User:Eugene M. Izhikevich/Proposed/Circadian rhythms

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(adj. and noun, from Latin circa, about, approximately, and Latin dies, day, or rather, in current usage, roughly 24 hours) relating to biological and other variations or rhythms with a frequency of 1 cycle in 24 ± about (~) 4 hours. See also chronobiology, chronomics, diurnal.


To standardize the terminology used when discussing rhythms with periods close to 24 h, Franz Halberg (b. 1919) introduced the term circadian in 1959. His original definition follows:

"The term circadian was derived from circa (about) and dies (day); it may serve to imply that certain physiologic periods are close to 24 hours, if not of exactly that length. Herein, circadian might be applied to all 24-hour rhythms, whether or not their periods, individually or on the average, are longer or shorter, by a few minutes or hours. Circadian thus would apply to the period of rhythms under several conditions. It would describe: 1. rhythms that are frequency synchronized with 'acceptable' environmental schedules (24-hour periodic or other) as well as 2. rhythms that are 'free-running' from the local time scale, with periods slightly yet consistently different from 24 hours (e.g., in relatively constant environments). (Halberg, 1959, p. 235) (42)

"The following definition of 'circadian' was adopted in 1977 by the International Committee on Nomenclature of the International Society for Chronobiology:

"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). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods slightly yet consistently different from 24 h … (Halberg et al., 1977)." (18)

Approximate limits

As in physics, nomenclature is based on frequency, f (or angular frequency ω=2πf) not on its reciprocal, the period, τ, so that an f higher than 1 cycle in 20 hours is called ultradian (and is a τ shorter than 20 hours) and an f lower than 1 cycle in 28 hours (τ longer than 28 h) is infradian, Figures 1-3. The period is best estimated by the extended cosinor, relying on linear-nonlinear least squares applicable to non-equidistant data, for the derivation also of confidence intervals for each parameter: the MESOR or rhythm-adjusted average; the double amplitude, or predicted extent of change, and the acrophase, a measure of predictable timing of change within a cycle.

Figure 1: Terminology follows usage in physics. The broader division of biosphere spectra into 3 domains uses the circadian range of 1 cycle in 20–28 hours as a reference for frequencies (not periods!) higher (ultra) or lower (infra) than circadian, in keeping with precedents of nomenclature in physics. © Halberg.
Figure 2: First, different frequencies were obvious for different variables, as drastically different as pulse and menstruation (top). Next, different "frequency regions" of different physiological systems were recognized (second row). Thereafter, several time-microscopically quantified rhythms were found in a single (the nervous) system (third row) or even in a single variable, the excretion of breakdown products of steroidal hormones, the 17-ketosteroids (17-KS) (bottom row). © Halberg.

As new heliogeophysical cycles were discovered, it seemed logical to look for counterparts and vice versa; thus, congruent periods with overlapping CIs (95% confidence intervals) were found, among others, in 17-KS excretion, Figure 3.

Figure 3: There are spectra in us (Halberg et al., Acta endocrinol [Kbh] 1965; 50 [Suppl 103]: 5-54), in a 15-year series of the daily excretion of urinary breakdown products of steroidal hormones, including, i.a., components of ~7, ~17-21, ~30 and ~154 (Halberg et al., in Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 16-25. days and of about ~9 years (Halberg et al., J Gerontol A Biol Sci Med Sci 2001; 56: M304-M324). Far- and near-transyears and quinmensals were added thereafter (Halberg et al., J Applied Biomedicine 2006; 4: 1-38. © Halberg.

Illustrative importance

a. Immediately applicable circadian marker rhythmometry for vascular disease prevention (based on automatically monitored blood pressure and heart rate, preferably for at least 7 consecutive days at 0.5 to 1.0-hour intervals, reveals risks of severe disease greater than hypertension and can be implemented with instrumentation obtained via BIOCOS ( with cost reduction and analyses, also of data collected systematically with conventional sphygmomanometry.

A set of vascular variability anomalies, VVAs, is depicted in Figure 4. A chronobiologically detectable circadian overswing of blood pressure, exceeding limits set by reference values of clinically healthy gender- and age-matched peers, constituting a risk of severe disease, such as ischemic stroke, Figure 5, or nephropathy, Figure 6, greater than that associated with hypertension (2), can be treated and often eliminated. This approach reduces the number of false positive and false negative diagnoses of high blood pressure: those not in need of treatment (false positive diagnoses, often mislabeled "white-coat effect") are spared the cost, stigma and any side effects and those who need treatment (false negative diagnoses, labeled masked hypertension) are spared target organ damage and subsequent adverse cardiovascular events. Other risks of alterations of circadian endpoints are also detected. If and only if their presence is confirmed in several 7/24 records, they become vascular variability disorders, Figure 7, and some are treatable, Figure 8 (18, 49).

Figure 4: An elevated blood pressure (MESOR-hypertension) and other vascular variability disorders, VVDs, are diagnosed either by cosinor with curve-fitting using least squares, as modeled abstractly in (a) to (c) or by thresholds (d) and (e): (a) MESOR-hypertension (MH), can be systolic (S-MH), diastolic (D-MH), or mean arterial (MA-MH), or any combination of the foregoing, incomplete when demonstrated only parametrically or only non-parametrically, the latter by an extent of excess during 24 h > 50 mmHg x h, complete when both approaches yield abnormal results. (b) Circadian Hyper-Amplitude-Tension (CHAT), which can be systolic (S-CHAT), diastolic (D-CHAT), or mean arterial (MA-CHAT), or a combination of the foregoing. (c) SBP-, DBP- or MAP-ecphasia without HR-ecphasia (odd timing of the circadian rhythm of BP but not of that in HR). (d) Excessive pulse pressure (EPP), when the difference in the MESORs of SBP and DBP for adults exceeds 60 mmHg. (e) A deficient HR variability (DHRV), defined as a standard deviation of HR less than 7.5 beats/minute. Thresholds remain to be replaced by reference values from clinically healthy peers (eventually with disease-free long-life outcomes specified further by gender, age, ethnicity and geography) (30). © Halberg.
Figure 5: 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 a circadian overswing, dubbed circadian hyper-amplitude-tension, abbreviated CHAT (last two columns on the right), 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 BP). As compared to patients with an acceptable circadian BP 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 6: CHAT (circadian hyper-amplitude-tension) is also associated with a large increase in the risk of nephropathy (see legend to Fig. 4). © Halberg.
Figure 7: Decreased heart rate variability (DHRV), circadian hyper-amplitude-tension (CHAT) and elevated pulse pressure (EPP) are separate cardiovascular disease risks. CHAT is one of several conditions related to the variability in blood pressure (BP) and/or heart rate (HR) that is associated with an increase in vascular disease risk. The circadian (or, actually, circaseptan) profile, with too large a pulse pressure (the difference between systolic [S] BP and diastolic [D] BP, i.e., between the heart's contraction or relaxation, or the extent of change in pressure during a cardiac cycle) and a decreased HR variability (gauged by the standard deviation of HR) in relation to a threshold, preferably eventually all in gender- and age-matched peers are two other risk conditions (as is an abnormal circadian timing of BP but not of HR, not shown). Vascular disease risk is elevated in the presence of any one of these risk factors, and is elevated further when more than a single risk factor is present, suggesting that these abnormalities in variability of BP and HR are mostly independent and additive. Abnormalities in the variability of blood pressure and heart rate, impossible to find in a conventional office visit (the latter aiming at the fiction of a "true" blood pressure), can raise cardiovascular disease risk (gauged by the occurrence of a morbid event like a stroke in the next six years) from 4% to 100%. By comparison to subjects with acceptable blood pressure and heart rate variability, the relative cardiovascular disease risk associated with a decreased heart rate variability (DHRV), an elevated pulse pressure (EPP) and/or circadian hyper-amplitude-tension (CHAT) is greatly and statistically significantly increased. These risks, silent to the person involved and to the care provider, notably the risk of CHAT, can usually be reversed by chronobiologic self-help, also with a non-pharmacologic approach in the absence of MESORhypertension. © Halberg.

Figure 8: Benidipine (taken once a day upon awakening, Rx2) was found in large Asian clinical trials to be associated with better outcomes than nifedipine (taken twice a day, in the morning and in the evening, Rxl). Reducing the incidence of CHAT may be the reason accounting for the difference (almost by a factor 2) in outcomes, whether strokes or all cardiovascular events are considered. © Halberg.

b. Marker rhythmometry for cancer using timing by circadian and about 7-day (circaseptan) rhythms in cancer markers such as CA130 or CA125 for patients with ovarian cancer as yet is expensive, but documented as useful (50, 51). Chronochemotherapy with unspecific marker rhythmometry (52) also seems preferable to timing by clock-hour which can fail (53), unless a rigorously validated standardized routine is ascertained. Using tumor temperature as a marker rhythm for chronoradiotherapy, 2-year disease-free survival was doubled for patients with cancers in the mouth, Figure 9 (1).

Figure 9: 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.

c. Susceptibility resistance cycles. In the laboratory, circadian rhythms in susceptibility make the difference between life and death, whether a stimulus was applied for seconds (like exposure to noise) or months (like implantation of a carcinogen), its effects can depend to an extremely high degree on statistically predictable circadian stages that account, among others, for the differences between high and low chances of developing a malignant tumor or of convulsions or survival from a bacterial toxin or a high dose of ethanol or of another drug, Table 1 and Figures 10-12 (47).

Figure 10: The history of susceptibility rhythms as extreme phase responses concerning rhythms in the response of the central nervous system. By 1955, the response to noise (>104 decibels [dB] >0.0002 dynes/sq cm rms pressure) was shown to be circadian stage-dependent in mice of the susceptible I strain, so that the convulsive risk by day was 11% and by night 65% in one group of young mice and 0% by day and 85% by night in another group (Proc Soc exp Biol [NY] 1955; 88: 169-173). There were more convulsions and more deaths from exposure to bells in a tub at the beginning of the daily dark span as compared to exposure of animals of the same inbred strain, gender and age, the other at the start of the daily light span in mice kept in light from 06:00 to 18:00, alternating with darkness. This was confirmed in a follow-up study, section A (Science 1958; 128: 657-658). Again, convulsions and death occurred in a stimulator with exposure to ~117 dB >0.0002 dynes/sq cm rms pressure at 21:00, but no deaths and fewer convulsions with exposure at 08:00, as seen in the left half of section A. The right side of section A shows not only that the timing of this susceptibility rhythm (on the fourth day after reversal of the lighting regimen) can be shifted along the 24-hour scale (can apparently be reversed), but also that, at the time investigated (perhaps as a transient), there is an overall increase in susceptibility. Section B, a 6-timepoint phase response curve in continuous darkness, shows the persistence of a response rhythm in DD, gauged by the survival time of mice after injection of a fixed dose of ethanol. Sections C and D show further phase response curves, i.e., drug-related results under conditions of a 12-hourly alternation of light and darkness. Time-macroscopic (E, left and middle) and time-microscopic (E, right) assessment of parameters of a rhythm in susceptibility to halothane given as an amplitude by the length of a vector and as the vector's direction, the acrophase, with their elliptical 95% confidence regions as measures of their uncertainties. For the acrophase, its 95% confidence limits (CL) are obtained by tangents to the error ellipse. Section F shows pentobarbital concentration in brain and serum of mice as a function of time after injection at circadian phases of short sleep duration (φ1) and long sleep duration (φ2). Section G shows, with their uncertainties, differences in the timing of phase responses to different agents affecting the mammalian central nervous system (Halberg F, Cornélissen G, Schwartzkopff O. Chapter 10: Implications and applications of circadian susceptibility rhythms: chronomics and anesthesia. In: Youan BC, ed. Chronopharmaceutics: Science and Technology for Biological Rhythm-Guided Therapy and Prevention of Diseases. Hoboken, NJ: Wiley; 2009. p. 217-255). © Halberg.
Figure 11: Phase-response summary of 24-hour synchronized susceptibility rhythm to ouabain displayed by original data as dots for the D8 mice and as triangles for the C mice. 75% of the D8 mice survive at one time the same dose of the drug that, at another predictable time (see similar time courses), kills 74% of comparable animals (Halberg F, Stephens AN. Susceptibility to ouabain and physiologic circadian periodicity. Proc Minn Acad Sci 1959; 27, 139-143). © Halberg.

Figure 12: It seems desirable for a phase response to a drug to be tested in different doses. Thus, best and worst times may be found, notably in chronotoxicity with doses of SU-4885, which kills most of the mice at one time and nearly 30% at another time. Mortality overall in all studies of SU-4885 chronotoxicity ranged from nearly -80% of the mean to over +80%. © Halberg.

d. Nutrition. Relative body weight loss from a fixed or ad libitum number of dietary calories differs markedly as a function of whether all of the calories were consumed as breakfast or as dinner, Figures 13-15 (63).

Figure 13: 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. /0309053412/html/361.html#pagetop (can be read free of charge at website; *.pdf of book can be purchased for $34.50). 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 14: Meal timing and body weight. In two separate studies on the effect of meal timing on body weight, a total of nine men and nine women consumed, some a fixed 2,000 kcal meal for 1 week, others a single free-choice meal for 3 weeks as breakfast-only (B) or as dinner-only (D). Body weight remained more or less unchanged on dinner only; a decrease of about 1 kg/wk was noted on breakfast only. When eating just a single meal within one hour of awakening (breakfast-only, gray bars) or not before 12 hours after awakening (dinner-only, black bars), with only one exception (subject 39), there is a relative body weight loss on breakfast-only as compared to dinner-only. © Halberg.
Figure 15: The rate of body weight change, i.e., the extent of overall relative body weight loss on breakfast-only vs. dinner-only, differs significantly (P<0.01) between the two schedules. © Halberg.

Degree of generality

Because of a high degree of generality on earth (43) and in extraterrestrial space (54), circadian rhythms constitute indispensable control information. By assessing the outcome of a procedure in different circadian stages, we may find the difference between a desired and an undesired effect of any stimulus, physical, chemical, biological or other. Their neglect can be associated with blunders in experimental results that lead to false conclusions and to years or decades of wasted research. Just as light-microscopy and now molecular biology have complemented the naked eye, and just as histopathology now routinely replaces the naked eye in examining a tumor, so a circadian (and broader chronobiologic) "microscopy in time" complements today's routine experimental and clinical procedures. Circadians have served to open the "normal range" of everyday physiology. Information on their alteration is critical to disease prevention. Likewise, in much of what we measure there is a built-in circadian time structure that underlies any biological function. It represents in the background, as in the foregoing, a vast complementary system critical to whatever one singles out in medical or biological practices. In each case, a mapping of circadian characteristics in inferential statistical terms seems useful and essential to those who carry out scientific endeavors (42-47).


Like nature, notably the weather and the broader climate, on earth and in space, with which it is intimately interwoven, life involves the recurrence of many cycles with vastly differing period, phase, amplitude and MESOR in about (the first circa) the same sequences of about (the second circa) the same phenomena with about (the third circa) the same extent, timing and kind of change at intervals that are about (the fourth circa), but extremely rarely all exactly the same (47). Variability during asynchronization is greater while circa-periodicities persist when organisms 1. are kept under ordinary conditions but deprived by surgery or genetics of the major transducer of the dominant synchronizing environmental cycle, such as the eyes, mediating the effect of a lighting regimen, or 2. are isolated under conditions rendered as constant as possible on earth, at least with respect to environmental light, temperature and societal interactions, e.g., living for months in a cave, and/or 3. are able to self-select the given regimen, e.g., of lighting and/or eating, or 4. are constrained to periodic regimens exceeding the range of synchronizability, whether these are, e.g., shorter than about-20-hour or longer than about-28-hour "days", implemented by the lighting regimen in the laboratory for certain rodents, e.g., light (L)/dark (D) 10:10 or LD14:14, or whether one administers regressive electric shocks at 12-hour intervals until the subject is disoriented in space and time. Under all these conditions, organisms show periods described as desynchronized, if not free-running from conditions with which they are shown to have been synchronized earlier, are resynchronized subsequently or can be compared with concomitant synchronized controls; rhythms are asynchronized if they differ with statistical significance from those found under synchronization with their environmental near (circa) match, such as a day.


Circadian includes rhythms with periods near 24 hours, whether or not they are frequency-synchronized with other cycles like society's 24-hour schedule or whether they are desynchronized if not free-running. While the primary synchronizer in the experimental laboratory is the lighting regimen for ad libitum-fed animals in the absence of a magnetic storm, there are secondary synchronizers. The timing of a diet offered with a restricted amount of calories can override the lighting regimen, and magnetic storms can influence rhythm characteristics (56) including phase (57). An abrupt shift of the primary synchronizer is followed by a gradual adjustment of circadian rhythms, that differs for various variables, is faster in the blood pressure and slower in peripheral tissue mitoses of mammals, faster with delays than with advances in schedule, and thus shorter after flights from east to west than after those from west to east, accounting for jet lags of different duration after flights in opposite directions. Adjustment can also involve polarity insofar as, in response to the same shift in routine, as after an intercontinental transmeridian flight some variables delay whereas others in the same organism advance.


Any endeavor in experimental or clinical biomedicine and beyond in transdisciplinary science benefits from the inferential statistical "isolation" of circadian and other rhythms by desirable hypothesis testing and the rejection of the zero-amplitude (no cycle) assumption and the usually indispensable estimation of characteristics of rhythms with their uncertainties, such as the period, and for each period, of measures of the extent and timing of change, the amplitude, A, and acrophase, φ, respectively, and waveform, the (A,φ) pairs of harmonics. Longer periods can also modulate circadians. These characteristics are best estimated by the extended cosinor method, Figures 16-19. As a dividend, the MESOR, a midline-estimating statistic of rhythm, the M, is obtained. As compared to an arithmetic mean, the M is usually more accurate in the case of unequidistant data, and more precise in the case of equally spaced data, Figure 16.

Figure 16: The MESOR usually provides a more accurate estimate of location than the arithmetic mean (A). When sampling is denser near the maximum (or minimum) of a periodic function than at other times, the arithmetic mean is biased toward that extremum, whereas the MESOR tends to be closer to the true average value of the given function (obtained when sampling is equidistant over an integer number of cycles). The MESOR usually also provides a more precise estimate of location than the arithmetic mean, notably when the data are characterized by a large-amplitude rhythm (B). This stems from the fact that the area around the MESOR is estimated after the variability accounted for by the rhythmic behavior of the data has been portioned out. © Halberg.
Figure 17: Illustration of the single-cosinor method. One or several cosine curves with known (or approximately known) periods are fitted by least squares to the data, yielding estimates for the following parameters: the MESOR, a rhythm-adjusted (or rather chronome-adjusted) mean value; the amplitude, a measure of half the extent of predictable change within a cycle; and the acrophase, a measure of the timing of overall high values recurring in each cycle. When a multiple-component model is fitted, estimates of the amplitude and acrophase are obtained for each component. When the different components are harmonically related, the amplitudes and acrophases of the harmonic terms qualify the waveform of the fundamental component, which can in turn be characterized by a magnitude (rather than amplitude) and orthophase (rather than acrophase), measures of the predictable extent and timing of change of the complex waveform. If the period is not known a priori, nonlinear least squares are needed to estimate M and (A,φ) of each component together with its respective period, the period being defined as the duration of one cycle. The acrophase is usually expressed in (negative) degrees, with 360˚ equated to the period length and 0˚ being set to the reference time (such as midnight preceding the start of data collection or the time of light onset in the case of circadian rhythms assessed in laboratory experiments, notably when staggered lighting regimens are used to facilitate the work during office hours without the need for around-the-clock sampling). © Halberg.
Figure 18: The advantages of rhythmometry are: 1. a more accurate and more precise estimate of the overall mean value provided by the MESOR. When data are non-equidistant, the estimate of the arithmetic mean but not of the MESOR may be biased, for instance when most of the data are collected near the acrophase of a rhythm and few data are collected near its bathyphase; when data are equidistant, the estimate of the MESOR usually has a smaller standard error (not shown); 2. the double amplitude represents the extent of predictable change within a cycle whereas the range may include outlying values that may but need not be biologically meaningful (in the case of technical blunders); 3. the acrophase represents a more robust measure of timing of overall high values than the time of a single value-based maximum. See also Figure 18. © Halberg.
Figure 19: See legend to Figure 18. © Halberg.


Some circadians are pertinent to integrative and/or molecular studies in any one of the sciences on the rim of Figure 19, including focus on mechanisms of circadian timekeeping under standardized, if not constant laboratory conditions. In each case, a mapping of circadian characteristics in inferential statistical terms seems desirable if not essential to aims such as those noted above under "Importance". Figures 21-23 are illustrative phase maps.

Figure 20: The senior author's endeavors that led him to chronobiology are described by invitation elsewhere and are available on the Internet (Halberg et al. 2003a); they constitute a figurative microscopy in time started with counts of circulating blood eosinophil cells (Halberg and Visscher 1950) under a real microscope, initiated in 1948, in developing a bioassay for corticosteroids at Harvard University (Halberg 1952); by 1950 in Minnesota, genetic differences in the extent of within-day changes in count and the rhythm in abnormal discharges detected by electroencephalography in patients with convulsive disorders, with Rudolf Engel (Halberg et al. 1952), led eventually to maps of cycles in the metabolism of the cell, the adrenal-hypothalamic-pituitary-pineal network, and to organismic cycles, including the hours of changing resistance (Halberg et al. 1955a) and from there to a chrono-physiology, pathology, pharmacology and toxicology (Halberg 1969). These studies were all carried out in an environment rendered as standardized as possible, yet originally only with respect to the availability of food, lighting and routines in the proximal habitat niche (Cornélissen and Halberg 1994, cf. Luce 1970, Reinberg and Smolensky 1983, Pauly and Scheving 1987, Touitou and Haus 1992, Chibisov 2005, Halberg et al. 2005b, Refinetti 2006). In this international center, it is also mandatory to record calendar date and geographic latitude and longitude, to check on as-yet uncontrolled but pertinent environmental conditions such as magnetic storms (Halberg et al. 2006; Jozsa et al. 2005). © Halberg.
Figure 21: Partial acrophase chart of the circadian system in the mouse illustrates a sequence of physiological tasks among more than 50 variables mapped herein.© Halberg.
Figure 22: Relative frequency synchronization with differences in timing (phase) and extent of change (amplitude) (the latter not shown) among several aspects of human physiological and psychological performance. Summary of authors' and others' published data. For method, see Chronobiology. © Halberg.
Figure 23: Circadian acrophase chart of urinary constituents of an unusually well-studied, clinically healthy man (Sothern et al., 1974). Note differences in circadian acrophases. © Halberg.


The partly genetic nature of circadian oscillations, apparent by 1950 from differences among inbred strains of mice, not only at a fixed circadian time, Figure 24, but also in extent of within-day differences, Figures 25 and 26 (Halberg & Visscher 1950) (67), was noted indirectly by free-running after blinding, seen time-macroscopically in Figure 27 and quantified time-microscopically in Figure 28. For human heart rate, heritability was recognized as emergenic, based on studies on twins reared apart, Figure 29 (58; cf. 59-62). For partly mapped average timing (phases) in circadian systems of populations, remove-and-replace approaches in humans and rodents lead to adrenocortical, Figure 30, and broader neuroendocrine, metabolic and other cellular mechanisms, Figure 31, that in turn led to molecular maps, Figure 32, a field in its own right.

Figure 24: Genetic diversity in averages requiring complementary examination of further genetic diversity in variability as such and of diversities in time. Data on eosinophil counts (Eos) in five stocks of mice (from Halberg et al. J Hematology 6: 832–837, 1951; cf. Proc Soc Exp Biol & Med 75: 844–847, 1950). Mice kept in L6-18D18-6. Sampling during fixed clock hours: 06:00 – 10:00. Concurrent study of additional stocks at the same fixed time of day reveals differences in mean value. © Halberg.
Figure 25: Circadian physiological variation in murine eosinophil counts (Eos). In four inbred strains and a hybrid (F1) stock (F Halberg and M Visscher. Proc Soc Exp Biol & med 75: 844–847, 1950). Note 1. Large genetic differences, gauged by one-way ANOVA across stocks at 08:00 (F=43.1; P < 0.001) and 00:00 (F=21.3; P < 0.001) representing differences in genome, and 2. Equally impressive diversity in time, in each stock, gauged by 08:00 vs. 00:00 difference, approximating, by only two timepoints, circadian component of chronome (t=11.3; P < 0.001 from paired t-test of relative 08:00 vs. 00:00 differences, expressed as percent of mean). The everpresent within-day difference can differ among stocks of mice. © Halberg.
Figure 26: Genetic diversity in variability as such, gauged by coefficient of variation (CV). Beyond genetic diversity in averages of eosinophil counts in five stocks of mice (from Halberg et al. J Hematology 6: 832–837, 1951; cf. Proc Soc Exp Biol & med 75: 844–847, 1950). Mice kept in L6-18D18-6. Sampling during fixed clock hours: 06:00 – 10:00. Prediction limits, derived from first 5 stocks of mice, are exceeded when 5 additional stocks are examined (hatched). Of interest with the genetic diversity in space among different stocks of mice is a genetic diversity in time gauged by coefficient of variation. © Halberg.
Figure 27: Macroscopic circadian desynchronization in mice after bilateral optic enucleation (dashed line connecting dots) visualizing the need for objective inferential statistical time-microscopic analyses. While sham-operated controls (solid line connecting open circles) show a daily peak at or close to the vertical 20:30 lines, peak temperatures of blind animals already on day 6 seem to diverge, rising while those of the other group are falling. A graph of the original finding of this separation of the two groups and the decision based thereon to continue measurement every 4 hours around the clock was interpreted as "paranoia". (At the time, in the pre-computer era, the provision of a periodogram on desk calculators took a week, and its checking another week. Today the approach with a moving fit of a 24-h cosine curve is preferred.) On the average, on top, peaks in temperature of the blinded group occur earlier and earlier, but there are uncertainties in such eyeballing. A transient antiphase at 22 to 23 days after blinding is readily seen. If, around that stage after blinding, 2-timepoint checks are carried out on the 2 groups, opposite results can be obtained on mice with and without eyes and later when they are again in phase, 2-timepoint checks show no difference, a puzzle readily resolved by an objective quantification of the rhythm characteristics. The need for this microscopy in time becomes obvious, notably if an inference is desired as soon as possible with an estimate of uncertainty. (Circadian desynchronization also characterizes congenitally blind ZRD mice.) © Halberg.
Figure 28: Top, section I: Desynchronization of circadian rhythm in core temperature of mice after blinding, seen time-macroscopically in IA, here leads, in IB, to time-microscopy with a chronobiologic serial section showing a different time course of the core temperature acrophases, φ, with early separation of the two groups by non-overlapping 95% confidence intervals of &phi. IC is a summary of individual periodograms that form two separate distributions; ID shows time relations among three variables in a 24-hour synchronized (top) or free-running (bottom) system (of mice, left, and of a human, right). Section II shows a spontaneous (α) rhythm in circulating corticosterone of mice in antiphase with the slope of an in vitro response rhythm to ACTH, a reactive (β) rhythm. The components of the chronome (time structure) are internally coordinated through feedsidewards in a network of rhythms that are more or less spontaneous (α), others primarily reactive (β) or modulatory at a single mapped frequency, such as a circadian (γ), IIC and IID, or at multiply mapped (δ) frequencies, IIE. The effect of one entity (the actor) upon a second (the reactor), such as the pituitary acting upon the adrenal cortical corticosterone production may be influenced, predictably insofar as rhythmically, by a third entity such as melatonin (the modulator) at the level of the pituitary and the same melatonin may act directly upon the adrenal. Reproducible sequences of attenuation, no-effect, and amplification, the time-qualified feedsidewards, replace time-unqualified feedbacks and feedforwards (IIC to E). In sections II and III, feedsidewards include the interaction of a modulator (such as ACTH) upon an actor (such as adrenocortical corticosterone production) acting upon DNA labeling in bone (the reactor). The roles played by endocrines can and do change in various feedsidewards that replace time-unqualified feedbacks and feedforwards. Chronomolecular mapping of circadian acrophases has also begun. © Halberg.
Figure 29: Around-the-clock ECG records from groups of monozygotic and dizygotic twin pairs reared apart document the heritability of the circadian amplitude of human heart rate. The intra-class correlation coefficient is statistically significant for the 70 monozygotic twins, but not for the 44 dizygotic twins. © Halberg.
Figure 30: Chronobiologic self-experimentation extended to groups of medical students and staff served to show that the adrenal glands are an important source of circadian rhythmicity. For instance, a circadian component of variation in the circulating eosinophil count could not be demonstrated for patients with adrenocortical insufficiency (bottom), whereas in healthy people with either restricted or unrestricted activity, this rhythmicity was not only demonstrable, but also amplified by enhanced motor activity. Whereas for patients with Addison’s disease a circadian rhythm in eosinophil counts could not be statistically validated, circadians persisted, however, for serum iron (P < 0.001) (top). Self-experimentation then leads to studies in the laboratory. © Halberg.
Figure 31: Polar cosinor displays also quantify a phase advance of rhythms after histologically validated bilateral SCN ablation in several tissues, with the exception of the stomach, which may respond to food directly rather than via the SCN. © Halberg.
Figure 32: Time-microscopic estimates were taken as the basis for the graphic presentation of the sequence of events. The chain of arrows shows this sequence from Bmall RNA above to the same substance below (closing the loop of the cycle). The next cycle might be presented as a continuation of the graph to the right and/or as a double plot. © Halberg.

Experimental background to the coining of "circadian"

By 1950, Franz Halberg (FH) had compared two groups of mice that happened to have rhythms with different phases, Figure 32, and two other groups exhibiting rhythms with different frequencies, Figures 26 and 27. In each case, he identified the difference in phase or frequency and avoided publishing the statistically highly significant but opposite, nonsensical differences on top of Figure 32). The ready chronobiologic interpretation of the findings on top of this figure indicated the importance of identifying circadian rhythms in cancer research and more broadly in any biological investigations. One must invariably look for any phase, frequency or other differences in parameters between the rhythms of two groups being compared. The top row of Figure 32 is a warning for investigators of stress or allergy whose research can be greatly misled if rhythms are not assessed. Thus, by 1950 it became clear that once-daily concomitant controls were not enough if a comparable stage of any rhythmic variable was not ascertained. Also at the outset, FH found further puzzling opposite differences between blinded and sham-operated mice at various times after surgery that were due to different average periods, Figure 26 and top row of Figure 27. By using rectal temperature as a marker rhythm, FH found ~23.5-hour periods in rectal temperature of mice after blinding, shown time-macroscopically in Figure 26 and time-microscopically in section I B-C and the left half of D in Figure 27. It became clear, as an important dividend, that the uncoupling from the lighting regimen by the loss of the eyes suggested a partly built-in nature of the rhythms, subsequently documented by the isolation of clock genes in mice and by studies of twins reared apart.

Figure 33: Importance of rhythms in assessing intervention effects, illustrated in relation to stress or allergy. A. Eosinophil counts seem to be lowered by fasting (and/or stress), when a 50% reduction in dietary carbohydrates and fats (with proteins, vitamins, and minerals similar to control group) was fed in the morning to C3H mice (dark column). (In this model, the naturally high incidence of breast cancer is lowered by a diet reduced in calories, not shown.) The result could have been interpreted as an adrenocortical activation and then assessed by eosinophil depression, with applications for treating breast cancer and for prolonging life. Steroids that depress eosinophil cell counts and perhaps mitoses could be a mechanism through which caloric restriction and ovariectomy act in greatly reducing cancer incidence. This tempting inference was never published. B. In view of the importance of this finding for the etiology of cancer, results were replicated on a larger group of animals; one week later, a follow-up study with more animals started at an earlier clock-hour, yielded confusing results, showing no statistically significant difference between the two groups of mice. C. After another week, another study starting at an even earlier clock-hour yielded results opposite to those in the first experiment when considered alone. These findings in C in themselves could have been interpreted as an allergic response, certainly contrary to the "stress" response in A. D. Sampling at intervals of a few hours in the third study, the stages called 4 and 5, hinted at the reason for the confusion: by sampling at different clock-hours, two groups of mice were found to be characterized by a circadian rhythm with different phases. Opposite effects thus became predictable. E. Abstract illustration of two circadian rhythms in antiphase. Differences in opposite direction or no effect are then anticipated from sampling at different clock-hours. © Halberg.

Longer-than-24-hour periods (frequencies lower than precisely 1 cycle in 24 hours) are usually seen for humans' activity-rest, rectal temperature and hormone excretion, Figure 20, Section ID, and for many other variables, i.a., blood pressure, heart rate, time estimation during isolation from society, e.g., in caves for up to several hundred days. The differences among inbred strains in extent of within-day change in counts of circulating blood eosinophil cells, hinted by 1950 at built-in rhythms and were major reasons prompting the "circa" in "circadian": blinded mice happened to have periods different than 24 hours, and the desynchronized periods varied further among some of the mice themselves, Section 3C in Figure 20. The methodological and intrinsic importance of circadian systems became apparent further from reactive rhythms, Figure 28 (middle and bottom sections); timing along the 24-hour scale accounted for the difference between inhibiting and stimulating DNA labeling.

History of semantics

Originally, FH had proposed, for synchronized vs. desynchronized rhythms, the terms dian vs. circadian at meetings of nomenclature committees in Basel in 1953 and later. In the absence of an environmental 24-hour synchronizer, different variables can assume different free-running periods. Even under 24-hour synchronized conditions, on the right side at the bottom, Section 2, of Figure 24 shows a drifting phase on top for blood pressure and a synchronized rhythm in activity/rest (sleep/wakefulness) in the same organism, one more reason for the use of the term in describing all synchronized, asynchronized or desynchronized rhythms under the concept of a circadian system. In Section 1 (left) at the bottom of Figure 34, a 95% confidence interval of the period, the small shaded box on the right end of the horizontal line visualizing the period, shows another major reason, namely that uncertainty, often large, is almost invariably involved in basic or applied studies of circadian rhythms.

Figure 34: Reasons for the use of "circa" in "circarhythms" include among several other considerations, the need for providing inferential statistical uncertainties that qualify the estimate of period shown as a 95% confidence interval of the period as a box at the right end of the horizontal period line (1. Statistical Uncertainty, left), apart from internal desynchronization of systolic blood pressure (SBP) from sleep-wakefulness (activity) in one and the same person living under a 24-hour synchronized hospital routine, assessed by 3 shifts of nurses (2. Endogenicity, right)! © Halberg.

Circadian time, HALO time, zeitgeber time and location

In investigations in the field, the use of local time is appropriate when the geographic locality is given (e.g., "tests were conducted at 1530 hours [3:30 pm] Eastern Time in New York, NY, USA"). It is essential to report the calendar date and location of each study so that any environmental factor, local as well as global, such as a magnetic storm or an extreme magnetic quiet or solar activity, can be looked up from routinely recorded physical databases. There can be geographic differences in environmental magnetic effects and, of course, the duration of the nocturnal photofractions differs with latitude. For laboratory studies involving cyclic regimens of alternating light (L) and darkness (D) as synchronizers, the expression "Hours After Light Onset" (HALO) is recommended and is applicable to nonphotic synchronizers, with appropriate change in abbreviation.

Equivalent is "Zeitgeber Time" (ZT). 0 HALO or ZT 0 correspond to the time of light onset, so that, for instance, ZT 15.5 or 15.5 HALO refer to a time point 15.5 hours after the lights are turned on. Synchronizers are clock-time or calendar-time givers but not physiological-time givers. When the length of the light-dark cycle is different from 24 hours, the HALO and ZT denominations allow for correction of the duration of each hour (thus, ZT 15.5 or 15.5 HALO under a 28-hour light-dark cycle refers to 15.5 synchronizer hours after light onset, even though this corresponds to 18.1 clock hours after light onset).

The recommended way to describe free-running circadian, circannual or other rhythms consists of assessing their periods by inferential statistical means, and of expressing the phases when they reach the periodically recurring overall highest values (acrophases) in degrees, 360 degrees being equated to the given period's length, and 0 degrees being set to a given reference time such as the time of release of experimental animals or plants into special, e.g., constant lighting conditions. This inferential statistical approach leads to objective indications of timing in degrees, radians or fractions of a cycle, each with 95% confidence intervals. Circadian or other cycle times are thus amenable to mapping in a succinct yet generally applicable and reproducible way, Figures 14-16.

Remaining semantic problem

Koukkari and Sothern write: "To standardize the terminology used when discussing rhythms with periods close to 24 h, Franz Halberg … introduced the term circadian in 1959 [as noted above under Origin]." The same book which cites exact definitions as an essay, however, restricts the use of "circadian" to presumably free-running rhythms. Some scholars (at this time a minority unfamiliar with the history of the field or with biomedical practice) prefer to use daily, diurnal or nycthemeral for a 24-hour synchronized rhythm and restrict the use of circadian to desynchronized rhythms. If this practice were generally followed in health care, the designation of a rhythm as synchronized or desynchronized from a given, e.g., 24-hour routine would be cumbersome insofar as it would require prior long-term monitoring in special environments and, in that case, perhaps more than one term, e.g., dian vs. circadian could be reconsidered. New technology for automatic monitoring of physiological functions and software for as-one-goes analysis may render such a dichotomy implementable, albeit not soon in general health care practice. At this time, in the majority of biomedical articles, circadian is used for both the synchronized and the desynchronized cases in biology and medicine and diurnal is mostly restricted to daytime, but the need to arrive at a consensus in all of science, including in particular physics, remains, unless one follows the practice of using a definition of terms in each report and allows these definitions to vary from one report to the next. The community of physicists has traditionally used diurnal to mean, "performed in or occupying one day; daily", notably in an astronomical context. But even in reference to physical matters such as environmental temperature, it seems awkward to read "a diurnal temperature rise during the day and diurnal fall at night". Usage of circadian or at least dian may also be more appropriate in this case, may also account for day-to-day variability, and may prompt reference to "a nocturnal temperature fall" instead.

Figure 35: In many circumstances the data are collected or are amenable to being collected over time, but the information is discarded after a mere visual inspection of a monitor's recording. Adding chronobiologic analytical procedures for the on-line processing and interpretation of the data would provide individual reference standards for rhythms with lower and lower frequencies while also providing continued check-ups capable of detecting the earliest rhythm alterations indicative of a heightened risk and thus enabling the prompt institution of treatment when indicated. (The analogy that a single 24-hour cycle from a circadian viewpoint corresponds to the radial pulse based on a single heartbeat has now been shared by others.) Right: Chronomodulation at different levels: in the left half, interplanetary solar and galactic factors (top right) are conceived as modulating socioecological conditions in the habitat (top left), acting upon the healthy or sick organism as a whole. © Halberg

References to books

Available free of charge on the Internet

1. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7. Minneapolis: Medtronic Inc.; April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL

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. Minneapolis: Medtronic Inc.; 1995. 12 pp. text, 18 figures. URL

- - - Other: 3. Ahlgren A, Halberg F. Cycles of Nature: An Introduction to Biological Rhythms. Washington DC: National Science Teachers Association; 1990. 87 pp.

4. Ajuriaguerra J de (ed). Symposium Bel-Air III. Cycles biologiques et psychiatrie / publié sous la direction du professeur J. 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, July 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. 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.

16. Halberg F, editor. Proc. XII Int. Conf. International Society for Chronobiology, Washington, DC, August 10-15, 1975. Milan: Il Ponte; 1977. 782 pp.

17. 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. University of Minnesota/Medtronic Chronobiology Seminar Series, #1, December 1991. Minneapolis: Medtronic Inc.; 1991. 21 pp. of text, 70 figures.

18. Halberg F, Carandente F, Cornélissen G, Katinas GS. Glossary of chronobiology. Chronobiologia 1977; 4 (Suppl. 1), 189 pp.

19. Halberg F, Cornélissen G, Halberg E, Halberg J, Delmore P, Shinoda M, Bakken E. Chronobiology of human blood pressure. Medtronic Continuing Medical Education Seminars, 4th ed. Minneapolis: Medtronic Inc.; 1988. 242 pp.

20. 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.

21. 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.

22. 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. 90 pp.

23. Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium, Chronobiological Analysis in Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. 186 pp.

24. Halberg F, Reale L, Tarquini B. (eds.). Proc. 2nd Int. Conf. Medico-Social Aspects of Chronobiology, Florence, Oct. 2, 1984, Istituto Italiano di Medicina Sociale, Rome, 1986, 791 pp.

25. 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.

26. Halberg F, Watanabe H. (eds.). Workshop on Computer Methods on Chronobiology and Chronomedicine. 20th Int. Cong. Neurovegetative Research, Tokyo, Sept. 10-14, 1990. Medical Review, Tokyo, 1992, 297 pp.

27. Hayes DK, Pauly JE, Reiter RJ, eds. Chronobiology: Its Role in Clinical Medicine, General Biology, and Agriculture, Parts A and B. New York: Wiley-Liss; 1990. (Progress in Clinical and Biological Research 1990; 341A & B.) A: 822 pp. B: 940 pp.

28. 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. Minneapolis: Medtronic Inc.; 1991. 3 pp. of text, 38 figures.

29. 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.

30. Otsuka K, Cornélissen G, Halberg F (eds). Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Science Publishing; 1993. 147 pp.

31. Pauly JE, Scheving LE, eds. Advances in Chronobiology, Parts A and B, Proc. XVII Int. Conf. Int. Soc. Chronobiol., Little Rock, Ark., USA, Nov. 3-7, 1985. New York: Alan R. Liss; 1987. (Progress in Clinical and Biological Research 1987; 227A & B.) A: 528 pp. B: 613 pp.

32. 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. Minneapolis: Medtronic Inc.; 1991. 4 pp. text, 4 figures.

33. Refinetti R. Circadian Physiology. 2nd ed. Boca Raton, FL: CRC Press; 2006. 700 pp.

34. Reinberg A, Halberg F, editors. Chronopharmacology. Oxford/New York: Pergamon Press, 1979, 429 pp.

35. Reinberg A, Smolensky MH. Biological rhythms and medicine. Cellular, metabolic, physiopathologic, and pharmacologic aspects. New York: Springer; 1983. 305 pp.

36. Scheving LE, Halberg F, editors. Chronobiology: Principles and Applications to Shifts in Schedules. Alphen aan den Rijn, Netherlands: Sijthoff & Noordhoff; 1980. 572 pp.

37. Scheving LE, Halberg F, Ehret CF, editors. Chronobiotechnology and Chronobiological Engineering. Dordrecht, The Netherlands: Martinus Nijhoff; 1987. 453 pp.

38. 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.

39. Smolensky MH, Reinberg A, McGovern JP, eds. Proceedings, Symposium on Chronobiology in Allergy and Immunology, X Int Cong Allergology, Jerusalem, Israel, 11 Nov 1979. Oxford/New York: Pergamon Press; 1980. 358 pp.

40. 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.

41. Touitou Y, Haus E, editors. Biological Rhythms in Clinical and Laboratory Medicine. Berlin: Springer-Verlag; 1992. 730 pp.

When no reference in this entire entry is given, see foregoing books and specifically:

42. Halberg F. Physiologic 24-hour periodicity; general and procedural considerations with reference to the adrenal cycle. Z. Vitamin-, Hormon-u Fermentforsch 1959; 10: 225-296 (introducing term);

43. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725 (scope of term);

44. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL (scope of term);

45. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440 (method);

46. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms. Biological Rhythm Research 2007; 38 (4): 275-325. (method);

47. Halberg Franz, Cornélissen G, Katinas G et al. Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian Rhythms 2003; 1: 2. 61 pp. (history).

Cited references:

48. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239. doi:10.1161/01.HYP.0000250392.51418.64.

49. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress: Part II, chronomics for an immediately applicable biomedicine. J Applied Biomedicine 2006; 4: 73-86.

50. Halberg F, Cornélissen G, Bingham C, Fujii S, Halberg E. From experimental units to unique experiments: chronobiologic pilots complement large trials. in vivo 1992; 6: 403-428.

51. Kennedy BJ. A lady and chronobiology. Chronobiologia 1993; 20: 139-144.

52. Halberg F, Prem K, Halberg F, Norman C, Cornélissen G. Cancer Chronomics I: Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy. J Exp Ther Oncol 2006; 6: 55-61.

53. Hrushesky W, Wood P, Levi F, Roemeling R v, Bjarnason G, Focan C, Meier K, Cornélissen G, Halberg F. A recent illustration of some essentials of circadian chronotherapy study design [letter]. J Clin Oncol 2004; 22: 2971-2972.

54. Halberg F, Vallbona C, Dietlein LF, Rummel JA, Berry CA, Pitts GC, Nunneley SA. Circadian circulatory rhythms of men in weightlessness during extraterrestrial flight as well as in bedrest with and without exercise. Space Life Sci 1970; 2: 18-32.

55. Klein JL. Statistical Visions in Time: A History of Time Series Analysis, 1662-1938. Cambridge, UK: Cambridge University Press; 1997. 345 pp.

56. Jozsa R, Halberg F, Cornélissen G, Zeman M, Kazsaki J, Csernus V, Katinas GS, Wendt HW, Schwartzkopff O, Stebelova K, Dulkova K, Chibisov SM, Engebretson M, Pan W, Bubenik GA, Nagy G, Herold M, Hardeland R, Hüther G, Pöggeler B, Tarquini R, Perfetto F, Salti R, Olah A, Csokas N, Delmore P, Otsuka K, Bakken EE, Allen J, Amory-Mazaudier C. Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts forecasts of geomagnetics. Biomedicine & Pharmacotherapy 2005; 59 (Suppl 1): S24-S30.

57. Chibisov SM, Cornélissen G, Halberg F. Magnetic storm effect on the circulation of rabbits. Biomedicine & Pharmacotherapy 2004; 58 (Suppl 1): S15-S19.

58. Hanson BR, Halberg F, Tuna N, Bouchard TJ Jr, Lykken DT, Cornélissen G, Heston LL. Rhythmometry reveals heritability of circadian characteristics of heart rate of human twins reared apart. Cardiologia 1984; 29: 267-282.

59. Li CC. A genetical model for emergenesis. Am J Human Genetics 1987; 41: 517-523.

60. Lykken DT. Research with twins: the concept of emergenesis. Psychophysiology 1982; 19: 361-373.

61. Lykken DT. The mechanism of emergenesis. Behavior 2006; 5: 306-310.

62. Lykken DT, McGue M, Tellegen A, Bouchard TJ Jr. Emergenesis: genetic traits that may not run in families. Am Psychologist 1992; 47: 1565-1577.

63. 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.

64. Shinagawa M, Kubo Y, Otsuka K, Ohkawa S, Cornélissen G, Halberg F. Impact of circadian amplitude and chronotherapy: relevance to prevention and treatment of stroke. Biomedicine & Pharmacotherapy 2001; 55 (Suppl 1): 125s-132s.

65. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc. 30th Ann. Cong. Rad., January 1977, Post-Graduate Institute of Medical Education and Research, Chandigarh, India, 8 pp.

66. Halberg F, Cornélissen G, Wang ZR, Wan C, Ulmer W, Katinas G, Singh Ranjana, Singh RK, Singh Rajesh, Gupta BD, Singh RB, Kumar A, Kanabrocki E, Sothern RB, Rao G, Bhatt MLBD, Srivastava M, Rai G, Singh S, Pati AK, Nath P, Halberg Francine, Halberg J, Schwartzkopff O, Bakken E, Shastri VK. Chronomics: circadian and circaseptan timing of radiotherapy, drugs, calories, perhaps nutriceuticals and beyond. J Exp Therapeutics Oncol 2003; 3: 223-260.

67. Halberg F, Visscher MB. Regular diurnal physiological variation in eosinophil levels in five stocks of mice. Proc Soc exp Biol (N.Y.) 1950; 75: 846-847.


As of January 2006, PubMed (the U.S. National Library of Medicine’s biomedical database) contained 50,000 abstracts of journal articles that could be retrieved by the keyword circadian three times as many as those catalogued 20 years earlier (33) for a term published in 1959 (42).

Table 1: Susceptibility rhythms leading to individualized inferential statistical chronopharmacology and chronotherapy

Year Description Author(s)
1952, 1953 2800-fold increase in sensitivity of a corticosteroid assay by accounting for circadian stage (Figure 1 in 2 vs. 1) Halberg (1, 2)
1955 Circadian susceptibility rhythm to noise Halberg, Bittner, Gully, Albrecht & Brackney (3)
1955 Circadian susceptibility rhythm to an endotoxin Halberg, Spink, Albrecht & Gully (4)
1958 Manipulability of a susceptibility rhythm by lighting regimen Halberg, Jacobson, Wadsworth & Bittner (5)
1958 Detection of (growth) hormone effect on mitoses depends on circadian stage Litman, Halberg et al. (6)
1959 Effect of ethanol depends on circadian stage Haus, Hanton & Halberg (7)
1959 Individualized sequential testing Johnson, Haus, Halberg & Wadsworth (8)
1959 Circadian susceptibility rhythm to a drug (ouabain) Halberg & Stephens (9)
1960 LD50 to whole-body X-irradiation depends on circadian stage Halberg (10, discussion)
1961 Circadian susceptibility rhythm to Librium Marte & Halberg (11)
1963 Circadian susceptibility rhythm to acetylcholine Jones, Haus & Halberg (12)
1964 Circadian susceptibility rhythm to fluothane Matthews, Marte & Halberg (13)
1967 Cosinor method Halberg, Tong & Johnson (14)
1969 Methodological and conceptual context Halberg (15)
1969 Chronotherapy with penicillin Reinberg et al. (16)
1970, 1972 Chronotherapy with arabinosyl cytosine (ara C) Cardoso et al. (17), Haus et al. (18)
1973 Rhythm in chronotherapeutic indices of hydrochlorothiazide and adriamycin Halberg et al. (19), Levine et al. (20), Shiotsuka et al. (21)
1974, 1975 Formulation of rules of chronopharmacology and chronotherapy; demonstration of shift of susceptibility rhythm to adriamycin by meal timing Halberg (22-24)
1977 Doubling of 2-year survival by timing radiotherapy Halberg (25)
1979 Ara-C chronotherapy brings about cancer cures Halberg, Nelson, Cornélissen, Haus, Scheving & Good (26)
1979 More antihypertensive chronotherapy Güllner, Bartter & Halberg (27)
1992 Individualized cancer marker-guided chronochemotherapy Halberg et al. (28)
1995 More antihypertensive chronotherapy and its optimization by timing Halberg et al. (29)
1997 Individualized sequential testing of chronotherapy Cornélissen, Halberg, Hawkins, Otsuka & Henke (30)
2006 Toxicity marker-guided chronochemotherapy Halberg et al. (31)

References to Table 1: 1. Halberg F. Some correlations between chemical structure and maximal eosinopenia in adrenalectomized and hypophysectomized mice. J Pharmacol exp Ther 1952; 106: 135-149.

2. Halberg F. Some physiological and clinical aspects of 24-hour periodicity. Journal-Lancet (Minneapolis) 1953; 73: 20-32. See Figure 1.

3. Halberg F, Bittner JJ, Gully RJ, Albrecht PG, Brackney EL. 24-hour periodicity and audiogenic convulsions in I mice of various ages. Proc Soc exp Biol (NY) 1955; 88: 169-173.

4. Halberg F, Spink WW, Albrecht PG, Gully RJ. Resistance of mice to brucella somatic antigen, 24-hour periodicity and the adrenals. J clin Endocrinol 1955; 15: 887.

5. Halberg F, Jacobson E, Wadsworth G, Bittner JJ. Audiogenic abnormality spectra, 24-hour periodicity and lighting. Science 1958; 128: 657-658.

6. Litman T, Halberg F, Ellis S, Bittner JJ. Pituitary growth hormone and mitoses in immature mouse liver. Endocrinology 1958; 62: 361-364.

7. Haus E, Hanton EM, Halberg F. 24-hour susceptibility rhythm to ethanol in fully-fed, starved and thirsted mice and the lighting regimen. Physiologist 1959; 2: 54.

8. Johnson EA, Haus E, Halberg F, Wadsworth GL. Graphic monitoring of seizure incidence changes in epileptic patients. Minn Med 1959; 42: 1250-1257.

9. Halberg F, Stephens AN. Susceptibility to ouabain and physiologic circadian periodicity. Proc Minn Acad Sci 1959; 27, 139-143.

10. Halberg F. Temporal coordination of physiologic function. Cold Spr Harb Symp quant Biol 1960; 25: 289-310. Discussion on LD50, p. 310.

11. Marte E, Halberg F. Circadian susceptibility rhythm of mice to librium. Fed Proc 1961; 20, 305.

12. Jones F, Haus E, Halberg F. Murine circadian susceptibility-resistance cycle to acetylcholine. Proc Minn Acad Sci 1963; 31: 61-62.

13. Matthews JH, Marte E, Halberg F. A circadian susceptibility-resistance cycle to fluothane in male B1 mice. Canadian Anaesthetists' Society J 1964; 11: 280-290.

14. Halberg F, Tong YL, Johnson EA. Circadian system phase—an aspect of temporal morphology; procedures and illustrative examples. Proc. International Congress of Anatomists. In: Mayersbach H v, ed. The Cellular Aspects of Biorhythms, Symposium on Biorhythms. New York: Springer-Verlag; 1967. p. 20-48.

15. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.

16. Reinberg A, Zagula-Mally ZW, Ghata J, Halberg F. Circadian reactivity rhythm of human skin to house dust, penicillin and histamine. J Allergy 1969; 44: 292-306.

17. Cardoso SS, Scheving LE, Halberg F. Mortality of mice as influenced by the hour of the day of drug (ara-C) administration. Pharmacologist 1970; 12: 302.

18. Haus E, Halberg F, Scheving L, Pauly JE, Cardoso S, Kühl JFW, Sothern R, Shiotsuka RN, Hwang DS. Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system. Science 1972; 177: 80-82.

19. Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE, Runge W, Spalding JF, Lee JK, Good RA. Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon host rhythms. Experientia (Basel) 1973; 29: 909-934.

20. Levine H, Thompson D, Shiotsuka R, Krzanowski M, Halberg F. Autorhythmometrically determined blood pressure ranges and rhythm of 12 presumably healthy men during an 18-day span. Int J Chronobiol 1973; 1: 337-338.

21. Shiotsuka R, Halberg F, Haus E, Lee JK, McHugh R, Simpson H, Levine H, Ratte J, Najarian J. Results bearing on the chronotherapy of hypertension: saluresis and diuresis without kaluresis can be produced by properly timing chlorothiazide administration according to circadian rhythms. Int J Chronobiol 1973; 1: 358.

22. 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.

23. Halberg F. Quando trattare /When to treat. Hæmatologica (Pavia) 1975; 60: 1-30.

24. Halberg F. When to treat. Indian J. Cancer 1975; 12: 1-20.

25. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc. 30th Ann. Cong. Rad., January 1977, Post-Graduate Institute of Medical Education and Research, Chandigarh, India, 8 pp.

26. Halberg F, Nelson W, Cornélissen G, Haus E, Scheving LE, Good RA. On methods for testing and achieving cancer chronotherapy. Cancer Treatment Rep 1979; 63: 1428-1430.

27. Güllner HG, Bartter FC, Halberg F. Timing antihypertensive medication. The Lancet, September 8, 1979: 527.

28. Halberg F, Cornélissen G, Bingham C, Fujii S, Halberg E. From experimental units to unique experiments: chronobiologic pilots complement large trials. in vivo 1992; 6: 403-428.

29. 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

30. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of antihypertensive response by self-starting cumulative sums. J Medical Engineering & Technology 1997; 21: 111-120.

31. Halberg F, Prem K, Halberg F, Norman C, Cornélissen G. Cancer Chronomics I: Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy. J Exp Ther Oncol 2006; 6: 55-61.

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