the timing of stroke onset. 3,22 However, some authors have raised concerns about the rhythmic nature of stroke onset, pointing out the possibility that the observed morning peak in stroke onset might be at least in part an epiphenomenon that mirrors the time point (ie, the morning hours) at which as yet undetected nighttime strokes are diagnosed. 23

Clinical Perspective p 290

Daylight saving time (DST) is used in many countries far from the equatorial zone to gain daylight in the evening by the convention of advancing clocks. 24 Typically, clocks are advanced 1 hour near the start of spring and are adjusted backward in autumn. Transition into or back from DST constitutes a sudden and arbitrary interference with the natural time pattern in which noon is approximately coincidental with the local culmination time of the sun. The present study was performed to characterize the effects of external clock change on the rhythmic pattern of stroke onset and to gain insight into which factors and mechanisms are its most relevant determinants.

Methods

Stroke Registry

The present study was based on a large prospective stroke registry provided by the Arbeitsgruppe Schlaganfall Hessen (Stroke Study Group of Hesse for details, see www.gqhnet.de). 25 This standardized, computerized registry is a countrywide quality-assurance measure based on state law in which all hospitalized stroke patients are supposed to be documented anonymously. Informed consent was not required before enrollment in the registry. At present, more than 100 hospitals participate in enrolling patients with a final diagnosis of transient ischemic attack (International Classification of Diseases, 10th Revision code G45), ischemic stroke (International Classification of Diseases, 10th Revision code I63), or intracerebral hemorrhage (International Classification of Diseases, 10th Revision code I61). All parameters relevant to the present analysis, including admission date, admission time, time of symptom onset (if known), gender, age, and severity of clinical symptoms on hospital admission (assessed with the modified Rankin scale), are recorded prospectively. For the present analysis, we screened data sets from patients admitted to the hospital between January 1, 2000, and December 31, 2005 (n=85 868). The time of hospital admission was reported in n=69 477 data sets, and this information was used for inclusion in the present study. In addition to the time of hospital admission, n=44 251 data sets also reported the time of stroke symptom onset.

Daylight Saving Time

In the European Union, Central European Time (CET, Coordinated Universal Time plus 1 hour) was transited into Central European Summer Time (CEST) for the following DST periods: March 26 to October 29, 2000 March 25 to October 28, 2001 March 31 to October 27, 2002 March 30 to October 26, 2003 March 28 to October 31, 2004 and March 27 to October 30, 2005. For every period, DST started after advancement of the clock from 2:00 am CET to 3:00 am CEST on the spring index day and ended after the clock was set back from 3:00 am CEST to 2:00 am CET on the autumn index day.

Statistical Analysis

To gain a uniform CET timeline, the time points of symptom onset and hospital admission were set back from CEST to CET values for patients admitted during DST periods. In the first step, we aimed to assess how stable the pattern of diurnal variation is over time and how this pattern is influenced by external clock change. To do so, we pooled patients according to their admission dates on a weekly basis over a 5-week period that either ended 1 day before the clock change or began 1 day after the clock change. Public holidays scheduled on weekdays (eg, Good Friday, Easter Monday) were excluded. Time points of both symptom onset and hospital admission were calculated in minutes after midnight. For descriptive purposes, the time points that reflected the 25th and 50th percentiles of the respective diurnal pattern were determined. The Mann–Whitney U test and Kruskal-Wallis test were used for statistical comparison of the overall diurnal patterns.

In a second step, we focused on characterizing the pattern of diurnal variation within the first week after external clock change to identify any gradual or stepwise adjustment. To do so, we pooled all patients admitted on the first and second day (ie, Monday and Tuesday) or on the fourth and fifth day (ie, Thursday and Friday) after the clock change and compared the time points of their symptom onset and hospital admission with those of the patients admitted on Monday/Tuesday or Thursday/Friday during the last 5 weeks before the clock change.

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

Results

Mean age of the patients was 72±13 years, and 50.2% were female. Twenty-five percent of the patients were documented as having transient ischemic attack, 64% as having ischemic stroke, and 8% as having intracerebral hemorrhage, whereas 4% could not be classified. Forty-five percent revealed slight to moderate neurological deficits on hospital admission (modified Rankin scale 0 to 2), and 54% had moderate to severe deficits (modified Rankin scale 3 to 5 1% not classified). Seventy-six percent of patients were classified as having arterial hypertension and 29% as having diabetes mellitus.

Figure 1 displays the diurnal variation of the time points of symptom onset (n=44 251) and hospital admission (n=69 479) for the entire data set (raw data, ie, CET in non-DST periods and CEST in DST periods). For both stroke onset and hospital admission, a diurnal rhythm with a morning peak was obvious. The time point that reflected the 25th percentile of the diurnal pattern of stroke onset corresponded to minute 480 after midnight (8:00 am ), and the time point that reflected the 50th percentile corresponded to minute 660 after midnight (11:00 am ). The respective values of the time points of hospital admission were minute 650 after midnight (10:50 am ) and minute 823 after midnight (1:43 pm ).

Figure 1. Diurnal pattern of stroke onset and hospital admission (raw data, ie, CET in non-DST periods and CEST in DST periods, categorized on an hourly basis).

As shown in Figures 2 and 3 , the pattern of diurnal variation of stroke onset and hospital admission was found to be stable within the 5-week periods before and after the external clock change (Kruskal-Wallis test, all P=NS) however, transition into DST resulted in a highly significant advancement of the time points of stroke onset within the first week after external clock change compared with the last week before the time shift, in reference to the uniform time line (ie, CET timeline −60 minutes for the time points in both the 25th and 50th percentiles of the diurnal pattern Mann–Whitney U test, P<0.001). Conversely, setting the external clock back from CEST to CET at the end of the DST periods delayed the time points of stroke onset significantly (by 60 minutes, respectively P=0.001) within the first week after external clock change. Respective values for the time points of hospital admission were −46 and −23 minutes for the transition into DST (from CET to CEST P<0.001) and 53 and 36 minutes for the transition back from CEST to CET (P<0.001). The shift of the time points of symptom onset and hospital admission remained significant when we selected males, patients with ischemic stroke, and patients with moderate and severe neurological deficits, respectively (Table).

Figure 2. Shift of the time points of stroke onset during transition into and back from CEST. Patients were pooled on a weekly basis. A uniform timeline was established by referencing the time points from patients documented in DST periods to CET. A, Time points are given in minutes after midnight. Bars represent the time points in the 25th (gray) and 50th (black) percentile of the diurnal pattern, respectively. N indicates number of patients per week. B, Frequency diagrams plotting the number of patients vs the time of day (categorized on an hourly basis) for the last week before the transition and the first week thereafter. The 1-hour shift of the morning peak is easy to discern.

Figure 3. Shift of the time points of hospital admission during transition into and back from CEST. For more details, see Figure 2.

Table. Shift of Time Points in the 25th and 50th Percentiles of the Pattern of Diurnal Variation of Stroke Onset and Hospital Admission During Transition to and From DST

A comparison of the pattern of diurnal variation on the first and second day (ie, Monday and Tuesday) after external clock change with that on Mondays and Tuesdays of the 5 weeks immediately preceding the clock change revealed a significant shift for the time points of both symptom onset and hospital admission (all P<0.05 Figure 4). The extent of this shift did not change on the fourth and fifth day (Thursday and Friday) after external clock change (values from the first and second day were compared with those of the fourth and fifth day and were assessed by means of z values derived from Mann–Whitney U tests Figure 4). Thus, the difference in diurnal profiles between the DST and non-DST groups was already evident on the first 2 days after external clock change and did not tend to increase further within the first week.

Figure 4. Comparison of the rhythmic pattern of time points of stroke onset and hospital admission on the first and second (ie, Monday and Tuesday [Mon+Tue]) and the fourth and fifth (ie, Thursday and Friday [Thu+Fri]) days after the clock change with that recorded on Mondays/Tuesdays and Thursdays/Fridays within the last 5 weeks before the clock change. The gray and black bars indicate time points in the 25th and 50th percentiles before the shift, respectively pink and red bars indicate time points in the 25th and 50th percentiles after the shift, respectively. P values and z values are derived from Mann–Whitney U comparisons. N indicates number of patients per group.

Finally, we performed a cross-check and compared the diurnal pattern of stroke onset on the first and second day after external clock change with that on Mondays and Tuesdays of the last 5 weeks before the clock change using the “raw” time points of stroke onset as documented in the registry (ie, CET values in non-DST periods and CEST values in DST periods). Despite a 1-hour advancement of the external clock during the transition from CET into CEST, a significant shift of stroke-onset time points was not obvious (0 minutes for the time points in both the 25th and 50th percentiles of the diurnal pattern P=0.540). Respective values for the transition back from DST to CET were also 0 minutes (P=0.855).

Discussion

In concordance with previous publications, the present investigation confirms that the time points of both stroke onset and hospital admission reveal a characteristic rhythmic day/night pattern, with a peak in the morning hours. 1–3 The large number of patients in the present database provided a unique opportunity for studying how these time patterns are influenced by the transitions into and back from DST. The major finding of the present study is that external clock changes from CET to CEST and vice versa evoked immediate shifts of the time points of stroke onset when the time points were referenced to a baseline time system (CET). This finding is of interest for consideration of the mechanisms that underlie the rhythmic pattern of stroke onset.

Several physiological systems and parameters, such as the cardiovascular system, blood pressure, platelet function, serum concentrations of circulating hormones and coagulation factors, blood viscosity, fibrinolytic activity, and cerebral vasomotor activity, reveal a characteristic pattern of day/night rhythmicity, predominantly peaking during the morning hours. 3–13 These rhythms are under control of the circadian system that generates endogenous rhythms with a period length of ≈24 hours (in humans, 24.2 hours) by molecular clocks comprising clock genes that interact in transcriptional/translational feedback loops. 16 Under natural conditions, the circadian system is entrained to the 24-hour period of the astrophysical day by external stimuli called “zeitgebers.” The most important zeitgeber is the photoperiod, ie, the change between night and day. In humans and mammals, photoperiodic information is transmitted to the circadian clock via the photopic and scotopic systems in the retina and a special set of photoreceptors that are located in the ganglion layer of the retina and that use melanopsin as a photopigment. 26–29 The transition to or from DST investigated here does not change the environmental photoperiod but represents a social cue. The issue of whether social cues may act as zeitgebers capable of entraining/phase shifting the human circadian system remains controversial. 30 Some authors have reported that social cues have negligible, if not zero, direct drive on the human circadian system. 31 Assuming that social cues would not affect the human circadian clock, the present results suggest that changes of the external clock elicit a direct (masking) effect on rhythmic body functions such as the sleep-wake cycle. In modern civilizations, the sleep-wake cycle is firmly synchronized to the time of the external clock, and external clock change is likely to abruptly shift the sleep-wake cycle of most individuals. Thus, the sleep-wake cycle and factors associated with awakening, including an increased physical activity, gaining a posture body position, and diagnosis of thus far undetected nighttime strokes, may be critical determinants of the diurnal time pattern of stroke onset. In our opinion, the latter point is particularly strengthened by the finding that heterogeneous types of stroke (ie, ischemic stroke, intracerebral hemorrhage, and transient ischemic attack) and different subtypes of ischemic stroke (ie, cardioembolic, large artery, and lacunar) all show a very similar pattern of diurnal variation of stroke onset despite a considerably different pathophysiology. 1–3,23 Unfortunately, it was not explicitly stated in the present database how many patients noticed their symptoms at the time of awakening. Thus, further studies are needed to investigate the influence of reduced awareness during sleep on the morning peak of stroke onset and hospital admission.

We cannot rule out the possibility that the changing of the external clock represents a zeitgeber that entrains the human circadian clock. If so, this entrainment by a social cue would occur rather rapidly, ie, within the first 24 hours after the stimulus provided by the external clock change. Notably, a rapid entrainment of the human circadian clock (within 24 hours) has also been observed when light stimuli at nighttime were applied as zeitgebers and shifts in melatonin rhythms were analyzed as readouts. 32

Missing data constitute a limitation of the present study. Although documentation is mandatory for all hospitals in Hesse, Germany, it is likely that a certain proportion of stroke patients were not registered. For instance, we cannot rule out that patients arriving during the night were less often documented than daytime patients. However, the present study did not investigate the diurnal profile of stroke onset and hospital admission per se but focused on profile shifts associated with DST transitions. It would be unreasonable to assume that patients were more likely to be entered into the database before the DST transition than afterward, or vice versa. Thus, we do not believe that missing data would have significantly influenced the present results.

In summary, the present study is the first to demonstrate that transition into or out of DST is coupled with an immediate shift of the time pattern of stroke onset. This suggests that exogenous factors associated with awakening are important determinants of the pattern of diurnal variation of stroke onset. As an alternative explanation, a rapid entrainment of the human endogenous clock within hours is unlikely. Future studies may investigate whether the diurnal variations in the frequency of onset of acute myocardial infarctions are influenced by external clock changes in a similar way. 33

Disclosures

Footnotes


IgE MEDIATED ALLERGIC REACTIONS IN MICE

IgE-mediated allergic reactions, including passive cutaneous and passive systemic anaphylaxis, are also regulated by circadian rhythms, in which the central and peripheral clock mechanisms and systemic glucocorticoids play central roles. The reactions are clinically relevant to human allergic disease, where circadian variability is reported, including exacerbations of allergic rhinitis and asthma in the early hours of the morning and chronic urticaria in the evening. Murine models of IgE-mediated allergy have demonstrated a complex interplay in the IgE/mast cell allergic response. If individual clock proteins, systemic corticosteroid production, SCN integrity, or local mast cell clock function is disrupted, the circadian rhythmicity of passive cutaneous anaphylactic and passive systemic anaphylactic reactions are lost [80]. Specific pharmacological inhibition of casein kinase with PF670462, leads to upregulation of PER2 expression, and IgE-mediated allergic reactions are attenuated [81].


Why are our circadian rhythms longer than 24 hours?

I've read that most people's circadian rhythms are slightly longer than 24 hours and has to regularly be "reset" by exposure to outdoor light. Why wouldn't our biologically rhythms be synced more closely to the 24 hour day? Is there any reason for this?

The short answer is we don't know exactly why that trait evolved, but it does have an effect on the alignment of circadian and sleep/wake cycles relative to the natural light/dark cycle.

The average human circadian period is about 24.15 hours, but differs slightly between individuals

First, as others have noted, the persistent idea that our intrinsic circadian period (i.e., the period we express in the absence of any time cues) is 25 hours is incorrect. This was shown to be incorrect about 20 years ago, yet maddeningly still appears in places like undergraduate psychology textbooks.

This number was obtained from experiments in which individuals lived in isolation from environmental time cues but were able to decide when to switch on/off the lights in their own living environment. This resulted in a feedback whereby light caused delays of the rhythm, effectively extending the period.

When all time cues and stimuli that affect the circadian clock are carefully removed, most humans express circadian rhythms within a small range around 24.15 hours. There are small individual differences in the circadian period. On average, females have slightly shorter periods, and on average the longer your circadian period the more your tendency towards going to bed later. While healthy individuals all tend to fall within a range of

24.7 hours, some studies have suggested that individuals with Delayed Sleep Phase Disorder can have longer periods (around 25 hours).

So long as your period is sufficiently close to your day-length, you can synchronize

Humans aren't unique in having a non-24-hour intrinsic circadian period. Some species have 24.5 hour periods on average, others have 23.5 hour periods on average. The important thing, from a functional perspective, is that the period is close enough to the day-length (24.0 hours in the case of Earth) to allow the circadian rhythm to be entrained (synchronized).

The circadian clock responds to certain environmental time cues, such as temperature and light. In humans, light is by far the most important factor in changing the timing of the clock. Our brain's master circadian clock is a group of cells in the hypothalamus called the suprachiasmatic nucleus, which lies just above the optic chiasm and receives inputs directly from the retina.

Depending on when in the circadian cycle you are exposed to light, the circadian clock responds differently. Light exposure early in the circadian day (i.e., in the hours around the time you would naturally awaken) advances the clock, or sets it forward. Light exposure in the late evening approaching bedtime and in the hours after bedtime delays the clock, or sets it backwards. This is partly why artificial light exposure at nighttime tends to cause people to have later circadian rhythms and more difficulty getting to bed early or waking up early (in addition, light exposure suppresses the nighttime release of the sleep-promoting hormone melatonin).

There is a maximum amount by which a block of daytime light can shift your circadian rhythm each day, which is around about 2 hours of advance or 3 hours of delay. This means an individual with an intrinsic circadian period of 24 hours could theoretically entrain to day lengths from about 22-27 hours, but in practice it would be extremely difficult and would require very carefully designed light exposure patterns towards either end of that range, due to the amount of resetting required.

As an example, this experiment attempted to entrain humans to a day length 1 hour longer than their intrinsic circadian period. Ordinary room light (100 lux) was sufficient to entrain the participants, but most failed to entrain using dimmer light (20 lux). Candlelight (1.5 lux) is sufficient to entrain most individuals to a 24.0 hour day, but not to a 23.5 hour day or a 24.6 hour (Mars) day.

The circadian period determines how the circadian rhythm is aligned with the natural light/dark cycle

The take-home message from the above is that if your circadian period is anywhere close to 24 hours (let's say about 23-25 hours), you're not going to have any difficulty entraining to the natural 24-hour light/dark cycle given a bright light source like the Sun. You might therefore say that close enough is good enough and there's no functional difference between a 23.8-hour period and a 24.2-hour period.

However, the difference is in where light exposure must occur in the cycle to achieve entrainment. An individual with a circadian period shorter than 24 hours needs more light exposure in their circadian evening than their circadian morning to achieve net phase delay each day. As a result, their circadian cycle will be aligned earlier relative to the natural light/dark cycle, so that more of the light exposure occurs relatively later in their circadian cycle.

Similarly, an individual with a period longer than 24 hours needs more light exposure in their circadian morning than their circadian evening to achieve net phase advance each day. As a result, their circadian cycle will be aligned later relative to the natural light/dark cycle, so that more of the light exposure occurs relatively earlier in their circadian cycle.

Your natural circadian period therefore has an important functional role in determining when you would naturally wake up and go to sleep relative to the natural light/dark cycle. Although, let's be clear that it's certainly not the only factor. For example, there is a tendency for humans (and many other mammalian species) to go to sleep later in adolescence. This may not be due to a significant lengthening of the circadian period, which seems to be quite stable across the lifespan, but rather to a change in the rate at which sleepiness builds up across the day.

If we look at different species, which each have different intrinsic circadian periods, they all occupy slightly different temporal niches. By this, I mean they are active during specific parts of the day, depending on a variety of ecological and biological factors, including how food availability varies throughout the day, how their predation risk varies throughout the day, and their own sensitivity to ambient temperature. One of the ways in which this timing difference is achieved is via differences in the circadian period.

We can therefore speculate that our period of

24.15 hours was selected due to it being in some way well-suited to our ancestral environment. People have also sometimes speculated that the natural variation in circadian period between individuals within a population ensures that different individuals are going to bed and waking up at slightly different times, allowing them to keep watch for the others, but again we're limited to speculation when it comes to determining why traits like this evolved.


Contents

Humans, like most living organisms, have various biological rhythms. These biological clocks control processes that fluctuate daily (e.g. body temperature, alertness, hormone secretion), generating circadian rhythms. Among these physiological characteristics, our sleep-wake propensity can also be considered one of the daily rhythms regulated by the biological clock system. Our sleeping cycles are tightly regulated by a series of circadian processes working in tandem, which allow us to experience moments of consolidated sleep during the night and a long wakeful moment during the day. Conversely, disruptions to these processes and the communication pathways between them can lead to problems in sleeping patterns, which are collectively referred to as circadian rhythm sleep disorders.

A circadian rhythm is an entrainable, endogenous, biological activity that has a period of roughly twenty-four hours. This internal time-keeping mechanism is centralized in the suprachiasmatic nucleus (SCN) of humans and allows for the internal physiological mechanisms underlying sleep and alertness to become synchronized to external environmental cues, like the light-dark cycle. [1] The SCN also sends signals to peripheral clocks in other organs, like the liver, to control processes such as glucose metabolism. [2] Although these rhythms will persist in constant light or dark conditions, different Zeitgebers (time givers such as the light-dark cycle) give context to the clock and allow it to entrain and regulate expression of physiological processes to adjust to the changing environment. Genes that help control light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY. [3] A full circadian cycle can be described as a twenty-four hour circadian day, where circadian time zero (CT 0) marks the beginning of a subjective day for an organism and CT 12 marks the start of subjective night. [4]

Humans with regular circadian function have been shown to maintain regular sleep schedules, regulate daily rhythms in hormone secretion, and sustain oscillations in core body temperature. [5] Even in the absence of Zeitgebers, humans will continue to maintain a roughly 24-hour rhythm in these biological activities. Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the day's activities, and rest at night. [6]

Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway. [7] Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals. Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance one's circadian cycle earlier in the day, leading to an earlier wake time. [8]

The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population suffers from a CRSD, many people are often misdiagnosed with insomnia instead of a CRSD. Of adults diagnosed with sleep disorders, an estimated 10% have a CRSD and of adolescents with sleep disorders, an estimated 16% may have a CRSD. [9] Patients diagnosed with circadian rhythm sleep disorders typically express a pattern of disturbed sleep, whether that be excessive sleep that intrudes on working schedules and daily functions, or insomnia at desired times of sleep. Note that having a preference for extreme early or late wake times are not related to a circadian rhythm sleep disorder diagnosis. There must be distinct impairment of biological rhythms that affects the person's desired work and daily behavior. For a CRSD diagnosis, a sleep specialist gathers the history of a patient's sleep and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO). [9] Gathering this data gives insight into the patient's current schedule as well as the physiological phase markers of the patient's biological clock. [ citation needed ]

The start of the CRSD diagnostic process is a thorough sleep history assessment. A standard questionnaire is used to record the sleep habits of the patient, including typical bedtime, sleep duration, sleep latency, and instances of waking up. The professional will further inquire about other external factors that may impact sleep. Prescription drugs that treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants are associated with abnormal sleep behaviors. Other daily habits like work schedule and timing of exercise are also recorded because they may impact an individual's sleep and wake patterns. To measure sleep variables candidly, patients wear actigraphy watches that record sleep onset, wake time, and many other physiological variables. Patients are similarly asked to self-report their sleep habits with a week-long sleep diary to document when they go to bed, when they wake up, etc. to supplement the actigraphy data. Collecting this data allows sleep professionals to carefully document and measure patient's sleep habits and confirm patterns described in their sleep history. [9]

Other additional ways to classify the nature of a patient's sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep. [8] Questionnaires like the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of sleep disruption. Specifically, these questionnaires can help the professional assess the patient's problems with sleep latency, undesired early-morning wakefulness, and problems with falling or staying asleep. [9]

Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders. [10]

CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. This category will be referred to as the intrinsic disorder type. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs. [ citation needed ]

Intrinsic Edit

    (DSPD): Individuals who have been diagnosed with delayed sleep phase disorder have sleep-wake times which are delayed when compared to normal functioning individuals. People with DSPD typically have very long periods of sleep latency when they attempt to go to sleep during conventional sleeping times. Similarly, they also have trouble waking up at conventional times. [citation needed] (ASPD): People with advanced sleep phase disorder exhibit characteristics opposite to those with delayed sleep phase disorder. These individuals have advanced sleep wake times, so they tend to go to bed and wake up much earlier as compared to normal individuals. ASPD is less common than DSPD, and is most prevalent within older populations. [citation needed]
      (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G). [11] Families that have this mutation in PER2 experience extreme phase advances in sleep, waking up around 2 AM and going to bed around 7 PM.

    Extrinsic Edit

      (SWSD): Approximately 9% of Americans who work night or irregular work shifts are believed to experience Shift work sleep disorder. [12] Night shift work directly opposes the environmental cues that entrain our biological clock, so this disorder arises when an individual's clock is unable to adjust to the socially imposed work schedule. Shift work sleep disorder can lead to severe cases of insomnia as well as excessive daytime sleepiness. [citation needed] : Jet lag is best characterized by difficulty falling asleep or staying asleep as a result of misalignment between one's internal circadian system and external, or environmental cues. It is typically associated with rapid travel across multiple time zones. [10]

    CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimer's disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments. [13] [14] [15] On one hand, it has been stated that people with AD have melatonin alteration and high irregularity in their circadian rhythm that lead to a disrupted sleep-wake cycle, probably due to damage on hypothalamic SCN regions typically observed in AD. [14] [15] On the other hand, disturbed sleep and wakefulness states have been related to worsening of an AD patient's cognitive abilities, emotional state and quality of life. [13] [14] [15] Moreover, the abnormal behavioural symptoms of the disease negatively contribute to overwhelming patient's relatives and caregivers as well. [13] [14]

    However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood. [14] Therefore, further studies exploring this field have been highly recommended, mainly considering the increasing life expectancy and significance of neurodegenerative diseases in clinical practices. [15]