Chronobiology

• Franz Halberg, University of Minnesota, Minneapolis, MN

Chronobiology (n., from Gk chronos = time, Gk bios = life and Gk logos = science) is a computer-aided tool for objectively quantifying, mapping and investigating mechanisms of biological time structures, including those in the otherwise neglected normal range. It is here defined by the criteria of the authors who do not claim to be representative of the views of others who accept the fiction of a relative constancy or homeostasis and hence do single-sample spotchecks used as imaginary "baselines". Chronobiology describes everyday physiology under ordinary conditions as well as after the standardization or constancy, as far as possible, of environmental temperature, lighting, the availability of food and other manipulable local conditions, while consulting records of as yet mostly unalterable variability in space weather and other conditions. The transdisciplinary effects of weather near and far are the topic of chronomics, which focuses on interactions among chronomes -- time structures -- in us and chronomes around us, from which the former developed in the first place. Chronobiology and chronomics, figurative microscopies and telescopies in time, isolate rhythms from chaotic changes and from trends (with age and/or with other varying internal chronobiology and external chronomics conditions). For example, chronobiology detects conditions such as a change beyond gender- and age-matched limits for blood pressure amplitude, \(A\) (a circadian blood pressure overswing that if consistent in certain populations can represent a risk of ischemic stroke within 6 years greater than that of hypertension).

History and applications

Chronobiology is a tool of a new biology, or rather of a new unified science. Indeed, studies of rhythms in and around us are steps toward a broader transdisciplinary science including all branches of biology, chemistry, physics, medicine, sociology, and in particular cosmology. Figure 1 sketches Minnesotan developments starting with counts of circulating blood eosinophils by light-microscopy and figuratively by microscopy in time, by repeating the counts around the clock, concomitantly with electroencephalograms in the early 1950s. Whatever the variable examined, it had an ~24-hour cycle. If the data were dense enough, cycles were shorter than 24 hours; if the time series was long enough, cycles were longer than 24 hours. After neighboring circadian, ultradian and infradian spectral regions were delineated, objective endpoints of time structure were formulated and assessed from a combination of time-varying and global analytical methods, i.e., by proceedings glocal in time and in space. The spatial slogan "think globally, act locally" was extended to analyses of the longest available time series at a given time and of its sections, varied systematically in length to obtain information in both the frequency and time domains, in the longer and shorter intervals analyzed.

Focus in the clinic and in the laboratory was directed upon adrenocortical/brain interactions, studied by a remove-and-replace approach, complemented by mitotic counts and cellular biochemistry, leading to the discovery by 1958 of circadian rhythms in RNA and DNA formation in this sequence within a mitotic cycle. Separate independent cellular peripheral as well as central oscillating mechanisms were eventually documented at the molecular level. Clock genes have been identified, among others, in the mammalian heart, where they are of particular interest since the circadian characteristics of heart rate were demonstrated to be inherited by studies on twins reared apart, revealing a high degree of emergenic heritability by a statistically significant intraclass correlation coefficient for monozygotes but not for dizygotes. A nucleated unicell, estimated to have existed on earth for millions of years, has highly statistically significant circadian rhythms with less prominent about 7-day rhythms. As a population, Acetabularia also mimics a circadecadal solar cycle. In continuous light, the circadian amplitude of electrical activity in Acetabularia is smaller than the circaseptan, and the latter is desynchronized from the societal week. Circadian rhythmicity in a prokaryote like E. coli, where it was first described, and in many other bacteria and in an archaeon demonstrates the importance of biological time structure from an evolutionary perspective. Cycles at the origin of life may have been a condition for their development, are ubiquitous in individuals and habitats, and of critical importance as a challenge in human affairs.

Figure 1: Chronobiology (center)-spawned transdisciplinary tools, chronomics and yet-to-be-developed chronobioethics, aiming to serve the health of individuals, the well-being of nations and the integrity of the cosmos. A microscopy in time revealed cycles in broader time structures with their mechanisms in living matter, resolved as chronobiology broadly. The alignment of the time series in biology with series from physics led to chronomics, a telescopy in time. The ~20-year cycles found in religiosity, crime and war can be mapped in some individual's blood pressure as a starting point for focus on diseases of nations by the study of individuals. Just as a micro-organism can multiply to produce a lethal toxin, so can a mentally ill individual, by infecting a population, produce both crime and terror. Starting with focus upon the psychophysiological mechanisms of underlying cycles of diseases of nations, complex relations will have to be resolved, perhaps the major task of applied biomedicine, if humanity is to meet the extremist challenges of our time via chronobioethics. © Halberg.

A few examples of chronobiologic applications include timing the intake of calories ( Figure 2), checking on responses to sodium intake ( Figure 3), timing drug treatment ( Figure 4), and radiotherapy ( Figure 5). The discovery of alterations in circadian blood pressure rhythm parameters constituting a risk greater than hypertension for stroke or nephropathy, see Figure 6 and Figure 7 (even in the absence of a high blood pressure, cf. Figure 8) is a critically important, underutilized chronobiologic finding. Sometimes as simple a decision as altering the timing of medication (cf. Figure 9), eliminates that risk.

Figure 2: Top: Three subjects consumed a single meal (2000 cal) per day, either in the morning (left) or in the evening (right). A cosine function with a period of 24 hours and a linear trend fitted concomitantly to the data were statistically significant 5 times (out of 6); \(P<0.05\) for non-zero slope of trend 4 times out of 5. (From Halberg F. Protection by timing treatment according to bodily rhythms: an analogy to protection by scrubbing before surgery. Chronobiologia 1974; 1 (Suppl. 1): 27-68.) Results from more rigorous and extensive study on additional subjects over longer spans with control of mental and physical activities support, ceteris paribus, the finding of a relative body weight loss on breakfast (Halberg F, Haus E, Cornélissen G. From biologic rhythms to chronomes relevant for nutrition. In: Marriott BM, editor. Not Eating Enough: Overcoming Underconsumption of Military Operational Rations. Washington DC: National Academy Press; 1995. p. 361-372. http://books.nap.edu/books/0309053412/html/361.html#pagetop. Bottom: Survival of mice dependent on housing conditions and timing of single daily meal. Young male BALB/c mice kept on LD12:1212 lighting regimen with 4-hour span of daily food accessibility. Initial group sizes: A = 19, B = 20, C = 16, D = 16, E = 20; 1/C: housed 1 per cage; 4/C: housed 4 per cage. In this case, density per cage (allowing cuddling) represents an advantage rather than a disadvantage, a point of chronoecology. Experiment set up in Minnesota after reading of many deaths associated with lack of food, lack of clothing and cool weather among the palm trees of Benares on the Ganges. (From Nelson W, Cadotte L, Halberg F. Circadian timing of single daily "meal" affects survival of mice. Proc Soc exp Biol [NY] 1973; 144: 766-769. © Halberg.

Figure 3: In a study by Kawasaki (1), the usual daily salt intake was redistributed to have either higher intake at lunch and lower intake at dinner or vice versa. Blood pressure was measured by ambulatory monitoring. As compared to the span when subjects had their usual salt intake, there was only a small numerical (not statistically significant) increase in both systolic and diastolic blood pressure when these subjects had the same total daily salt intake but with a higher amount at lunch and a smaller amount at dinner. By contrast, when sodium intake was reduced at lunch and increased at dinner, both the systolic and diastolic blood pressure of these subjects was statistically significantly decreased. 1. Kawasaki T, Itoh K, Cugini P. Influence of reapportionment of daily salt intake on circadian blood pressure pattern in normotensive subjects. J Nutr Sci Vitaminol 1994; 40: 459-466. © Halberg.

Figure 4: Top: Techniques are available to test on an individualized basis the efficacy of treatment. One such method consists of testing the equality of rhythm parameters before and after the start of treatment. In the case of this 75-year old man, the same dose (240 mg) of the same drug (Diltiazem HCl) was given either upon awakening (left) or during an interruption of sleep (right). The change in timing of medication was associated with both a further decrease in the MESOR of systolic blood pressure and with a decrease in the circadian amplitude of this variable. Timing treatment (chronotherapy) can hence be useful to treat CHAT as well as MESOR-hypertension. Bottom: Control charts of daily MESORs of systolic (left) and diastolic (right) blood pressure of a 75-year old man treated with 240 mg of Diltiazem HCl when the timing of this medication was changed from awakening to bedtime. While the series of daily MESORs is proceeding "in control" (i.e., before the change in timing of medication), the cumulative sum (CUSUM) comprises two line graphs that generally stay within the limits of the "decision interval" (shaded area). The two curves signal increase and decrease in mean, respectively. When one curve breaks out of the (shaded) decision interval boundary, it provides the rigorous validation of the decrease (in this case) in daily blood pressure MESOR. The time at which the MESOR changed is estimated by tracking the line segment leading to the breakout back to the last occasion on which it lay on the horizontal axis. In this case, the breakout occurs around April 10 and the decrease in blood pressure is estimated to have occurred shortly after the change in timing of medication. © Halberg.

Figure 5: Treatment timing at peak tumor temperature leads to faster tumor regression (left) and to more than doubling of the 24-month survival rate (0 on abscissa, right), as compared to reference groups treated 4 or 8 hours before or after the tumor temperature peak (+8, +4, -4, -8 on abscissa, right) or "as usual" (last column, right) (23). © Halberg.

Figure 6: Relative risk of cerebral ischemic event for various factors, computed as the ratio of the incidence of morbidity that occurred among patients presenting with the tested factor by comparison with that among patients not presenting with the tested factor. Results of a 6-year prospective study on 297 patients indicate that the risk associated with CHAT is larger than that of all other risk factors considered (obesity, high cholesterol, male gender, alcohol consumption, presence of familial antecedents, smoking, age above 60 years, and an elevated mean value of blood pressure). As compared to patients with an acceptable circadian blood pressure amplitude, patients with diastolic CHAT have a risk 8.2 times larger (i.e., they have a 720% increase in risk) of having a cerebral ischemic event within 6 years of monitoring. © Halberg.

Figure 7: CHAT is also associated with a large increase in the risk of nephropathy (see legend of Figure 6). © Halberg.

Figure 8: An excessive circadian blood pressure amplitude is a risk factor for ischemic stroke independentfrom the 24-hour mean (MESOR). © Halberg.

Figure 9: Top: Changing timing of medication (ΔRx) during consecutive spans shows varying efficacy of treatment at different clock-hours to be related to times after awakening. An empirical approach to chronotherapy: immediately after diagnosis, one should ascertain that the treatment is effective. Optimization of treatment effects by timing can be achieved for the individual patient by systematically changing, e.g. advancing the time of treatment. Successful treatment of MESOR-hypertension assessed by a self-starting cumulative sum control chart (Cornélissen et al. 1997). To optimize his hypotensive treatment (Rx), a just-diagnosed 24-year-old individual (TT) switched his Rx first every 17 days by 4 hours and then mostly at shorter intervals. Note statistically significant decrease in MESOR, evidenced by the breakout outside the shaded decision interval of the negative CUSUM line (top graph). With continued Rx, the blood pressure MESOR leaves the decision interval, indicating a statistically significant decrease in overall blood pressure. Bottom: Changing timing of medication (ΔRx) during consecutive spans shows risk of iatrogenic CHAT: one should ascertain that one does not induce circadian hyper -- amplitude-tension (CHAT) by inappropriate timing of anti-hypertensive medication. In this 24-year old man (TT) who advanced the time of treatment by 4 hours every 17 days initially and at shorter intervals thereafter, treatment in the evening was associated with iatrogenic CHAT, raising the question whether the risk of MESOR-hypertension may not have been traded for the even higher risk of stroke that CHAT represents (see p. 30 of Halberg et al. 1995). Iatrogenic circadian hyperamplitude-tension, CHAT, induced by treatment at 20:00 daily, was silent to office visits. TT may have traded benefit (lowering of the MESOR of blood pressure, Fig. 15a) for something worse (circadian overswinging of blood pressure). This danger applies to some hypertensives (who tend to have a large circadian amplitude of blood pressure) to whom treatment time is not specified by the care provider, as was the case for TT (or is specified for bedtime). A few others who took hypertensive medication at bedtime were also found to have CHAT. The figure also shows the assessability of otherwise undetected harm by as-one-goes sequential analysis. © Halberg.

Chronobiology subdivisions

Some subdivisions of chronobiology are:

• Chronoanalysis provides, i.a.,

1. checks of the validity of a cycle by the fit of a model such as a (set of) cosine curve(s) for a test of the zero amplitude^∆, A, assumption and if A=0 is rejected,
2. dynamic parameters such as the amplitude, \(A\ ,\) and the acrophase, \(\varphi\ ,\) and the \((A,\varphi)\) pairs of harmonics (the latter to assess the waveform), in addition to a MESOR, M, short for Midline-Estimating Statistic Of Rhythm, as compared to the arithmetic mean. The M is usually more accurate in unequidistant data and more precise in equidistant data; and
3. non-parametric endpoints derived from stacking over a known or newly found time scale such as a period in whatever body function is being analyzed.

• Chronophysiology replaces the fiction of "baselines" in an imaginary homeostasis by dynamic parameters and eventually with complement feedbacks and feedforwards in organisms by feedsidewards in a collateral hierarchy of living things and of external-internal interactions. The same stimulus, if its timing is analyzed, has very different effects at certain predictable stages of a rhythm's time scale. Responses can then be quantified in light of reference values, as for instance by a parametric and nonparametric summary (sphygmochron) of blood pressure and heart rate variability over time, qualified by gender, age and ethnicity in health, Figure 10, eventually to be extended to each (clinically or otherwise) relevant periodicity, chaotic endpoint, such as a correlation dimension, and linear or other trend involved.

Figure 10: Responses can then be quantified in light of reference values, as for instance by a model-based and stacking-based summary (sphygmochron) of blood pressure and heart rate variability over time, qualified by gender, age and ethnicity in health, eventually to be extended to each clinically relevant periodicity, chaotic endpoint and trend involved. © Halberg.

• Chronohygiene for prehabilitation detects risk elevation by an alteration of rhythm characteristics before as well as after deviations in the overall mean occur, thus recognizing an elevation of disease risk and covert pathology before pathology becomes overt and symptomatic by a conventional approach relying on a normal range. For instance, the monitoring of blood pressure and heart rate in time, combined with chronobiologic data analysis (chronobiometry), detects unfavorable constellations of certain temporal parameters early, e.g., before hypertension occurs. Prehabilitation is concerned with the improvement of health by the implementation of prophylactic intervention aimed at disease risk-lowering, relying on procedures such as the scheduling of food intake (timing, Figure 2). Exercise must not be scheduled so that it inadvertently induces a circadian blood pressure overswing. Meditation, prayer, self-hypnosis and other activities could explore any influence by the time structures of both the organism and its environment. Societal and broad environmental-organismic interactions such as those in association with the about 10-year solar activity cycle and/or magnetic storms have effects that may eventually lead to a space weather report and to corresponding preventive research (see Chronomics). The study of genes associated with disease in the current genome research may well be complemented by the genome mapping in the light of characteristics such as the circadian periods, amplitudes and phases both in the more readily assessed 24-hour synchronized state and under conditions of desynchronization or multiple synchronization.

• Chronotherapy involves timing treatment to maximize the desired effects while minimizing the undesired effects. Whenever possible, treatment is timed to marker rhythms for each desired effect and for each undesired effect, Figure 4 (bottom half) and Figure 5. Chronotherapy requires a set of different variables in the case of cancer, including a physical marker, such as tumor temperature, Figure 5, or a chemical tumor marker such as CA125 and/or hematological gauges of the bone marrow's integrity, and vascular variables, to gauge cardiotoxicity, among others. When blood pressure and/or heart rate reveal a vascular variability disorder, VVD, Figure 11, the same chronobiologically interpreted ambulatory BP monitoring (C-ABPM) may provide information concerning the need for treatment and for its timing and for the validation of both its desired and some of its undesired effects, Figure 11, in order to avoid the status quo with misdiagnosed VVDs, Figure 12, described in Figure 11 and Figure 13.

Figure 11: Abstract visualization of vascular variability anomalies, VVAs, found in 7-day around-the-clock records. If replicated several times, VVAs can be called vascular variability disorders, VVDs. © Halberg.

Figure 12: the incidence of VVDs was assessed in a clinic population of 297 patients. Blood pressure (BP) and heart rate (HR) of each subject were monitored around the clock for two days at 15-minute intervals at the start of study. Each record was analyzed chronobiologically and results interpreted in the light of time-specified reference limits qualified by gender and age. On this basis, MESOR-hypertension (MH, diagnosed in 176 patients), excessive pulse pressure (EPP), CHAT (a circadian overswing), and a deficient heart rate variability (DHRV) were identified and their incidence related to outcomes (cerebral ischemic attack, coronary artery disease, nephropathy, and/or retinopathy). Outcomes, absent at the start of study in these non-diabetic patients, were checked every six months for six years, to estimate the relative risk associated with each VVD alone (primary diagnosis, PD) or in combination with 1, 2, or 3 additional VVDs. Earlier work showed that CHAT was associated with a risk of cerebral ischemic event and of nephropathy higher than MH, and that the risks of CHAT, EPP, and DHRV were mostly independent and additive. It thus seemed important to determine the incidence of each VVD, present alone or in combination with one or more additional VVDs. The 176 patients with MH were broken down into 103 (34.7% of the population of 297 patients) with uncomplicated MH, 55 (18.5%) with MH complicated by one additional VVD, 15 (5.1%) and 3 (1.0%) with MH complicated by two or three additional VVDs. In the last group, all three patients had a morbid outcome within six years of the BP monitoring. Ambulatory BP monitoring over only 48 hours, used for diagnosis, is much better than a diagnosis based on casual clinic measurements, yet its results apply only to groups. With this qualification, of the 176 patients with MH, 73 (42.2%) had additional VVDs that further increase their vascular disease risk, and that are not considered in the treatment plan of these patients since current practice does not assess these VVDs. This proportion may be smaller when VVDs are diagnosed on the basis of a 7-day record (available for CHAT). Results related to EPP (bottom left), CHAT (upper right), and DHRV (bottom right) illustrate that these conditions can be present in the absence of MH in as many as 12 (4.0%) of the 297 subjects. Since they do not have MH, it is unlikely that these subjects would be treated from a conventional viewpoint, even though their vascular disease risk can be as high as or even higher than MH. Evidence suggests that treating these conditions may translate into reducing morbidity and/or mortality from vascular disease. Another lesson is that around-the-clock monitoring of BP and HR interpreted chronobiologically is needed, even in the absence of MH, to detect vascular disease risk associated with VVDs such as CHAT and DHRV, that cannot be assessed on the basis of casual clinic measurements, so that non-pharmacologic and/or pharmacologic intervention can be instituted in a timely fashion before the occurrence of adverse outcomes. Once implemented across the board rather than in selected patient populations, vascular disease could be curbed to a much larger extent at relatively low cost if the monitoring is offered directly to the public and care providers become involved only after detection of a VVD. A website has to be built to educate, interest and serve many people and to provide cost-free analyses in exchange for the deidentified data, that as a pool are used for monitoring solar effects upon the biosphere. On a small scale, these services are now provided worldwide by the world-wide BIOCOS project (corne001@umn.edu). This ongoing personalized yet also societally oriented approach is an alternative to a polypill that as yet flies blind in the sense that it neither detects nor treats VVDs and VVSs. © Halberg.

Figure 13: A popular drug, if prescribed without personalised surveillance, can induce a vascular variability anomaly, VVA, and if it persists in several 7-day/24-h profiles, a vascular variability disorder, VVD, such as Circadian Hyper-Amplitude-Tension (CHAT). A change in the time when the drug is taken can make the same dose of the same drug in the same person beneficial or vice versa. At one administration time (before noon), Hyzaar induces CHAT in diastolic BP and exacerbates a preexisting CHAT in systolic BP (red). At another time of administration, Hyzaar eliminates a pre-existing VVD (green). These opposite effects were found in tests at six medication (Rx) times, each Rx time with the same drug dose administered for about a month, with half-hourly surveillance of BP during the last week of each span. These differences occur as a function of the timing of the drug’s use along the scale of 24 hours. Original study by Dr Yoshihiko Watanabe.

Figure 14: Principles of oncochronotherapy (top), evolved first to lower toxicity based on the discovery of susceptibility-resistance rhythms to a variety of stimuli; eventually, we aimed for the timing of best therapeutic efficiency, goals pursued in the laboratory first, followed by clinical studies of chronoradiotherapy, wherein oncostatic efficiency gained major focus. The final goal is the best temporal compromise between effectiveness and tolerance, as shown abstractly at the top of this figure on the right. At the bottom on the left, toxicity studies summarize a susceptibility rhythm to adriamycin with its uncertainty; in the middle, clinical studies with timing by peak tumor temperature show faster regression and doubling of 2-year disease-free survival that remains to be tested further; the promise of circadian and circaseptan cancer marker rhythms is implied at the bottom on the right. © Halberg.

Figure 15: Acting on the basis of conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure records, CHAT may remain unrecognised by both those administering treatment and those receiving it. The illustration of Pieter Brueghel's The Parable of the Blind Leading the Blind is reproduced by kind permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the City of Naples.

The very active field of chronomolecular biology is a chapter unto itself, far beyond the details of mechanisms approached as biological clocks. Pertinent to a broader chronobiology are the findings that infradians -- such as half-weekly, weekly, circaparasemiannual, half-yearly, para-annual, transyearly, yearly and even transtridecadal modulations of the circadian rhythm characteristics -- are now demonstrated to have important associations in health and disease. Infradians and some ultradians (such as the courtship song of a fruit fly) may be tied to the circadian system, as may be the development of a roundworm in the laboratory. More important questions awaiting answers based on models from humans for whom womb-to-tomb monitoring of at least some vital functions is indicated.

In Biological Rhythms in Clinical and Laboratory Medicine, Touitou and Haus wrote:

Together with the recent advances in chronopharmacology, [the] application of [chronobiologic concepts and methods to clinical medicine] appears now timely and in some areas urgent. ... The human time structure is a basic fact of our existence, no matter if one wants to study it or not. … [Thus,] Chronobiology and its subspecialties, like chronopharmacology, will certainly play an important role in the clinical medicine of the future. [1]

Whether this prediction of the 1950s becomes reality may depend on the recognition of the roles played by weather in space as well as on earth and on the recognition that just as heating and air conditioning have become important for human existence, so will be heretofore not generally recognized aspects of space weather, the topic of chronomes, complementing chronobiology, just as telescopes complement microscopes, to enable us to comprehend what our human senses have not yet identified [2, 3].

References

Origins

• a. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725, for introducing term;
• b. Cambrosio A, Keating P. The disciplinary stake: the case of chronobiology. Social Studies of Science 1983; 13: 323-353, history;
• c. Halberg F et al. Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf, history

Methods

• a. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440, method
• b. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms. Biological Rhythm Research 2007; 38 (4): 275-325. http://dx.doi.org/10.1080/09291010600903692, method
• c. Halberg F. Quo vadis basic and clinical chronobiology: promise for health maintenance. Am J Anat 1983; 168: 543-594, maps
• d. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL http://www.msi.umn.edu/~halberg/), maps

Books: Available on the Internet

1. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL http://www.msi.umn.edu/~halberg/)
2. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18 figures. URL http://www.msi.umn.edu/~halberg/
3. Ahlgren A, Halberg F. Cycles of Nature: An Introduction to Biological Rhythms. Washington DC: National Science Teachers Association; 1990. 87 pp.
4. Ajuriaguerra I de (ed). Symposium Bel-Air III. Cycles biologiques et psychiatrie / publie sous la direction du professeur I. de Ajuriaguerra. Geneva: Georg / Paris: Masson et Cie; 1968. 423 pp.
5. Aschoff J, Ceresa F, Halberg F, editors. Chronobiological aspects of endocrinology. 8th Capri Conference, 1974. Chronobiologia 1, Suppl. 1. Milan: Il Ponte; 1974. 509 pp.
6. Aschoff J, Ceresa F, Halberg F, editors. Chronobiological aspects of endocrinology. 8th Capri Conference, 1974. Stuttgart/New York: Schattauer; 1974. 463 pp.
7. Birkenhäger WH, Halberg F, Prikryl P, editors. Proc. Int. Symp. on Hypertension, Brno, Czechoslovakia, April 9-10, 1990. Brno: Masaryk University, 1990. 182 pp.
8. Carandente F, Halberg F, editors. Chronobiology of blood pressure in 1985. Chronobiologia 1984; 11: #3. p. 189-341.
9. Cornélissen G (editor), Schwartzkopff O, Niemeyer-Hellbrügge P, Halberg F (co-editors). Time structures -- chronomes -- in child development. International Interdisciplinary Conference, Nov. 29-30, 2002, Munich, Germany. Neuroendocrinol Lett 2003; 24 (Suppl 1). 256 pp.
10. Cornélissen G, Halberg E, Bakken E, Delmore P, Halberg F, eds. Toward phase zero preclinical and clinical trials: chronobiologic designs and illustrative applications. University of Minnesota Medtronic Chronobiology Seminar Series, #6, September 1992. Minneapolis: Medtronic Inc.; 1992. 411 pp. Second extended edition, February 1993.
11. Cornélissen G, Halberg E, Haus E, O'Brien T, Berg H, Sackett-Lundeen L, Fujii S, Twiggs L, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronobiology pertinent to gynecologic oncology. University of Minnesota/Medtronic Chronobiology Seminar Series, #5, Iuly 1992. Minneapolis: Medtronic Inc.; 1992. 25 pp. text, 7 tables, 30 figures.
12. Dunlap JC, Loros JJ, DeCoursey PJ, eds. Chronobiology: Biological Timekeeping. Sunderland, MA: Sinauer Associates; 2004. 406 pp.
13. Ferin M, Halberg F, Richart RM, Vande Wiele R, eds. Biorhythms and Human Reproduction. New York: John Wiley & Sons; 1974. 665 pp.
14. Foster R, Kreitzman L. Rhythms of Life: The Biological Clocks That Control the Daily Lives of Every Living Thing. London: Profile; 2004. 320 pp.
15. Fraisse P, Halberg F, Lejeune H, Michon JA, Montangero J, Nuttin J, Richelle M, eds. Du Temps Biologique au Temps Psychologique. Paris: Presses Universitaires de France; 1979.
16. Graeber RC, Gatty R, Halberg F, Levine H. Human eating behavior: preferences, consumption patterns and biorhythms. NATICK/TR-78/022 Technical Reports. Natick, Mass.: U.S. Army; 1978. 287 pp.
17. Halberg F, editor. Proc. XII Int. Conf. International Society for Chronobiology, Washington, DC, August 10-15, 1975. Milan: II Ponte; 1977. 782 pp.
18. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P, Bakken E, International Womb-to-Tomb Chronome Initiative Group: Chronobiology in space. Keynote, 37th Ann. Mtg. Japan Soc. for Aerospace and Environmental Medicine, Nagoya, Japan, November 8-9, 1991. University of Minnesota/Medtronic Chronobiology Seminar Series, #1, December 1991, 21 pp. of text, 70 figures.
19. Halberg F, Carandente F, Cornélissen G, Katinas GS. Glossary of chronobiology. Chronobiologia 1977; 4 (Suppl. 1), 189 pp.
20. Halberg F, Cornelissen G, Halberg E, Halberg I, Delmore P, Shinoda M, Bakken E. Chronobiology of human blood pressure. Medtronic Continuing Medical Education Seminars, 4th ed. Minneapolis: Medtronic Inc.; 1988. 242 pp.
21. Halberg F, Kenner T, Fiser B, editors. Proceedings, Symposium: The Importance of Chronobiology in Diagnosing and Therapy of Internal Diseases. Faculty of Medicine, Masaryk University, Brno, Czech Republic, January 10-13, 2002. Brno: Masaryk University, 2002. 206 pp.
22. Halberg F, Kenner T, Fiser B, Siegelova J, editors. Proceedings, Cardiovascular Coordination in Health and Blood Pressure Disorders. Brno, Czech Republic: Medical Faculty, Masaryk University; May 24, 1996. 65 pp.
23. Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006.
24. Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. 304 pp. http://web.fnusa.cz/files/kfdr2008 /sbornik_2008.pdf
25. Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Noninvasive Methods in Cardiology, Brno, Czech Republic, July 7-10, 2009. (Dedicated to the 90th Anniversary of Prof. Franz Halberg.) 402 pp. http://web.fnusa.cz/files/kfdr2009/sbornik_2009.pdf
26. Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium, Chronobiological Analysis in Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. 186 pp.
27. Halberg F, Reale L, Tarquini B. (eds.). Proc. 2nd Int. Conf. Medico-Social Aspects of Chronobiology, Florence, Oct. 2, 1984. Rome: Istituto Italiano di Medicina Sociale, 1986. 791 pp.
28. Halberg F, Scheving LE, Powell EW, Hayes DK, eds. Chronobiology, Proc. XIII Int. Conf. Int. Soc. Chronobiol., Pavia, Italy, September 4-7, 1977. Milan: Il Ponte; 1981. 394 pp.
29. Halberg F, Watanabe H. (eds.). Workshop on Computer Methods on Chronobiology and Chronomedicine. 20th Int. Cong. Neurovegetative Research, Tokyo, Sept. 10-14, 1990. Tokyo: Medical Review; 1992. 297 pp.
30. Hillman DC, Cornélissen G, Scarpelli PT, Otsuka K, Tamura K, Delmore P, Bakken E, Shinoda M, Halberg F, International Womb-to-Tomb Chronome Initiative Group. Chronome maps of blood pressure and heart rate. University of Minnesota/Medtronic Chronobiology Seminar Series, #2, December 1991, 3 pp. of text, 38 figures.
31. Koukkari WL, Sothern RB. Introducing Biological Rhythms: A primer on the temporal organization of life, with implications for health, society, reproduction and the natural environment. New York: Springer; 2006. 655 pp.
32. Otsuka K, Cornélissen G, Halberg F (eds). Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Science Publishing; 1993. 147 pp.
33. Prikryl P, Siegelova J, Cornélissen G, Dusek J, Dankova E, Fiser B, Vacha J, Ferrazzani S, Tocci A, Caruso A, Rao G, Fink H, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronotherapeutic pilot on 6 persons may guide tests on thousands: Toward a circadian optimization of prophylactic treatment with daily low-dose aspirin. University of Minnesota/Medtronic Chronobiology Seminar Series, #3, December 1991, 4 pp. text, 4 figures.
34. Refinetti R. Circadian Physiology. 2nd ed. Boca Raton, FL: CRC Press; 2006. 700 pp.
35. Reinberg A, Halberg F, editors. Chronopharmacology. Oxford/New York: Pergamon Press, 1979, 429 pp.
36. Reinberg A, Smolensky MH. Biological rhythms and medicine. Cellular, metabolic, physiopathologic, and pharmacologic aspects. New York: Springer; 1983. 305 pp.
37. Schaefer KE, editor. Man's Dependence on the Earthly Atmosphere. New York: Macmillan; 1962. 416 pp.
38. Scheving LE, Halberg F, editors. Chronobiology: Principles and Applications to Shifts in Schedules. Alphen aan den Rijn, Netherlands: Sijthoff & Noordhoff; 1980. 572 pp.
39. Scheving LE, Halberg F, Ehret CF, editors. Chronobiotechnology and Chronobiological Engineering. Dordrecht, The Netherlands: Martinus Nijhoff; 1987. 453 pp.
40. Scheving LE, Halberg F, Pauly JE, editors. Chronobiology, Proc. Int. Soc. for the Study of Biological Rhythms, Little Rock, Ark. Stuttgart: Georg Thieme Publishers/Tokyo: Igaku Shoin Ltd.; 1974. 784 pp.
41. Suda M, Hayaishi O, Nakagawa H, editors. Biological Rhythms and Their Central Mechanisms. Naito Foundation. Amsterdam: Elsevier North-Holland Biomedical Press; 1979. 453 pp.
42. Takahashi R, Halberg F, Walker C, editors. Toward Chronopharmacology, Proc. 8th IUPHAR Cong. and Sat. Symposia, Nagasaki, July 27-28, 1981. Oxford: Pergamon Press, 1982, 444 pp.
43. Touitou Y, Haus E, editors. Biological Rhythms in Clinical and Laboratory Medicine. Berlin: Springer-Verlag; 1992. 730 pp.
44. Valleron AJ, Macdonald PDM, eds. Biomathematics and Cell Kinetics. Amsterdam: Elsevier/North-Holland Biomedical Press; 1978. 431 pp.
45. Youan BC, ed. Chronopharmaceutics: Science and Technology for Biological Rhythm-Guided Therapy and Prevention of Diseases. Hoboken, NJ: Wiley; 2009.

GLOSSARY

(modified or amplified from Chronobiology glossary cf. Halberg F, Carandente F, Cornélissen G, Katinas GS. Glossary of chronobiology. Chronobiologia 1977; 4 [Suppl. 1], 189 pp) where more information (^∆) can be found.

Large ongoing international cooperative projects such as those revolving around chronobiologic self-help in health care often pose semantic problems that jeopardize the implementation of the work and lead to waste. This glossary should reduce, if not eliminate, semantic misunderstandings and thus contribute to the success of ongoing projects such as that on The BIOsphere and the COSmos, BIOCOS. Steps being implemented toward international cooperation require a selection of comparable if not unified reference standards. Only thus can the definition of certain rhythm (cycle) characteristics become meaningful. By the same token, there is the need for using comparable analytical procedures that are generally applicable to systematically collected and stored data on blood pressure, heart rate and on other time series. Broad international agreements can be reached toward the factual as well as semantic standardization of information capture, transfer, storage, analysis and updating from appropriate (data) bases: the characteristics of rhythms, estimated at different times and in different localities, will become amenable to a more facile and meaningful, direct comparison and integration. These are challenges and opportunities for the development of a serially updated individualized health form, card, booklet or equivalent, such as a cellphone, containing the information necessary for the precise early recognition of risk and thus for endeavors toward the prevention of diseases of individuals and (when data are pooled from many individuals) for learning about solar effects upon societal ills, for the development of countermeasures. In this glossary, the as yet uninitiated reader may also find a stimulus toward gaining an interest in the time dimension necessary to reach a more dynamic understanding of the entire field of biology and broader science as it relates, beyond personal health, to society's ills and to our environment, in the atmosphere of the sun as a whole in which we happen to live.

ACROPHASE θ, φ, Φ measure of timing; the lag from a defined timepoint (acrophase^∆ reference) of the crest time in the function ∆ appropriately approximating a rhythm^∆ ; the phase^∆ angle of the crest, in relation to the specified reference timepoint, of a single best fitting cosine (unless another approximating function is specified.)

Units: angular measures: degrees, radians; time units: seconds, minutes, hours, days, months, years, decades, centuries etc.; or physiological episodic units: number of heart beats, respirations etc. Angular measures are directly applicable to any cycle^∆ length and hence are proposed for general use because of greater familiarity; degrees (with 360 degrees equated to period of rhythm) are preferred over radians.

AMPLITUDE, A measure of one half the extent of rhythmic change in a cycle^∆ estimated by the sinusoidal (or other) function used to approximate the rhythm^∆, e.g., difference between maximum ∆ and MESOR ∆ of a best fitting cosine.

Units: original physiological units, e.g., number of heart beats, mmHg in blood pressure, etc.

ANGULAR FREQUENCY, ω special case of frequency^∆ of a periodic process expressed in degrees or radians per unit of time obtained by equating one cycle^∆ to 2π, e.g., ω in equation y(t) = M + A cos(ωt + φ) used to approximate a rhythm. Observe relation between angular frequency and frequency: ω = 2π/ τ = 2πf since frequency is the reciprocal of the period^∆: f = 1/ τ Note: equivalent to angular velocity, usually visualized on polar coordinates.

CHAT Circadian hyper-amplitude-tension or circadian overswing, with circadian double amplitude exceeding the upper limit(s) of reference value(s) derived from peers matched by gender and age.

CHRONODESM time-qualified reference interval, e.g., time-qualified prediction or tolerance interval.

CHRONOBIOLOGY Computer-aided study in the biosphere of time structures, chronomes consisting of cycles, trends (that can be parts of cycles longer than a time series) and deterministic (and other) chaos (that can generate cycles).

CHRONOMICS Computer-aided study of interacting time structures in the biosphere and in its environment.

CIRCADIAN Relating to biologic variations or rhythms^∆ with a frequency^∆ of 1 cycle^∆ in 24 ± 4 h; circa (about, approximately) and dies (day or 24 h).

CIRCASEMISEPTAN half-weekly variation. Circasemiseptans characterize widely differing phenomena, such as the behavior on different lighting regimens of an enucleated giant green alga, or an aspect of the biochemistry of (anucleate) platelets and even sudden human death. Thus, in the last few decades in Canada, most sudden human cardiac deaths peak on Mondays, with a second peak on Thursdays. A 3.5-day cosine curve fits such data better than a 7-day cosine curve.

CIRCASEPTAN about-weekly variation. Some human hormonal bioperiodicities, including rhythms, follow a roughly weekly pattern, such as those in circulating cortisol. Circaseptans are also found to characterize death from a mouse malaria or the rejection of allografts of heart, pancreas or kidney in untreated rats. Human kidney transplant rejection episodes are also more likely to occur around the 7th, 14th, 21st and 28th days after operation, or near other multiples of 7 post-operative days.

CIRCATRIGINTAN variation, such as the human menstrual cycle, that approximates a month in duration; such bioperiodicities, including rhythms, are also found before menarche and after menopause, and in men.

CONGRUENCE overlying or overlapping uncertainties (e.g., 95% confidence intervals) of 2 or more periods estimated in a time series

COSINOR statistical summary preferably with display of a biologic rhythm's amplitude^∆ and acrophase^∆ relations, on rectangular or polar coordinates; along the latter, by means of the length and the angle of a directed line, shown with a bivariate 95% or other statistical confidence^∆ region computed (at chosen trial period^∆) 1) to detect a rhythm^∆ (by a confidence^∆ region not overlapping zero, along rectangular coordinates, or the center of the plot, the pole, along polar coordinates) and 2) to estimate confidence^∆ intervals for the rhythm parameters.

Notes: among procedures for the analysis, mostly, of short time^∆ series, three kinds of cosinor have been designed in an integrated routine, each appropriate to a different situation: 1) Single cosinor, cosinor-S procedure applicable to a single biologic time series (from an individual or group); 2) Group mean-cosinor, cosinor-G: a cosinor procedure applicable to data from 2 or more individuals for characterizing a rhythm in that particular group only; 3) Population mean-cosinor, cosinor-P: the original cosinor procedure applicable to parameter ∆ estimates from 3 or more biologic series for assessing the rhythm characteristics of a population. All three cosinors use a cosine function: g(t) = M + A cos(ωt + Φ)

DEFICIENT HEART RATE VARIABILITY (DRV) a standard deviation of heart rate (determined around the clock for 7-days at 1-hour or shorter intervals) below the threshold of 7 beats/minute, a criterion to be further qualified for gender and age.

DESYNCHRONIZATION state of two or more previously synchronized rhythmic variables that have ceased to exhibit the same frequency^∆ and/ or the same acrophase^∆ relationships and show changing time relations.

ECPHASIA odd acrophase outside reference values of gender and age- matched peers

ECFREQUENTIA odd frequency outside reference values of gender and age- matched peers

ENTRAINMENT interaction between two or more organismic rhythms^∆ or the effect upon rhythm(s) of an (external) synchronizer^∆ resulting in identical frequencies among interactions or in frequencies constituting integral multiples of one another (frequency^∆ -- multiplication or demultiplication).

EXCESSIVE PULSE PRESSURE above the threshold of 60 mmHg (determined in a record of 7 days at 1-hour or shorter intervals), a criterion to be further qualified for gender and age.

FREE-RUNNING pertaining to continuance of bioperiodicity with a natural frequency^∆ usually at least slightly different from any known environmental schedule.

FREQUENCY, f the number of occurrences of a given type of event or the number of members in a population falling into a specified class.

Note: in the study of periodicity it is the number of cycles occurring per time unit, i.e., f is the reciprocal of the period (τ) f = 1/τ

GLOCAL and GLOCALITY adjective and noun, respectively, beginning with the first syllable of GLObal and ending with the last syllable of loCAL, as "smog" is formed from SMoke and fOG. "Glocal" is proposed to designate, in principle and as method, an approach that is global and local both in time and in space. This is 1) global, both a) in time, insofar as it relates to the structure (or chronome) of a time series as a whole (in the longest available data series) and b) in space, insofar as it wishes to do so from the earth and other locations, such as the solar system, as a whole, as possible and reasonable and 2) local, again a) in time, insofar as it wishes to examine separately a set of intervals of different lengths and b) in space, namely separately from each of several terrestrial and other locations. As an example the incidence pattern of natality, morbidity or mortality can be studied in global and local statistics by spectra of entire time series and in intervals of each of the series of different length. In combination with spectral windows of an entire series, aligned gliding spectral windows, focusing on a given frequency region, and chronobiologic serial sections, focusing upon a single or few frequencies and their time course, are glocal procedures. The slogan "think globally, act locally" can thus be extended spatiotemporally.

INFRADIAN relating to certain biologic variations or rhythms ∆ with a frequency ∆ lower-than-circadian^∆

LEAST-SQUARES METHOD estimation technique for determining quantities by minimizing the error (or residual) sum of squares. In a linear model, this method produces the best linear unbiased estimate (b.l.u.e.) in terms of variance. Note: two types of least-squares methods are considered: linear or nonlinear.

MARKER RHYTHM rhythm^∆ of use in practical monitoring and, where appropriate, decision-making -- in applied or basic physiologic or pharmacologic work, in preventive health maintenance (prophylactic marker rhythm), risk monitoring (risk marker rhythm), for diagnostic purposes (diagnostic or screening marker rhythm), for timing therapy (chronotherapeutic marker rhythm) or for assessing therapeutic response (response marker rhythm) without any implication of necessarily causal relations between the process and its rhythmic marker.

MESOR, M rhythm-determined average of Midline Estimating Statistic of Rhythm, e.g., in the case of a single cosine approximation, the value midway between the highest and lowest values of function ∆ used to represent a rhythm^∆

MESOR-HYPERTENSION, MH for systolic and/or diastolic blood pressure, a transient^∆ or lasting elevation of the circadian^∆ (about-24-h) rhythm-adjusted mean (MESOR, M^∆) as validated statistically against the person's (patient's) own MESOR at another time and/or against a peer reference standard.

PERIOD (Greek τ) duration of one complete cycle^∆ in a rhythmic variation.

Note: biologic rhythms can be analyzed in terms of a spectrum^∆ with statistically significant components in several spectral^∆ domains. Period notation is customary within a given region or (e.g., circadian^∆) domain of the spectrum. Frequency^∆ (defined as the inverse of the period f= 1/τ) notation facilitates discussions of phenomena involving several broad spectral domains.

PREDICTION INTERVAL a range of values expected to contain, on the average, a specified proportion of a population or of a distribution (of values) from an individual.

RESONANCE property of a system oscillating (or capable of oscillating) with some natural frequency^∆ (or rhythm^∆) to exhibit an increased amplitude (or to begin oscillating) when subjected to an external periodic influence or force with a frequency similar to that of the system, the amplitude of the resonant frequency increasing as the outside periodic influence approaches the natural frequency of the system.

RHYTHM a periodic component of (biologic) time^∆ series, demonstrated by inferential statistical means, preferably with objectively quantified characteristics (i.e., frequency^∆ f, acrophase^∆ [phi], amplitude^∆ A, MESOR^∆ M, and/ or waveform^∆ W).

SYNCHRONIZER, Sy environmental periodicity determining the temporal placement of a given biologic rhythm^∆ along an appropriate time scale, by impelling the rhythm to assume synchronization, i.e., its frequency^∆ or an integer multiple or submultiple of its frequency and a specifiable acrophase^∆ Note: also called zeitgeber, a time-giver, entraining agent (ever though the environmental cycle does not give time), clue or cue. Adjectives primary, dominant and secondary describe relative roles played by different environmental synchronizers. In several strains of inbred mice fed ad libitum, the lighting regimen is the primary synchronizer of the blood eosinophil rhythm. Adjectives dominant and modifying also can be used to describe the effect of a given environmental factor in relation to a given rhythm. Under unusual circumstances a secondary synchronizer may become dominant. Thus in C3H (Minnesota) mice subjected to a 50 percent restriction in dietary calories, the feeding time (of a diet restricted in calories) may be dominant over the lighting regimen. Moreover, under conditions of time-restricted access to food, synchronization by the lighting regiment may be largely though not fully overridden by meal timing. Thus, limited access time to food can be largely but not entirely dominant over lighting regimen with respect to the synchronization of the rhythm in telemetered intraperitoneal temperature. A secondary effect of the lighting regimen remains apparent as the result of interference between synchronizers. Finally, a rhythm can be influenced by secondary synchronizers and modifying factors, modulators, or, more generally, influencers.

ULTRADIAN a variation with a frequency higher than 1 cycle in 20 hours, i.e., with a period of less than 20 hours. An example of an ultradian is the sleep-wake cycle of patients with narcolepsy, a sleep disorder in which patients fall asleep several times daily, e.g., with average periods of 1.7 hours.

VASCULAR VARIABILITY ANOMALY (VVA): an alteration of variability as compared to that of healthy peers, found in a 7-day record of hourly or denser measurements analyzed as a whole, of blood pressure or heart rate. Examples are MESOR-hypertension; CHAT (circadian hyper-amplitude-tension); odd timing, or ecphasia; odd frequency, or ecfrequentia; excessive pulse pressure and deficient heart rate variability.

VASCULAR VARIABILITY DISORDER (VVD) a VVA replicated in at least three 7-day profiles at hourly or shorter intervals, each analyzed as a whole.

VASCULAR VARIABILITY SYNDROME (VVS) two or more VVDs present simultaneously in the same patients replicated in three 7-day/24-hour records.

External links

• Dr. Halberg's home page

See also

Circadian, Diurnal, Chronomics

Sponsored by: Eugene M. Izhikevich, Editor-in-Chief of Scholarpedia, the peer-reviewed open-access encyclopedia

Reviewed by: Anonymous

Accepted on: 2011-03-17 20:46:12 GMT