(a) We turn from a master clock serving regulation for constancy to an integrative internal-external collateral hierarchy for physiological coordination. Homeostasis postulates that physiological processes remain largely within certain ranges in health and seeks departure from such “normal values” to diagnose overt disease. Thereby, variability within the normal range, however, is often dealt with as if it were narrow, random, or trivial, the body striving for at least a relative “constancy.” The alternative, rather than complement, to this status quo, on the left of this figure, is learning about the rules of rhythmic and chaotic variations that take place within the “usual value” ranges that led to the postulation of a “biological clock” that would enable the body to keep track of time. By removal and replacement experiments, it was located first in the adrenal, shown to be responsible for some but not for other circadians that persisted after brain ablation. The fact that single cells and even bacteria are genetically coded for a spectrum of rhythmic variation indicates that the concept of “clock” needs extension. Beyond clocks and calendars, we recognize a biological week, a biological decade, and also other rules found in variability, such as deterministic chaos and the long-known trends, some of which may turn out to be cycles. When the giant alga Acetabularia, a prominent model of a “clock,” is placed into continuous light, its spectrum of electrical activity reveals the largest amplitude for a component of about 1 week rather than of 1 day. When over a decade of studies on this alga are pooled, an about-10-year cycle emerges in the data set as a whole. The alignment of spectral components and chaos and trends in and around us has also begun. Long-term longitudinal, but not yet entire, lifetime monitoring of critical variables complements current linked cross-sectional (hybrid) reference values required for preventive health and environmental care. Changes occurring within the usual value range as longer, and still longer cycles are resolvable as chronomes, with a (predictable multifrequency) rhythmic element, which allows us to measure the dynamics of everyday life, in order to obtain, e.g., warnings before the fait accompli of disease, so that prophylactic measures can be instituted in a timely way and to detect heretofore largely undetected or unquantified environmental effects. The abstract sketch of the sector structure of the interplanetary magnetic field (shown on the top right by three visible arrows, the fourth being covered by another circle showing solar flares) is an idealized presentation of the sector structure in the interplanetary magnetic field. The parameters of the solar wind are much more variable than originally visualized when first described, as sketched by irregular solar flares. Associations of helio- and geomagnetic variability, myocardial infarctions, and strokes are accumulating and are just the tip of the iceberg, with a profound effect of magnetism (recognized by Gilbert in 1600), apparent in the human ECG, notably in the auroral region. In external-internal interactions, a broad spectrum of rhythms (in both the environment and in living matter) organizes deterministic and other chaos and trends. Trends pursued long enough may become low-frequency cycles, e.g., for the detection of any risk elevation and for timely action (© Halberg Chronobiology Center). (b) In the absence of systematic chronome mapping, with seemingly ample documentation, a decrease over several years in metabolites related to the adrenal and the male gonad (in the excretion of 17-ketosteroids) may be described as a sign of aging, notably of the declining sex gland activity, and may be published as such in any professional journal (but see Fig. 6.1c ) [20, 21] (© Halberg Chronobiology Center). (c) A surprising increase in steroidal metabolites (gonadal activity?) of a man in his 50s constitutes a statistically but not biologically significant effect which may encourage speculation, perhaps by post hoc ergo propter hoc reasoning about how the increase in 17-ketosteroid excretion (rejuvenation?) came about. The authors were tempted to publish Figs. 6.1b and c separately in different professional journals to show that referees are unlikely to question trends and to validate the need for longitudinally and concomitantly mapping all three elements (chaos, rhythms, and trends) of chronomes instead of spotchecks of aging irrespective of rhythms [20, 21] (© Halberg Chronobiology Center). (d) By unmasking an about-9-year rhythm, this figure resolves any controversy that may have arisen from the separate viewing of Figs. 6.1b and c. To the extent that in the future such rhythmicities can be reproduced repeatedly on each of several different persons, the task still ahead of us, and to the extent that such cycles reveal a nonoverlap of the 95 % confidence intervals with those of cycles in solar activity or in geomagnetic disturbance indices, one may postulate that such changes, like the circadians or the about-7-day (circaseptan) rhythms, are built into us by an evolutionary integration of life into its environmental invisible nonphotic chronome in the velocity changes of the solar wind. Corpuscular effects, e.g., from the sun, complement the effect of visible light and readily recognized temperature and can be ascertained beyond similar spectral signatures and cross-spectral coherence by remove-and-replace approaches, including superposed epochs (© Halberg Chronobiology Center). (e) The same data set is shown, as the case may be, as a deviation (upward or downward, on the left of this figure) either from its mean, shown as a horizontal line (top) or as a deviation from the best-fitting 24-hour cosine (bottom). In the next column from the left to right, the deviations are shown by the length of lines, irrespective of sign; on the average they are smaller when related to the cosine curve, as compared to their mean, as best seen in the third pair toward the right, where the deviations are squared: the squares at the bottom, as deviations from the cosine curve, are obviously smaller than those at the top, as further summarized by the length of two columns on the extreme right. The thus-unqualified method of least squares underlies both the computation of a mean, as a step for computing deviations from the mean or from other standards. A wealth of information from time series in life and other science reveals the importance of a known pertinent mathematical model. In the illustrative example used herein, human breast surface temperature can be approximated by a cosine curve. The original use of least squares also depended on prior independent information on the movement of heavenly bodies in ellipses, derived from Kepler and available to Gauss. Gauss developed the least-squares method and used it to predict the location of a lost “planet,” Ceres (now classified as an asteroid or dwarf planet), where Olbers found it on December 31, 1801. In the case of the chronome of breast surface temperature analyzed in this figure, the method awaits broad application for the detection of very early changes in the female breast prior to the appearance of a cancer rather than merely to look at a hot spot (© Halberg Chronobiology Center). (f) Dots only on the top left apply to all four graphs showing four of the characteristics resolved by least-squares rhythmometry with the method of Gauss visualized in Fig. 6.1e. The great variability of single blood pressures notwithstanding, the relatively small hatched quadrangles or hexagons show the relatively small uncertainty of characteristics based in several days of around-the-clock measurements (© Halberg Chronobiology Center). (g) Original data: Time plots of two circulating substances, endothelin-1 (top) and cortisol (bottom), on the left are shown in a polar representation by the cosinor method on the right. A methodological point is the nonoverlap of the graph’s center (pole) on top by the darkened error ellipse of the 8-hour vector, describing by its length the extent of change or amplitude, and, by its angle, the time of high values, acrophase, endpoints visualized along rectangular coordinates for blood pressure in Fig. 6.1f. The nonoverlap of the pole by the error ellipse corresponding to the 8-hour cosine curve fit rejects the zero 8-hour amplitude assumption, in keeping with an 8-hour rhythm for endothelin-1. This figure also shows that in the same circulation of seven healthy medical students, on the average, cortisol (bottom) can reveal statistically highly significant 24-hour and 12-hour components, but no 8-hour component, since the corresponding darkened error ellipse (c) overlaps the pole, the opposite of what is seen on top, where the ellipses of the 24- and 12-hour components include the pole, results also seen from tables accompanying the graph. Endothelin sometimes in some people obeys a “24-hour clock,” but at most times in most people, it exhibits a primary 8 hour rhythm. The designation of a “clock” has no heuristic value in this case and many others and need not obscure the search for mechanisms (© Halberg Chronobiology Center). (h) Circadian acrophase mapping is much more extensive than shown in this chart that suffices to reveal the principle of synchronization with differences in phase. Major advances beyond this chart include (1). the preparation of such a chart for many more variables of the individual subject and (2). the extension from phases to include amplitude and waveform at all pertinent periods, thereby to detect modulations with ever lower frequencies, including those shown in Figs. 6.1i and j, indeed for some individual subjects (© Halberg Chronobiology Center). (i) The cycles in geomagnetic disturbance (first two rows) and the Schwabe (and Hale) cycles of solar activity have counterparts in the biosphere. For phase relations, see Fig. 6.1j (© Halberg Chronobiology Center). (j) Sequence of events following extrema of solar activity (gauged by relative phase relations). Delays from solar extrema are aligned, irrespective of the calendar date of study, for different subjects, locations, and/or variables to reveal an apparent bunching of biological extrema with respect to those of the solar cycle. Focus on maximum or minimum depends on the documented positive or negative association of the given variable with Wolf numbers (gauging solar activity). (S)BP, (systolic) blood pressure; HR, heart rate; HRV, heart rate variability gauged by standard deviation; MI, myocardial infarction; 17-KS, urinary 17-ketosteroid excretion; WN, Wolf’s relative sunspot number. Note the degree of generality of about-10-year changes shown on this chart and elsewhere for events in populations as in Minnesota myocardial infarctions or in probable genetic changes gauged by sectors in colonies of air bacteria (determined by Piero Faraone). This circadecennian chart can now be complemented by an about-10-year periodicity in the circadian phase and relative amplitude of oxygen evolution in Acetabularia acetabulum, found by Dewayne Hillman. Miroslav Mikulecky has also mapped a set of circadecennians in human pathology, from diabetes to leptospirosis, along with changes in human productivity gauged by a cycle in numbers of published titles. From growth gauged by human neonatal and other anthropometry to religious motivation, about-21-yearly changes abound. Only illustrative examples are shown here. The limitations of single or only a few cycles are overcome in terms of numbers insofar as large numbers of individuals must be similarly timed to provide the population rhythms depicted, based in some cases upon millions of individuals; they are overcome in terms of length by a 112-year series. Furthermore, subject RBS continues to self-measure over 10 physiological variables about five times/day on the average for most days for 35 years. His example needs emulation for lifetimes. Analyses of RBS’ data serve to emphasize the need for denser automatic series so that deterministic and other chaos can also be assessed. Information on circadecennians has already suggested that many more controversies such as those that could have arisen from Figs. 6.1b and c, had the latter been obtained by different investigators on different individuals, can be avoided. The systematic government-sponsored monitoring, at least on some test pilots, seems mandatory for a solid biological and transdisciplinary science (© Halberg Chronobiology Center). (k) About-21-year cycles in Minnesotan neonatal birth weights, shown in this graph, also characterize detrended data (not shown) from Denmark, during the same span, but happen to be in antiphase. Moreover, in 112 years of data from the late Boris Nikityuk, results of other neonatal anthropometry show about-20-year cycles, but birth weight is frequency-multiplied to an about-10-year cycle in Moscow but not in Alma-Ata. The near-antiphase between the time course of circavigintunennians in data from Minnesota and Denmark during the same span, documented at each site, with large numbers of individuals as well as a frequency multiplication at one of two other sites, remains a transdisciplinary challenge in a multifactorial situation (© Halberg Chronobiology Center)

(a) By eyeballing alone of Section IIA on the right, the circadian rhythm in core temperature seems to be lost in the rat with a SCN lesion. Simple stacking reveals the persistence of a circadian rhythm in telemetered core temperature for individual animals (Section IB top), but with a smaller within-day change (IB) as compared to controls (IA). This finding is also seen after averaging in Section IIB bottom. Microscopy (C), apart from quantifying the rhythm by cosinor, reveals a great amplitude lowering by bilateral SCN ablation and a phase advancement seen as an earlier and shorter vector. Section IIC thus validates by the nonoverlap of the center or pole of the graph, by the error ellipse representing a 95 % confidence region, that the removal of the SCN is compatible with the persistence of a statistically highly significant circadian rhythm in core temperature quantified with its parameters and their uncertainties. The polar cosinor displays in Fig. 6.2b also quantify a phase advance of rhythm 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, again as seen by the shorter vector for the B (SCN-ablated) group, as compared to longer and later vectors for the sham-ablated S group. When the ablation, unintentionally, as discovered at post-mortem, was unilateral (U), the circadian amplitude is enhanced (Section I bottom), a finding suggesting a subtractive coupling between the two SCN. Section III is in keeping with the speculation of an effect by lunar factors upon the “free-running” period of about 24.8 hours found in controls or unilaterally ablated animals. If this should be in part a lunar effect, it is lost in animals subjected to bilateral suprachiasmatic lesions (© Halberg Chronobiology Center). (b) The SCN coordinates a collateral hierarchy that can be quantified in terms of amplitude and phase: the major effect of bilateral SCN ablation is thus far invariably, comparably to the behavior of core temperature in Fig. 6.2a, an advance in phase for the L animals in eight cases out of eight, with a reduction in amplitude, except for DNA labeling in the stomach (Section III). Section VI shows a microscopic phase and amplitude chart summarizing the findings in the other sections for a number of variables other than core temperature, studied as marker rhythm in Fig. 6.2a, confirming and extending the scope of the lesson learned in Fig. 6.2a: the SCN, rather than being a master clock leading to the abolition of all rhythms when ablated bilaterally, is compatible with their persistence, except for water drinking among the functions investigated. A subjective time-macroscopic interpretation-based impression that led to the master clock illusion (e.g., Fig. 6.2a, Section II right) is thus resolved by quantification (© Halberg Chronobiology Center)

For any data series (whether from physics, chemistry, biology, psychology, or sociology), characterized by a spectrum of rhythms, a MESOR (midline-estimating statistic of rhythm or rather of a chronome-adjusted mean) can be computed and has merits: as compared to the arithmetic mean of the same series, the MESOR is usually more accurate and more precise (© Halberg Chronobiology Center)