(1969) Halberg CHRONOBIOLOGY PDF

ANNUAL
REVIEWS Further
Quick links to online content
Copyright 1969. All rights reserved
CHRONOBIOLOGYl,2 1036
By FRANZ HALBERG
Periodicity Analysis Lab oratories, Department of Pathology
Univer sity of Minnesota, Minneapolis
INTRODUCTION
The study of physiologic rhythms, overlapping a number of traditional
disciplines in biology and medicine, depends also on progress in engineering
benefitting, as it does, from modern technology for the sensing and tele
Annu. Rev. Physiol. 1969.31:675-726. Downloaded from www.annualreviews.org
metering of body functions and from advances in electronic computer

science. Computers already process data much more efficiently and quickly
by University of South Florida on 04/29/13. For personal use only.
than was heretofore possible; their contribution to the study of biologic

rhythms, however, is yet more important. Precisely because of their high
speed and efficiency, they enable us not only to do the "old" kinds of tasks
better, but also to resolve new dimensions, e.g., to detect rhythms that
could not possibly have been uncovered otherwise by all too laborious hand
computations (1). By virtue of this fact, the electronic computer yields for
the student of biologic time structure what the microscope or the electron
microscope resolves for the student of spatial structure (2) .
One purpose of this review will be to illustrate developments in the dis
play of objective quantitative estimates of rhythm parameters in terms of
their level, amplitude and various phase relations at each of several fre
quencies. This is done with a view toward the future of a field which may
become a domain of quantitative biology, even though the major part of
work thus far, including that published during the last few years, has been
done primarily by naturalists who relied on the visual inspection of data.
Endpoints from quantitative rhythmometry here reviewed will bear upon
healthy human beings and a few laboratory animals, notably nonhuman
primates and rodents, included as illustrative examples for comparative
physiologic purposes.
Problems relating to the phase shifting of rhythms, again with the prin
cipal focus upon primates, will be alluded to with special reference to long
distance, transmeridian travel.
Alterations of rhythms, notably as a function of drug administration or
disease, will not be discussed, since they have been dealt with at a number
of recent symposia (10-14) . The information here reviewed represents the
background for the as yet unanswered questions: 1. whether rhythm altera
tion might represent an early etiologically determinant stage in disease, or
at least a sign of threatening, even if as yet not established, illness and, if
so, 2. whether correction of rhythm alteration will prevent or alleviate
1The survey of literature for this review was concluded on September 1, 1968.
IWork supported by the United States Public Health Service (5-K6-GM-13,981)
and by NASA (NGR 24-005 -006 and NAS 2.2738).
675
676 HALBERG
certain diseases. Answers to these questions may eventually be provided by

means of developments such as (a) sensors for nuisance-free collection of
time series on biophysical, biochemical, and more broadly behavioral vari·,
abies; (b) means for automatic data transfer to a medium and into a format:
directly amenable to analysis (e.g., on magnetic tape) ; and (c) means for a.
so·called microscopic evaluation of rhythms (e.g. , by electronic computer
programs) . Such technical developments, prompted largely by plans for
extraterrestrial research, embody a worthwhile bonus to life on this planet.
Some definitions will be necessary in order to introduce rhythms as an
aspect of the broader field of chronobiology.
Most of the work based exclusively upon the viewing of data plotted as a function
of time-in chronograms-and interpreted as representing a physiologically unquali
fied "clock", will not be evaluated here. The use of chronograms to evaluate the
variability contributed by factors such as an unqualified time of day has been dis
cussed elsewhere (3); it also remains beyond our scope herein.
For the aforementioned kinds of contributions, as well as for more rigorous ap
proaches to rhythms, the interested reader can be referred to a number of symposia
(4-16,292), books (17-27), recent review articles (28-30, 286), a handbook on biologic
data (31), and a bibliography on time series (32).
COMMENTS ON TERMS USED
Rhythms, synchronizers, and bio rhythms Whether they are viewed

.-
" macroscopically" or " microscopically" (see below) , rhythm s can be defined

as statistically validated physiologic changes recurring with a reproducible
waveform. Rhythm in "macroscopic" terms denotes a reliably periodic
� '
aspect of data displayed as a function of time. A " microscopically" defined
rhythm constitutes a periodic component of biologic time series with an
objectively quantified (average) period, T, and/or (average) acrophase (crest
time) cfJ, and an (average) amplitude C demonstrated to be different from
zero by inferential statistical means ( 1 , 2; d. Figure 1 and Tables 1-3) .
Endpoint and confidence interval estimates for these rhythm paramo
eters, and also for the level Co, are obtained by the use of approximating
functions [inter alia, by functions of the form: J(t) Co+ C cos (wt+cfJ) , where
=
w is the angular frequency and t = time) as sketched in Figure 1 .

Synchronizers, time-givers o r entraining agents, clues or cues (4, 5, 1 7 ,
1 8, 2 1 ) are environmental factors determining the temporal placement o f a
given rhythm along an appropriate time scale (e.g. , uniformly demarcated
"local time" and, preferably, also the separately coded Greenwich Mean
Time) . The adjectives "primary" and "secondary" describe the 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; the lighting effect overrides any secondary
effect of feeding time, under usual laboratory conditions. The 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
CHRO NOBIOLOGY 677
CaH (Minnesota) mice subjected to a SO per cent restrIction in dietary
calories, the feeding time may be dominant over the lighting regimen.
Moreover, a rhythm can be influenced by secondary synchronizers and other
modifying factors-modulators or, more generally, influencers.
A biorhythm is a rhythm which, if it be amenable to frequency synchroni
zation and thus to phase-shifting by a known synchronizer, persists after
elimination of the synchronizer effect. For a biorhythm the minimal number
of persisting periods (which depends upon the system) and any damping
noted during the persistence test also chould be indicated, with the test con
ditions, such as blinding or constancy of light (or darkness) , environmental
temperature, ad libitum feeding. For instance, in our hands the cirdadian
rhythm in intraperitoneal temperature telemetered at 10' intervals from 6

blinded mature, inbred Minnesota Sprague-Dawley rats, kept singly housed
with food freely available at 24 ± .5° C environmental temperature in light

and darkness alternating at 12-hr intervals persisted with a 24.3 ± .03 hr
period during an entire 1 16-day test span, with a circadian amplitude of
.57 ± .030 C corresponding roughly to that of .61 ± .020 C in 5 concomitantly
evaluated intact rats with a 24 ± .00 hr period.
Chronobiology and its subspecialties - Chronobiology" is the study of
. "
the temporal characteristics of biologic phenomena, leading to an objective

description of biologic time structure.
Biologic time structure, in turn, can be defined as the sum total of non
random and thus predictable temporal aspects of organismic behavior
including bioperiodicity, developmental changes, and age trends. Biologic
time structure characterizes individuals as well as groups of organisms or
of their subdivisions: organ systems, organs, tissues, cells, and intracellular
elements (including electron microscopic ultrastructure) .
Chronobiology includes, among other "subspecialties":
1. "chronophysiology"-investigation of temporal features in physio
logic behavior and of physiologic factors underlying biologic temporal char
acteristics ;
2. "chronotoxicology"-investigation of undesired or harmful effects
from chemical, physical, or other agents including poisons, pollutants, and
overdoses of drugs upon biologic temporal characteristics and as a function
of biologic timing;
3. "chronopathology"-investigation of alterations in biologic temporal
characteristics as a function of disease and as determinants of disease;
4. "chronopharmacology"-investigation of drug effects upon biologic
temporal characteristics and as a function of biologic timing.
Considerable information is available in fields 1. and 2. above (29, 30, 33) ;
fields 3. and 4. are no longer utopian concepts but they will have to be ampli
fied on the basis of further work.
All subspecialties of chronobiology usually involve the collection of ob
servations, measurements, or counts recorded as a function of time, i.e. , or
time series. However, occasionally chronobiologic observations may describe
an apparently unique phenomenon, rather than a recurring one; for example,
678 HAL BERG
(34, 35) or death (36, 37) in populations of humans or rodents (38).

birth
Macroscopic versus microscopic approach (2, 39).-Chronobiology (also
chronophysiology, chronopathology, etc.) can be considered to be "macro
scopic" when it evaluates biologic temporal characteristics:
1. with time as the sole reference frame for the raw (or averaged) data;
2. by the procedures of classical biometry, such as analyses of variance.
computations of correlation or of regressions (or of both) among others;
3. without the explicit endeavor not only to separate the biologic temporal
characteristic under study (a "desired" signal, e.g., a rhythm) from
the effect of other unidentified or unevaluated factors (biologic noise)
but also, and in any event, to evaluate parameters by inferential sta
tistical point and interval estimations.

Biologic noise for a student of rhythms is the sum total of variability
stemming from unidentified or unevaluated sources and interfering with the

signal to be evaluated, i.e., with one or several rhythms. Different kinds of
errors in measurement, in counting or in other observations-errors that
may be random, systematic or even "blundering"-are part of the noise
term. In a given time series or time function transformed into a frequency
spectrum, variance or energy corresponding to biologic noise is spread mo�e
or less uniformly through the entire spectral domain amenable to such a
transformation. By contrast, variance accumulated in a more or less sharply
defined spectral region, e.g., a narrow spectral band or line, may correspond
to a rhythm.
The temporal characteristic studied in such macroscopic periodicity
analysis is a bioperiodicity, which can be defined as a rhythm plus noise.
"Microscopic" chronobiology, on the other hand, evaluates biologic
temporal components, preferably in edited data ( 1 74, 175) :
1. after isolation from biologic noise;
2. on the basis of inferential-statistical summaries in terms of a prominent
frequency lor period T (i.e., reciprocal I), Table I, and/or phase, cp,
Table II, of some appropriate approximating function, as indicated in
Figure 1 (40) , as well as with further assessment of waveform, where
indicated and practical (62, 63, 336);
3. with the estimation of objective, numerical and relativized endpoints
(41) and of confidence intervals for each biologic temporal endpoint
(42, 43) ;
4. when indicated, in terms of displays of such results in the domains of
I. T, and cp as well as time t.
For instance, a biologic temporal component such as a rhythm with a
given frequency can be evaluated not only in terms of a correlation function
(44-46) and variance as a function of frequency in a variance spectrum
(47-53, 64) but also in terms of quotients derived, e.g., from variance spectra,
such as the circadian quotient CQ (53, 58); in terms of amplitude as a func
tion of frequency in a periodogram (46, 59-61); in a periodic regression (62)
or in the least squares spectrum (1); in terms of amplitude-weighted phase in
CHRO NO BIO LO GY 679
TABLE I
ILLUSTRATIVE SPEORUM OF RHYTHMS
.
MEDIAL FREQUENCY LOW FREQUENCY
DOMAIN ;
O.Sh -. T .;;; 6d T - 6d
REGIONS:
Rest-Activity
Sleep-wakefulness Menstruation
Electroencephalogram Responses to drugs

RHYTHMS 17-Keloslerold excrelion
Blood constituents with spectral components
in: Urinary variables In all regions Indicated

Metabolic processes, above and in other
generally domains
"o. .. al.s and regl •• s [namod a".rdl.g to lroq ...c, criteria] dell".IId accordl.g I. ro lprocal '. I••••
(Ij c
perlodl't)of fu a lon apprulmating rhyth . f1 s=suQnd. h=hoar, d=day.
d m
Sneraf � arlables tlamlned thus far exhibit statlsthally slgalffcaat components In SlYlnl spectral .omaili.
F ossil circa dian , c irca trigintan (a bout 30- da y) an d c ircann ual rhythms have
gaine d in tere st for p oss ible use in pale o- bi o- ge oc hr on ome tr y (20 7-216, cr. al so 21 7,
218) . Ass uming tha t the len gth of the year has been reas ona bly c ons tan t, chan ges in
el n gth oft he da y an d mont h c onsi de re d on t he ba sis of as tron omi cal evi dence (21 7,
218) have been al igne d, inter alia, w ith p ossi ble a bout- mont hly an d a bout-ann ual
groupin gs of p re sume d cir cad ian growth line s in f ossil organi sms-a s compa re d t o
c orresp on din g group in gs in c urren tl y l v
i in g ma rine inve rte bra tes (20 7, 216 ).
TABL E II
•
SYMBOlS AND. TERMS FOR DIFFERENT ACROPHASES
SYMBOL [ILLUSTRATIVE PHASE

TERM PHASE REFERENCE REFERENCE]
[0000 on Day 1 Of
L study
]
mid-dark span for
man, mid-light span
1
for rodents
body core temper- ]

alure acrophase
•
As est imates o"f a rh,thll's liming In relatlo. 10 dlfferenl phase references.
680 HALB ERG
Least Squares Fit of 24 - Hour Cosine Function (Continuous Line)
to Intraperitoneal Temperatures (x) of on Adult Female MSD Rqt.
Telemetry at N 30' intervals for 24 hours
u.u -co + C cos (wl+.p) Key:

Co = meon level, in DC
C" amplitude, in °C
w "angulor frequency, fixed at
3600/24h ' 15°/h
38.5 sf"= .07 "C
t = time. in hours
4> = computative ocropho �I
,,
in degrees from oouu
SE • standard errar
� 38.0
C'_86 'C
OJ-
�
-0
�
E
----- r
� 37.5
"1
\I
V
36.5
.p. -109° CI of .p , -100° 10 -liS'
I
I
I
I rp. -199·---:iI-----?!CI of <p , -190° 10 -20eo
I
I
I
I
I
CI' of> ±(SE"IC x 112.31)' 95 'Y. confidence inlerval
I
I
Ugh1ing
u ! ��====�"IIII��I1"��===:'::====�
Regime'!.:
1 8 00 0000
°° 00 1 800 2400
Clock ho r (GMT): 06 12
-Degrees
1 from 00° 0 bI - 96 I
- 1 8I 0 -270
I
-360
from mid-L: ° -90 - 180 -270 -360
FIG. 1. Imp utatio n of level, amp il tude, and acr op hase by a least- sq uar es fit as a first
step in the cosinor p rocedur e; such imp utations ar e inter mediate comp utations rather
than being endp oi ntsi n themselves (42) . Note in any event two of theseveral k inds of
acr op hases, computative and external (d. Table II). (Internal acrophase not shown. )
the cosinor (1, 42; cf also 63); in terms of a phase not weighted by the ampli
tude (43) under certain conditions only (42, 43) ; or in terms of a rhythm
adjusted level. Table III indicates how some of these procedures yielding
distinct displays are related in terms of computational procedure.
The biologic temporal component isolated from noise, evaluated by such
microscopic rhythmometry as a mathematical function fitting the data, is
the quantified rhythm.
It is realized that the meaning of the terms "microscopic" and "macro-
CHRONOBIOLOGY 681
TABLE III
CLASSICAL "MACROSCOPIC" "MICROSCOPIC"

COMPLEMENTED BY
BIOMETRY Of RHYTHMS RHYTHMOMETRY
Key:
•••••• "MACROSCOPIC" BIOMETRY
__ "MICROSCOPIC" RHYTHMOMETRY
.............. RtLAlEO PROCEDURES
Th is table ig nores th e pr oblems ass ociated with data collecti on, editing and
fi lteri ng----p
-s ec ialized tasks th at aregr eatly facili tated by elect ronic comp uter meth ods
(cf . e.g ., 42, 43, 47-50, 53-5 7, 59-64).
scopic" is changed when they are used to denote methods for the resolution
of rhythms. The term macroscopic then refers to findings from classical
biometry displayed in the time domain only. By contrast, the word "micro
scopic" used in the context of certain techniques for rhythmometry indi
cates the higher level of r esolution of rhythms by such methods, i.e., their
"isol ation" f rom nois e, and th e f easibi lity of es tim atin g th e p ar am et ers of
each "isolated" rhythm.
E lectroni c comp uters s erve for pr ep ari ng mos t rapi dly and effi ciently th e macr o
s copic disp lay of rhy th ms as well as for th e is ol ation of a rh yth m and for th e su bs e
qu ent esti mati on of it s par amet ers. Rh yth mometry th us depends r ath er h eavi ly y et
682 HALBERG
not critically upon electronic computers. For certain limited rhythmometric purposes,
mechanical or optical analyzers may be used in conjunction with a desk calculator, in
lieu of an electronic computer. In any event, and in contrast to a microscopic analysis
of tissues, a "microscopic" analysis of time series, like the study of so-called micro
scopic aspects of physics, does not necessarily depend upon the use of a microscope.
Transient misunderstandings arising from the use of terms such as microscopic
seem to be a lesser disadvantage than the probable confusion that can be a nti cipated
from the coining of completely new words. Understanding of words such as microscop
ic, when used in the context of rhythmometry elsewhere, may be facilitated by plac
ing them under quotation marks at the outset.
In contrast to widespread practice, reference to terms such as clocks, oscillators, or
other physical analogies or models will be avoided so far as possible, notably in defm
ing the endpoints of biologic rhythms. Analogies, e.g., to light microscopy, can indi
cate the level of resolution achieved by certain approaches; they must not bias the ob
jectivity of the measurements and the interpretation of what has been measured. Con
sequently, reference will be made to those measurable aspects of a rhythm that can be
a pproximated by a mathematical function--e.g., in Figure 1. The endpoints of rhythms
are to represent objective, numerical, and inferential-statistical aspects of physiologic
variables.
UNITS OF RHVTHMOMETRV
In the service of medicine, it is particularly worthwhile to attempt to

quantify objectively a statistical and microscopic chronobiology, by analogy
to statistical and microscopic physics. As such ambitious aims may be
realized, the new definitions of the endpoints of a rhythm lead to new u nits
such as the acrophase in Table I I . When the endpoints and units are mean
ingfully defined, one can more readily satisfy the condition that certain char
acteristics of a bioperiodicity under study be invariably expressed numeri
cally and that such numbers be comparable from case to case and biologically
meaningful as well.
I n the microscopic approach',
statistical procedure can be made available i n the form of a given electronic
computer program or set of routines, after ascertaining the predictive value
of the results obtained with the program in various biomedical test situations.
For this purpose, the selection of reference standards for endpoints of
rhythms, like the selection of the analytical procedure, must be standardized.
To the extent that pertinent international agreements can be made on a
broader basis toward such steps of standardization, the results on endpoints
of rhythms obtained at different times and in different localities will be more
directly and more reliably comparable. Tables IV to XIII demonstrate
halting first steps in this direction. The aerophases of certain circadian rhythms
summarized objectively in these tables agree remarkably well in studies on
healthy subjects carried out by different investigators and methods many
years and time zones apart. These acrophases thus may serve as reference
standards for possible chronopathology such as that reported for certai n
emotional disorders (95, 274-277) or cancer (285).
Tables IV to XIII serv e as illustrative examples of endpoints fr om
TABLE IV
CIRCADIAN RHYTHM OF HUMAN PLASMA 17-HYDROXYCORTICOSTEROlD IN SAMPLES OF

TIME SERIES FROM DIFFERENT GEOGRAPHIC LOCATIONS (d. 105)
Circadian
Noise-to- P
N of subjects* Level, Co
signal or Rhythm amplitude C acrophase cI> or q, t Author(s), Year, Ref.
[M, h ] Co±SE'
(SE"/C) detection
(.95 confidence limits)
n
:I:
11 [3-6] 9.7±1.0 <.04 2.6( .2to5.0) -1240(- 34 to -181H Bliss et al. 1953 (91) �
0
12 [1-12] 10.7±1.2 <.001 5.1 (2.7to7.5) - 99° (- 37 to -137) Migeon et al. 1956(92) Z
13 [3] 13.5± .9 .005 4.1(2.3to6.0) -1000(- 63 to -137) Halberg et al. 1961 (93) 0
I:l:I
8 [3] 7.4± .9 <.002 5.3(2.7to7.9) -113°(- 61 to -151) Doe 1966(94) -
0
10 [8] 9.8± .8 <.002 4.6(2.3to6.9) - 71° (- 41 to -111) Curtis et al. 1966 (95) t""'
10.4± .7 7.2(3.6to 10.8) 0
7 [5,10] <.003 -105° (- 81 to -126) t McClure 1966(96) C)
21 [4,6] 14.5±1.6 <.001 6.2(5.2to7.3) - 89° (- 72 to -107) Krieger et al. 1966 (97) -<
13 [4,8J 20.6± .6 <.001 2.0(1.0to3.1) -103°(- 64 to -144) Bridges et al. 1966(98)
7 [4] 11.9± .9 <.005 4.9(2.7to7.1) -1120(- 83 to -169) Knapp et al. 1967 (99)
26 [2-8 J 10.0±1.5 .61t 3.4 -124°t Linquette et al. 1967 (100)
5 [3-8 J 12.2±1.2 .168 8.7(5.8to11.5) - 76° (- 57to - 95) Cade et al. 1967 (101)
8 [3] 8.6± .9 <.05 2.1(.04to4.2) - 920(-312 to -120) God
r on
* Total span of study 24 h for all subjects. Co and C in ",g/100 m!.
t T= 24 h= 360°; 1 h = 1 5°. cI> reference middle of habitual sleep span; <I> reference = local midnight. Acrophases with latter reference
=
indicated with (t) sign.

t Decimals shown as subscripts indicate doubtful significance.
0-
oo
C;J
684 HALBERG
TABLE V
CIRCADIAN RHYTHM OF HUMAN 17-HYDROXYCORTICOSTEROID EXCRETION IN SAMPLES
OF TIME SERIES FROM DIFFERENT GEOGRAPHIC LOCATIONS (ce. 105)
Circadian
N of subjects
Site of study (N of da ys) amplitude C (mg/hr) acrophase <1>* Author(s), Ref.
USA
(Minnesota) 4(5) .15(.04to .26) -129°(- 83to -200) Halberg & Haus (unpubl.)
(Minnesota) 8(1) .12(.06to .17) -153°(-128to -177) Doe (94)
(Maryland) 7(2) .11 (.06 to .16) -154°(-123 to -1 81) Bartter et aI. (103)
(Pennsylvania) 9 (1) .09(.0410 .14) -144° (-104 to -183) Curtis et aI. (95)
(Minnesota) 1(34) .17(.13 to .20) -130°(-I17to -144) Haus & Hal ber g (104)
Mexico 1(20) .05(.04to .06) -159°(-145 to -173) Pelia (105)

1(12) .03(.01to .05) -133° (-103 to -163)
1( 8) .10(.08to .12) -112°(- 77to -130)
1( 9) .09(.07to .11) -110°(- 87to -132)
1(12) .07 (.05 to .09) -118°(-109to -139)
1 ( 6) .04(.0210.06) -115°(-105 to -142)
Sout h Dutch Guiana 10(2) .08(.05to .11) -169°(-14310 -192) Halberg & Simpson(106)
10(2) .11(.07 to .15) -164°(-13410 -202)
Scotland 10(2) .18(.06to .23) -165°(-152to -175) Halberg & Simpson (106)
10 (2) .19(.11 to .28) -157° (-1 33 to -182)
France 12(1) .07(.05 to .09) -138° (-121 to -155) Reinberg(105)

6(2) .08 (.04 to .12) -146°(-115to -176) Reinberg ot aI. (107)
6 (2) .06(.01to .11) -135°(- 77to -191)
Germany 9 (2) .15 (.08 to .22) -143° (-127to -195) Hofmann, Halhuber et al.
9(2) .18(.07to .29) -142° (-121 to -178) (105)
Austria 10(3) .9( .lto 1.6) -166° (- 89 to -223) GUnther et aI. (108)
10(25) 3.6(2.4t04.7) -173° (-ISOto -194)
10(25) 3.7 (2.1t05.3) -188°(-165 to -206)
10(25) 4.5(2.8t06.2) -176°(-154to -195)
10(3) 2.8(1.3 to 4.4) -169° (-139to -196)
Italy 31 (1) .17(.15to.19) _134° (-12410 -1 43) Ceresa (109)
Thailand 13(1) .06(.02 to .10) -150°(-106to -194) Marotta & Linw o ng (110)
Australia 8 (1) .06(.03 to .09) -103°(- 85 to -133) Gordon et aI. (102)

(tetrahydro-F)
• T= 24 h =360°; 1 h = 15°.<I> r eference =middle of habitua l slee p span.
rhythmometry. The reader can consult the original references for information
on the kind of subjects providing the sampl es analyzed, their age, sex, genet
ic background, nutritional state, and other characteristics. Such details, as
well as references to the biophysical or biochemical methods employed and
to the standardization for data collection, also must be specified before such
endpoints can more generally be used.
TABLE VI
CiRCADIAN RHYTHM OF HUMAN POTASSIUM EXCRETION IN SAMPLES OF TIME
SERIES FROM DIFFERENT GEOGRAPHIC LOCATIONS (cf. 105)
Cir ca dia n
N ofs ub je cts N oise -to- P

Site ofst udy (N of days ) si gna l or Rhyt hm am plit ude ct a cr ophase <1>* Author(s ). Ref.
[t.t (SE"/C) dete cti on -------
(.95 c onfi de nce li mits )
US A
(Mi nnes ota ) 5(5) [4, 8] < .005 1 . 3 ( .7 t o 1 . 9) -161°(- 98t o -202) Ha ber
l g(105) (')
(Mi nnes ota ) 8 (1) [3] < .00 1 2 . 1 (1.4 t o 2 . 8 ) -157° (-130 t o -181) Doe (94) ::I:
i':l
(Ne w Y ork) 8(1) [4, 9] < .00 1 1.4( .9t o 1 . 9) -11 7°(- 95t o -1 7 1 ) Krie ger ( 1 1 1 ) 0
Z
0
Fra nce 1 (21) [2- 7] . 11 1 . 2 ( .9 to 1.4) -159°(-146 t o -172) Rei nber g(105) o:l
.....
4(1) [4] < .025 3 . 2 (1.4 t o 4 . 9) -15 1°(- 87 t o -189) Rei nber get a l. ( 1 12) 0
r-'
0
Ger ma ny 9(2) [3- 15] < .002 1 .0 ( .5t o 1 . 5) -149°(-125 to -215) Ha lhuber , H ofma nn,et �
9(2) [3- 1 5] < .02 1 .6 ( .4t o 2 .8 ) -156° (-1 26 t o -189) a l. (105)
Austra ila 10 (3) [1.5, 10] < .0 1 1 .6 ( .8t02. 3) -158°(-132t o -1 77) Gu nt her e tal.( 108)
10 (25) [1.5, 10] <.0 1 1 .8 (1.2 t o 2 . 4) -155°(-139 to -174)
10(25) [LS, to] < .0 1 1.5 (1.0 t o 2 . 1) -150° (-137 t o -1 74)
10 (25) [ 1.5,10] < .0 1 1 . 5{.8t02 . 2) -140°(-123 to -16 7)
10(3) [1.5, 10] < .0 1 1.3 ( .6t o 1 . 9) -150°(-1 1 7 to -18 7)
Austra ila 8(1) ["'3] < .00 1 2 .6 (1.6 t o 3 . 3) -123°(- 92t o -143) Gord on et a l.( 102)
.. T=24 h=3600; 1 h= 15° . <1>= mi ddle of habit ua l s el e p s pa n. 0\
t Am plitu de ex pressed i n me q/hr . 00

til
686 H ALB ERG
TABL E VII
CIRCADIAN RHYTHM OF HUMAN HEART RATE (BEATS/MIN)IN SAMPLES OF
TIME SERIES FROM DIFFERENT GEOGRAPHIC LOCATIONS (cf. 105)
Circadia n
N of subjects Noise-to- P
(N of days ) s ignal or Rhythm amplitude C acrophase <1>* Author(s). Ref.
(AI, hI (SEnIC) detection
Minnesota
I (516) [�8) .081 6.6 (5.4 to 7.7) -282° (-272 to -292) Halberg (105)
5 ( 5) [4,8) <.01 8.5 (3.1 to 13.8) -210° (-187 to -273) Halberg (105)
France
1 (21) [2-10) .lta 9. 3 (7.2 to 11.4) _219° (-203 to -236) Reinberg (105)
Austria
10 (25) [1.5. 10) <.01 2.7 (1. 7 to 3.7) -206° (-160 to -236) GUntheretal.
10 (25) [1.5. 10) <.01 2.6 (1.1 t04.1) -228° (-198 to -263) (108)
10 (25) [1.5. 10) <.01 2. 5 ( .7 t04. 3) -225° (-195 to -291)
10 ( 3) [1.5. 10) <.05 3.9 (1.1 to 6.6) -196° (-169 to -277)
• T=24 h=360o; I h=15°. cI> reference=middle of habitual sleep span.
Moreover, most of the information summarized in Tables IV to XIII is

obtained transversely, i.e., in studies covering only one or a few periods of
the rhythm investigated. on groups of subjects. Because of this limitation in
length of time series, the average period of the rhythm is not estimated, be
yond stating at a certain level of statistical confidence that a rhythm with
the frequency fitted or with a frequency close to that fitted characterizes the
data (42). Thus, in several estimations of circadian acrophase and amplitude
there remains some uncertainty as to period, whether the period fitted is pre
cisely 24 hr in length (Tables IV-XIII) or is different from the exact 24-hr
length (some of the analyses summarized in Figure 6).
EN DPOINTS OF RHYTHMS-CRITERIA TO BE
MET AND PITFALLS TO BE AVOIDED
Let us assume, first, that observations covering many cycles of a rhythm

under study are available longitudinally on each of a number of individuals.
\Ve may assume, next, that in such series certain physiologic rhythms exhibit
changes from one cycle to the next-changes that cannot readily be assessed
by inspection of data plotted as a function of time, i.e., in a chronogram.
Since in such plots of data along the 24-hr scale, one may not consistently
find any rhythm markers comparable, say, to the P, Q, or T of an electro
cardiogram, reproducible features of certain waveforms in the chronogram
can be described more meaningfully by endpoints derived from certain (ordi
nary and/or generalized) harmonic analyses complemented by inferential
statistical methods.
C H RO N O BIO LO GY 687
TABLE VIII
CIRCADIAN RHYTHM IN TIME ESTIMATION (COUNT FROM 1 TO 120) IN SAMPLES
OF TIME SERIES FROM DIFFERENT GEOGRAPHIC LOCATIONS (d. 105)
Circadian
N of subjects Noise�to� P
Author(s)
(N of days) signal or Rhythm amplitude C acrophase $*
Ref.
[dt,h] (SE"IC) detection
Minnesota
1 (516) [�81 .19. 2.7 (1.7 to 3.7) - 2° ( -341to -24) Halberg (lOS)
5 (5) [4, s] <.001 5.2 (4.7 to 5.S) - 7° (-344 to -98) Halberg (lOS)
Austria
( .8 to 6.4) -18° (-355 to -64)
10 (25) [1.5, 10] <.01 3.6 Gunther et a!.

10 (25) [1.5, 10] <.01 4.5 (1. 7 to 7.2) -34° ( - 19 to -42) (108)
10 (25) [1.5, 101 <.01 5.3 (2.7 to 7.9) _20° (- 14 to -72)
• T = 24 h =360°, 1 h = 15°. $ reference =middle of habitual sleep span.
TABLE IX
CIRCADIAN RHYTHM IN 17-KETOSTEROID EXCRETION BY HEALTHY
ADULTS IN DIFFERENT GEOGRAPHIC LOCATIONS* (d. 277)
Circadian
N of subjects
C
Author(s)
Site of study (age range) amplitude acrophase<p
Ref.
[N of days ]
Males
USA (Minnesota) 1 (37)[34] .17 (.IHo .20) - 99° (- 78 to -126) Haus & Halberg (104)
USA (Minnesota) 4 (19-49)[10] .11 (.01 to .22) -133° (-355 to -171) Halberg & Haus (unpubl.)
Japan 3 (28-33)[I] .11 (.01 to .22) -107° (-354to -168) Sakai (113)
Denmar k 1 (44)[1) .08 (.05 to .11)· -131°(-110to -152) Halberg et aI. (1)
1 (52)[5] .05 (.02 to .07) -124° ( - 96 to -153)
USA (New York) 11 (20-43)[10] .07 (.0410.11) -124° ( - 91 to -158) Vestergaard & Leverett (114)
Thailand 13 (19-23) [1 ) .07 (.04 to .09) -108° (- 89 to -127) Marotta & Linwong (110)
Females
USA (Maryland) 7 (yg. adult)[2] .04 (.01 to .08) -136° (-123to -181) Bartter et aI. (103)
USA (New York) 11 (20-43) 10 [ ) .07 (.03 to .11) -124° (- 88 to -158) Vestergaard & Leverett l114)
* C in mg/hr; cf> in degrees, with 360°=24 hr. cf> reference = middle of habitual sleep span.
A microscopic alteration of the circadian acrophase in urinary 17�ketosteroid of depressed patients is recorded
(277; cf. 113); a possibly broader multivariable chronopathology of tbis illn ess deserves scrutiny (274-276,
287-290).
TABLE X
0\
CIRCADIAN RHYTHMS IN NONHUMAN PRIMATES, PRESUMABLY UNDER CONDITIONS OF SYNCHRONIZATION 00
WITH A. 24-HOUR SOCIAL (AND/ OR LIGHTING) ROUTINE 00
S pecit; s* . . Cir cadi an N oi. se - to-

PhYS1?loglC
Circ adi an
N of su bJe cts Leve l C s!7' Au thor(s )
Co ±SE
? ampli tu de C
N of days van able (SE ! C) or
.
Re f.
[At, h]
(.95 confide nce i nt. ) P val ue . confide nce ar c)
(95
Blood C ons ti tue nts

7 lvfm, 1 [3] P oly mor phonucle ars, 10± 1 3 (0 to 7) .687 - 13 2°+ Mi ge on e t al.
(1000/mm3 ) ( 1 16 )
Lymphocy te s 6± .5 2 (.6to3) .4 2. - 30 1°+
(1000/m m3 )
E osi nophi ls (/mm3 ) 374± 29 205 (12 1 t o 28 9) . 20. - 35 9° (- 338 to- 22)+
17- hy dr oxy cor ti- 35± 2 16 (10 to 22) .16s - 85° (-
coster oi ds :r:
(p g/ l00 ml) >-
lOlvfm, 1 [ 2, 4] 17 - hy dr oxy cor ti- 48± 3 6 9 (26 to 1 12) .005 - 17 7° -
( 1 73 to- 18 1)++ M as one t al . r-'
coster oi ds
(p g/ 100 ml)
(1 17) �
:;0
He ar t R ate 0
1 Cebus albifrons, He ar t r ate ( be ats 99± 1 29( 25 to 33 ) .0 73 -156° -1
( 48 to- 164)+ Winget e t al .
1 [.5] per min ) ( 118)
Tem per ature (oq
l Cebus albifrons, Dee pbody 37 . 7± .04 1 . 9 (1 .8 to 2 .0 ) .043 - 17 4°(- 16 9 to- 179)+ \\"ingetetal.
1 [.5] ( 1 18 )
llvfm,4[.25] Br ai n 38 . 7± . 16 1 . 5( 1. 4 to 1 .6 ) .023 - 2 1 1°(- 208 to- 2 13 )+ S tr oe be l
(1 19)
32lvf irus, 1 [6] Re ctal 38 . 1± .05 . 7 ( .6 to . 9) .09. - 226°(- 2 16 to- 237)+ H onjoe t al.
(120 )
2 Mm, lMcyano- Axi llary 38 .0± .04 .8 ( . 7 to .8 ) .00 1 - 197°(- 18 3 t o- 2 11)+ Sim ps on e t al .
molgus; 1 Papio (1 2 1 )
hamadryas; 1
Cercopithecus
p atas, 7 [ 2]
... M=lvfac aca, m=mulatta. '" re fere nce =mi ddle of dai ly dark s pan; '"re feren ce = l ocal mi dni gh t
CHRONOBIOLOGY 689
TABLE XI
CIRCADIAN RHYTHMS IN SUSCEPTIBILITY TO POTENTIALLY HARMFUL AGENTS*
Dilute Brown ( Ds) and Bagg-Albino (C) Mice
Circadi an
Inbred Agent tested, dosage
strain (endpoint recorded) amplitude C acrophase <p from
( % of mean) mid L -
Ouabain; .5 mg/. 2 cc/20 g

b.wt.; % mortality 6 2(57-6 7) -3 15° (-305 to -324)
Librium; 5 . 4 mg/20 g b.wt.;

survival time 19 ( 6 -24) -220°(- 184 to - 26 3)
Ds
White noise; 104 db; % with
convulsion 67 (31-103) -128° (- 98 to -159)
Dimethylbenzanthracene;
. 05 ml .5%; % w/tumor 24( 1 3- 35) - 56°(- 27to- 85)
Ouabain; .15mg/ . 2 cc;

% mortality 3 1(26-36 ) -283°(- 16 4 to- 302 )
E thanol; .8 cc 25%;
% mortality 41 (23-59) -107° ( - 80 to -134)
C
Methopyrapone; 325-400
mg/kg b.wt.; % mortality 23 (11-35) -1050 ( - 82 to -128)
Endotoxin; 1 00
p.g/ . 2 cc/20 g
b.wt.; % mortality 71 (4 7-95) - 37° (- 18 to - 57)
* Animals maintained on regularly alternating light/dark cycle [L(060L 1800)/D

(180L0600 )] (see reference 122).
In principle, all curves can be accounted for by harmonic analysis, and

the indications for this method at first seem universal. In practice, the
fewer the data points available on a variable and the more nonsinusoidal the
"shape" of a rhythm, the more difficult it is to describe this rhythm with the
fit of a few sines and cosines. A more or less sinusoidal form becomes an
essential requirement for a meaningful harmonic analysis whenever the
number of available data points is so restricted that only a single cosine
function can be fitted. In such instances, the dangers of uncritical curve
fitting indeed are great. To drive this point to the absurd, a single cosine
function fitted to a single cardiac cycle in an electrocardiographic tracing
would do no more than obscure the information On P, QRS, and T so -
690 HALBERG
TABLE XII
CIRCADIAN PARAMETER ESTIMATIONS ON VARIABLES

INFLUENCED BY CORTICOSTEROID
Circadian amplitude C* Circadian acrophase '"

Physiologic variable
Gross motor activity 65 (23 to 107) -160° (-123 to -198)

Liver phospholipid labeling 13 ( 9 to 17) -164° (-146 to -182)
Colonic temperature -161° (-125 to -196)
Depression of blood eosinophil count 98 (62 to 134) -181° (-160 to -202)
Depression of pinnal mitoses 44 (26 to 62) -201° (-179 to -223)

Liver glycogen 92 (89 to 111) -294° (-288 to -30G)
* C given as % of mean. '" from mid-L. Mice maintained on regularly alternating

light:dark cycle [L(0600-1800) : D(18M-0600)] T fitted=24 h=3600j 1 h=15° (see 65
and 123),
readily and usefully available when the original tracing in time is viewed by
the naked eye. Nonetheless, when such rather obvious pitfalls ar e kept in
mind, th e fitti ng of certain harmonic functions to longitudinal data can be
carried o u t in order t o procure reproducible endpoints o f circadian o r o ther
rhy thms, and in the process, o ther equally v exing and co mmon pitfalls
that stem fro m .the exclusively macroscopic v iewing of a chronogram may
be avoided. In any event, rhythm characteristics-whether e valuated
macroscopically or microscopically-must meet several requirements:
TABLE XIII
ACROPHASES OF 24-HOUR SYNCHRONIZED CIRCADIAN ADRENAL CYCLE
AND ITS NEUROENDOCRINE INTERACTIONS. MOUSE
Circadian acrophase (.95 confidence arc)

�* �
Physiologic variable
from mid-L from serum corticosterone '"
Serum corticosterone 66° (- 42 to - 89)

Adrenal corticosterone 79° (- 47 to -112)
Hypothalamic CRF ggo (_ 11 to -147)
Adrenal reactivity to ACTH -235° (-210 to -258) -169° ( - 144 to -192)
(in vitro)
Pituitary ACTH -339° (-319 to -359) + 87° (+ 107 to + 67)
* L(06°0-1800): D(18oo-06M); T fitted=24 hr=3600; 1 hr=15° (see 123-126, also

127-128).
CHRO NOBIOLOGY 691
1. The average period length T of the rhythm and/or its acrophase ¢
should be determined objectively. In this context, objectivity requires that:

(a) The method used for determining the Tor cP of an individual's rhythm
be applicable throughout an entire sampling span, whatever its length T,
when T»r.
(b) It be applicable to time series from any and all available subjects in a
sample.
(c) When a given procedure is applied to the same time series by different
investigators, their inferences as to a T or a cP be similar or preferably the
same.
2 . Endpoints other than Tor cP, such as the extent of rhythmic change-
i.e., the amplitude C and the level around which rhythmic changes recur
Co-should also be objectively evaluted, in keeping with (a) to (c) above.
3. All endpoints should be expressed in numerical form.
4. Statistical dispersion indices should be sought for each endpoint.

Even in longitudinal studies on a given individual, some approximation
of their statistical confidence limits should be given with numerical endpoints
such as the ¢ and the C or the T of a rhythm.
Given the test of the same hypotheses and other things being comparable,
work meeting the above four requirements promises to lead to a more com
plete and more reliable description of biologic phenomena than studies ig
noring these same methodologic desiderata. Furthermore, any biologic re
search aimed at interpreting the factors underlying a given physiologic
change will be particularly useful if it enables one to make reliably predictive
statements. From this pragmatic viewpoint, we are led to yet another
methodologic point:
5. Whenever possible, the results of any method of analysis should be
checked by additional sampling aimed at validating the predicted temporal
behavior of a r hyt hm.
For instance, if a T of 23.5 hr is detected for the circadian rhythm of a
given variable in one individual or group, whereas a T of 2 4 hr is found for the
same variable in another individual or group, and if the rhythms' phases in
the two individuals or groups also are known, a large difference in the
temporal placement along the 24-hr scale of the crests of the two rhythms
can be predicted to occur on certain days. The presence or absence of this
difference can be readily and economically checked by additional sampling
at a few appropriately chosen time points during single 24-hr spans, as wiJl
become apparent from the study of Figures 2 and 3 (29, 65, 66) .
Of course, similar considerations apply to differences in the circadian
period of two or more variables in the same organism. One variable may
exhibit a component wi th T == 24.5 hr, whereas another variable in the same
organism conceivably maintains a T 24 hr: accordingly, large deviations
=
fro m the usual phase relation of the circadian components of these two vari
ables can be anticipated at certain predictable times. Furthermore, such
alterations of internal timing may result in undesirable or even deleterious
692 H ALB ERG
Ph ase-drift of Desyn chronized Circadian Rhythm

in Body Temperature of Blinded Mature CBC mice
Compared wi th 24- h -synchrani�ed Circadian Rhythm
" "
of Sham-operated contrOls
TIME (days after surgery)
I 3 8 13 18 23 28 33 38 43 48-(19531
1963 1953
<>---<>
�--.
Group-mean �_f:��;��:;otion ---� �O'"-- &: ..

Rectol ·c 37
Temperature '-Bilateral Optic Enucleation
3 6��--L-��---L-L��__�
3 5 10 15, 20 25 I 5 10 15 20
May 1953 June
TIME (date)
FIG. 2. Reproducibility of circadian desynchronization following blinding in

studies on CBC mice and C mice done 10 years apart with different sampling tech
niques. A study on CBC's in 1953 is summarized by open circles connected with con
tinuous lines. Note that results on cp obtained in 1963 are within the 95 per cent con
fidence interval computed for results on q, obtained a decade earlier. The confidence
interval is referred to as confidence arc on the graph simply to indicate the particular
method used for computing it, i.e., the cosinor (42). Note also from the bottom of the
graph that average levels of body temperature (1953 data only are shown) are roughly
the same in both blinded animals and controls. Thus, rhythmometry detects a clear,
quantifiable, and reproducible alteration of rhythm after blinding, whereas the more
classical study of levels fails to detect an effect. In all studies, light daily from 0600 to
1800 alternated with darkness.
effects at certain predictable times. This possiblility of a p redictab ly re

curring chron opathol o gy then becomes amenable to testing at appropriate
times, i.e., when the largest deviation from the usual internal timing can be
anticipated from the very rhythmometry yielding the two initially considered
values OfT_ Rigorous data supporting this line of thought are as yet unavailable.
CHRONOBIOLOGY 693
9 %
5.0
).19%
I
I
I
:
b
c
l!!
e f
1.3
<5
FIG. 3. Time relations of circadian rhythms in liver glycogen, serum corticoster

one, and rectal temperature in C mice at 21 days after surgery. The "transient anti
phase" seen macroscopically from this plot was predicted on the basis of microscopic
results shown in Figure 2.
Condition l(a) stated above requires that there should be no "good" and "bad"
fractions of a time series, such that some can be interpreted and others cannot.
Rhythmometry must be applicable even to sections of a time series so noisy that in
vestigators rightly refrain from drawing inferences solely from the inspection of their
chronograms--otherwise the "microscopic" method can hardly prove its usefulness
in clinical or experimental medicine or in biology. One must not end up in the difficult
situation of suggesting to a patient that his record is "not good enough" for the time
694 HALBERG
being and that perhaps he should return at some other time when his record might
be amenable to evaluation. This status quo prevails in more than one contemporary
approach to rhythms ; it not only limits a priori any application of rhythmometry in
medicine but invalidates many an inference in biology as well.
Condition l (b) stated above attempts to ascertain that the results of longitudinal
group studies will be more nearly representative of a population investigated since
the data from all individuals sampled are required to be amenable to the same analy
ses. Unless this condition is met, one may again be embarrassed by having to advise
certain patients that they are not amenable to rhythm evaluation. By the same token,
the choice by a biologist of "good" animals over "bad" ones from a specified sample
impresses one as a most questionable endeavor. I ndeed, condition (a) above comes to
mind: what is to prevent the "good" one from turning "bad" ?
All of the above criteria of objectivity, although self-evident and minimal, are not
invariably met by some of the methods most widely used for studying rhythms. A
case in point is the so-called behavior day chart-a display familiar to child psy
chologists-where, for example, spans of sleep and wakefulness are displayed as

black and white areas along a 24-hr scale and strips from consecutive days are
mounted· one under another. One can then observe, for instance, onsets of sleep or
wakefulness on consecutive days and can readily see whether these recur at the same
times of day, or consistently somewhat earlier or later. For this purpose---rather than
for the objective quantification of the mUltiple endpoints of rhythms-such charts
often are satisfactory in themselves; many biologists, too, rely largely if not ex
clusively upon the interpretation of similar strip charts displaying 24-hr records of
motor activity mounted one below the other in the order in which they are obtained.
Historically such approaches have provided most interesting information and their
continued use for certain purposes of orientation can be recommended ; yet one must
not confuse the viewing of such a chart with a quantitative inferential statistical
study of rhythms, precisely because one may thus fail to meet even the minimal ob
jectivity criteria (a) to (c) stated above-quite apart from the circumstance that
quantitative information on certain parameters such as level or amplitude is almost
irretrievably lost.
Difficulties resulting from the interpretation of some charts can be illustrated by a
specific example. Two senior clinical investigators independently commented in
print on the same behavior day chart of an infant on self-demand feeding. In the
original report displaying the behavior day chart, problems of rhythmicity were a
side issue alluded to in small print. The original author noted that prior to the de
veloping rhythm's synchronization with the societal 24-hr cyclic routine, sleep and
wakefulness in this infant recurred with a period of 23 hr. Another author, finding
the graphic record and reproducing it, apparently did not read the small print, pre
sumably since he did not read the language of the original text ; he reports from viewing
the same behavior day chart that the period of the sleep-wakefulness rhythm in
" "
this infant was initially longer than 24 hr, rather than shorter.
Nothing is gained when the "interpretation" of a rhythm's period can drastically
differ from one investigator to the next. Rather, much harm wiII be done if similar
procedures should continue in exclusive or even primary use in studies on human
beings directed at clinical applications, among others. Let us assume that the two
clinical investigators alluded to above arrive at their discrepant interpretations in the
(as yet) hypothetical situation of studying a period alteration in disease with the
endeavor to correct it-rather than being concerned, as they were, with physiologic
aspects of the infant's development on a schedule of self-demand feeding. In the
CHRONOBIOLOGY 695
former situation, one clinical investigator might attempt to slow down a rhythm in
terpreted by him as being pathologically too fast. The other, on the basis of the same
evidence, would aim at speeding up the rhythm-interpreted by him as being too
slow. Such actions should justly be questioned: the field of chronobiology as well as
that of a fledgling chronopathology can gain only discredit from confusion that could
be avoided (for applicable methods see lower half of Table 2 in Ref. 39).
SINGLE FREQUENCY VERSUS SPECTRAL ApPROACHES

Rhythms can be studied at different levels of complexity, determined by
the number of (a) spectral components with distinct frequencies-one fre
quency one rhythm ; (b) physiologic variables investigated (58) ; and (c)
=
study conditions.
Single-frequency approaches.-
(a) One frequency--one physiologic variable-one condition. Surveys of
rhythms under one condition in field or laboratory abound but are mainly
macroscopic, except for some first halting microscopic steps on human data,
Tables IV-IX, on nonhuman primates, Table X, and on rodents, Tables
XI-XI II.
(b) One frequency-one physiologic variable-several conditions. This
approach, widely prac tic ed , has been a preferred one in limited studies on a
given rhythm ; thus one may focus upon a circadian rhythm, a circannual one,
or any other frequency in the given time series. In evaluating a single
rhythm under varying conditions, one may follow, for instance, the syn
chronization of the rhythm with a societal routine and its desynchronization
from that routine--as suggested for the case of a circadian rhythm in
Fi gu r es 2 (3, 66) and 4 (67) and for the case of a circaseptan rhythm in
Figure 5 (1).
(c) One frequency-several physiologic variables-one or several conditions.
An illustrative example at this level of complexity is a macroscopic map of
the time relations among circadian rhythms in body core temperature, blood
cortiocosterone and liver glycogen levels, Figure 3 (d. also corresponding
microscopic summary in 65) . Among very many others, macroscopic cir
cadian chronograms also are available for the rhythms in flashing, lumines
cence glow, cell division, and photosynthetic capacity in Gonyaulax polyedra
(d. Figure 1 in 68) . I n many cases the chronogram does not allow for a quan
tification of a rhythm, as may be seen from the chronograms of circaseptan
rhythms in Figure 5. Figure 6 (78-80) , in turn, explores microscopically
the phase relation of two circadian rhythms in (a) blinded mice (r 2 3 . 5 or
=
23.4 hr) as well as in sham-operated controls and in (b) human beings, each
isolated in a separate cave, and following their subsequent resynchronization
with a societal routine [d. Figure 4 (67) ].
The macroscopic phase relations of circadian rhythms during human
isolation in a bunker for spans of several weeks have been discussed by
Aschoff & Wever (69-77) . Series of observations covering 9 days of isolation
696 HALBERG
RESOLUTION OF CmCADIAN RHYTHMS IN UNEQUALLY SPACED NOISY DATA ON RECTAL TEMPERATURE
AND URINARY 17·HYDROXYCORTICOSTEROID EXCRETION OF A HEALTHY FEMALE SUBJECT
a) during isolation in a cave fOl' about 3 months, and
"
b) during synchronization with a 24-hr societal routine for another month .
CLIPPED
CH.RONOGRAMS
for
Macroscopic
Inspection
PERGRESS/VE
AMPLITUDE and
ACROPHASE
for
Prelim inary
Microscopic Evaluation
of above two series
o +-��-l--/.
�\,...QI
.
No Isolation Isololion No Isolalion
FIG. 4. Phase relations of circadian rhythms in the urinary excretion of 1 7-hy

droxycorticosteroids and in rectal temperature of a woman during isolation in a cave
and following resynchronization with a 24-hr cyclic societal routine. Clipped chrono
gram of the time series shown on top. (For clipping, values above or below the mean
±3 standard deviations were repeatedly equated to the nearer of these limits until
the result of this iterative procedure was no longer associated with a, change in mean
and standard deviation to the nearest four decimal places. Extreme values thus
"clipped" are indicated by a dot on top of the corresponding chronogram.)
A macroscopic inspection of these time plots is barely contributory; long-period
changes of some rcgularity---{;orresponding presumably to the menstrual cycle (79)
are apparent for rectal temperature in particular and changes with shorter periods
also are suggested by the record, yet it seems unjustified on the basis of inspection
alone even to attempt to ascribe a precise period to a circadian rhythm or to discuss
the phase relations of circadian components in the two time series.
By contrast, the display of acrophase in the bottom row-part of the microscopic
approach-indicates first that the rhythms of both functions changed their period
during isolation-only to be resynchronized with a 24-hr cyclic routine thereafter;
second, that the rectal temperature acrophase lagged behind that for 1 7-hydroxycor
ticosteroid excretion during isolation, as well as following resynchronization; and
third, that resynchronization of body temperature occurred considerably faster than
that of 1 7-hydroxycorticosteroid excretion. The latter finding may be related at least
in part to the circumstance that on the day of emergence from the ca . e the ", of rectal
" J ." .
CHRONOBIOLOGY 69 7
have been reported by Schaefer et al. (81 , 82) with special reference to the
respiratory subsystem.
When the results from different studies, each limited to a single rhythm,
i.e., to a single spectral component in one or several physiologic variables,
are viewed in toto, they reveal a broad spectrum of physiologic rhythms
extending from periods of a millisecond or so to periods measured in years.
Such a spectrum of rhythms (with different frequencies) for a number of
different variables was conceived and depicted by Golenhofen & Hilde
brandt (83, 84) and by Aschoff (85, d. 88-90) . Their abstract spectrum,
along with a reference to more recent work by Pye & Chance (86) , is dis
played at the top of Figure 7. Aschoff emphasizes two theoretical points :
1. that a broad spectrum of rhythms constitutes a physiologic entity, and

2. that-like rhythms with frequencies much higher than one cycle per day
circadian rhythms or rhythms with lower frequency also have endogenous

features. Two more important steps lead to the abstract scheme shown at
the bottom of Figure 7 and have already been docum ented (1) by concrete
spectral work involving the concomitant estimation of several rhythms
(with different frequencies) in the same time series. One step is a conceptual
one derived from concrete work, i.e., that distinct spectral regions character
ize not only different physiologic time series, as suggested earlier, but one
and the same variable as well. The second step was the actual concomitant
objective estimation of the several spectral components as endpoints
satisfying the criteria 1. to 5. on page 69 1 (d., e.g., Figure 8) (1).
Multi-frequency approaches.-
(a) Several frequencies-one physiologic variable--one condition. Variance
spectra have been used to assess concomitantly several rhythms with differ
ent frequencies-circadian to circannual-in rectal temperatures measured
on individuals synchronized with an institutional routine (49, 50, 53, 87) .
(b) Several frequencies-one physiologic variable--several conditions.
Least squares spectra, as well as variance spectra, have demonstrated con
comitantly circadian and circatrigintan (menstrual) (29, 53, 79) components
in body core temperature of healthy women subjected to a 24-hr cyclic social
temperature was nearer its usual temporal placement in relation to the synchronizer
than was the .p of 1 7-0HCS.
From the pergressive amplitude diagram-third row from top-it can be seen
that the amplitude, notably that of the rhythm in 1 7-0HCS excretion during isola
tion, showed no indication of damping, as a conditioned reflex phenomenon might be
expected to do. If there was a difference between the amplitude at the end of isola
tion and that upon resynchronization, this measure of the extent of circadian periodic
change in 1 7-0HCS excretion indicated a more marked rhythm at the end of isolation
than following resynchronization.
Adding confidence limits to each C and .p estimate makes such a preliminary eval
uation more defini!}ye ; these limits can now be routinely and automatically plotted
by fast computer-d,rected plotters.
o� +-��__�-,�__��-,��-,__��
JIl\ ..('IlI.UO\� ijCIOO
\'lltl;a\ ,gS'l/tl\
l'l\�;
Urine Volumes
oO'oO 'no.oo 'cu

f\J\,.QQ' VO\� t.I .Q'J'oO
\'if.>'l/tl\ \�I() t% lt"
Schedule of Self-administered Male Sex Hormone Treatments
310 274 ". 344 2.2
_ Actl....
� Inocliv.
FIG. 5. Human urinary 1 7-ketosteroid excretion chronogram in top row and per
gressive acrophase (cf» diagrams computed with half-year intervals for analysis in the
second row, and with I-year intervals in the third row. Substantial amounts of an
drogen were repeatedly self-administered by the subject at "A" and after "B" for the
last 3 years of study, but not before "A" (1). Note after "B" in the pergressive
acrophase diagrams the desynchronization of circaseptan rhythms in 1 7-KS, a
phenomenon not detected for urine volumes in the row next to the bottom.
CHRONOBIOLOGY 699
I NTERNAL TIMING OF R HYTHMS

I N RECTAL TEMPE RATURE AND ADRENOCORTICAL FUNCTION
IN SYNCHRONIZ E D AND DESYNCHRONIZED CIRCADIAN SYSTE MS
FIG. 6. Adrenocortical acrophase�auged by urinary 1 7-0HCS in human beings

(67) or by serum corticosterone in inbred C mice (65)-leads body core temperature
acrophase within "-'1/4 circadian period. Internal timing is similar in mice and man
in these cases: '" is comparable when the circadian periods are of 24-hr average length
in mice and men subjected to a 24-hr cyclic synchronizer effect and after the blinding
of the mouse (65, 66) or under conditions of human isolation in a cave (67, 78-80)
when the rhythms are desynchronized from the 24 hr day
- .
synchronization; alterations in period length of these two spectral compo

nents have been recorded in a woman in the absence of a societal synchroniza
tion, with the menstrual component shortening as the circadian one
lengthened during 3 months' isolation in a cave-on "self-demand" lighting
of low intensity (79).
Infradian spectral components have been recorded in disease and are
of par ticular chronopathologic interest when their p rominence in the spec
trum is associated with a marked reduction in the prominence of circadian
rhythms (49) .
700 HALBERG
u
;:;
-'
0
0
iii w
>- -,
:!: a>
0- ..:
EI>: �w
w e>
OL -, l
!!, z
0 0; ��
��
� ..: �.
"' ;!; "g
� �
::1
e»
W
"II
t IS
Z ::;;;
� I!!
-2
8�
::: '"
I- W
w e>
Z -'
", Z
��
OL e( �
z
0
'"
I;
� )5 Z
;q
ci :=;
,.
0
C
o: � '2
u
ffi -'
'"
e(
I>: :>
S 0-
I>: w
0
e:
U
W
« �. .:.
'2 0-
� I- '" '"
Z i<l !'1 �
�
iii u
� x ;:;
o e(
:i i5 � ,, o
lI; ::! :l;
� � -'
0
ffi -'
0
"I
0;
I- e( >-
W " :!:
� ;;
0-
�� o�
it ",
-, 0
e( '"
!5 -
0- ..
'b
::;;; 0 ci
.... 0- >-
u
1- ", Z
I-
I>:
:=;
W
!g
0
t!
W ....
i5 � ...
::;;; '" �-'
'"
0
....
FIG. 7. Changing concepts of the spectrum of rhythms (39, 52).
For human urinary 1 7-ketosteroid excretion, circadian, circaseptan

(about 7-day) , circavigintan (about 20-day) , circatrigintan (about 30-day) ,
and circannual (about a year) rhythms have been concomitantly demon
strated during spans with and without androgen administration , Figures
5 and 8 (1).
(c) Several frequencies-several physiologic variables-one or several condi
tions. Spectral components with several different frequencies were also
evaluated in the urine volume of the healthy man whose 1 7-ketosteroid
CHRONOBIOLOGY 70 1
1.100+
' 0.282
PERIOD ESTIMATES, AMPLITUDES AND STANDARD DEVIATIONS IN FOUR DOMAINS ANALYZE D

B Y WINDOWS O F LEAST SQUARES SPECTRA O F HUMAN 17- KETOSTEROID EXCRETION OVER
16 CALENDAR YEARS
KEY
Amplitude
One
Standard
Deviation
Number of
Determinations
Window of //" ,
(same for all non-circadian estimotes.)
period domain ,-'
FIG. 8. Reproducibility, from one data section to the next, of certain rhythms
with a .elatively low frequency in the urinary 17-ketosteroid excreted by a healthy
man. A ..ow in heavy print visualizes certain comparable estimates for the much more
prominent circadian rhythm of urinary 17-ketosteroid excretion (1). Such components
may contribute to the intermittency of certain diseases (25-26, 1 15, 1 76-187, 287-
290) believed to be more or less cyclic. Apart from medical problems, the circannual
component continues to be of particular interest to avian physiologists (85, 1 88-203),
among others (325, 330).
702 HALBERG
excretion rhythms are summarized in Figures 5 and 8 (1). This self-study by

a scientist spanned a decade and a half : the circannual rhythms of this
subject as well as components with higher frequency thus could be con
co m i tantl y examined. The circannual rhythm in 17-ketosteroid excretion
was prominent but apparently not synchronized with the calendar year,
whereas the circannual rhythm in urine volume was clearly i-year synchro
nized. When in this case of circannual rhythms the analyses suggest the
occurrence of different prominent periods in a give n spectral region for each
o f two variables, a comparison of the phase relations among these variables
at sli ghtl y d i ffere nt fr equ en cies is not meaningful. This same inference also
holds during the last 3 years of this study (1) when the non-7-day (6. 93-day)
circaseptan 1 7-KS component differed with statistical significance from the

7-day-synchronized circaseptan component of urine volume in the same sub
( 1) the prominent
ject. However, for the first 10 years of the same study

frequencies in these two physiologic variables were the same ; comparison of
their phase relations does then become of interest and reveals a phase
difference, demonstrated in Figure 9.
The student of circannual rhythms can record longitudinally but 60 to 70 individual
cycles in a lifetime; for the same number of cycles the student of circadian rhythms
requires "only" 2 months or so; students of high frequency rhythms, of course, ob
tain a very large number of cycles within a fraction of the span covered by a single
circannual or even circadian cycle. For this reason, perhaps, the multifrequency,
multivariable approach continues to be applied primarily in the high frequency do
main of rhythms (d. 279-283, for studies of interactions among rhythms in eNS
function and respiration) , where, of course, the total study duration requirements are
more modest. The multifrequency approach already can be extended to cover con
comitantly the domains of high and medial frequency ; thus circadian components of
the human electroencephalogram have been quantified (41 ) .
HUMAN RHYTHMS, LONG-DISTANCE TRANSMERIDIAN TRAVEL AND ODD

ENVIRONMENTS; PHASE-SHIFTS AND PHASE-DRIFTS
This problem area, notably that of post-travel adaptation, comprises a

number of related, yet distinct topics.
Relatively early, several authors report on rhythms during sea travel
( l 29- 1 3 1) .
Second, physiologic observations, or quite often i mpressions, from trans
m eri di an flights are numerous ( 1 32-1 52). Any effects of relatively sh o rt
distance transm eridian fligh ts i nvolving the crossing of no more than a single
time zone or tw o , al th o u gh p erti n e n t in the same connection, apparently
have been ignored as a field of study. Discussion continues on problems re
volving around the adaptation to a new schedule of living after a flight (333,
334) ; attention also has been paid to rhythms and physiologic performance
d uri ng flight (148) . In preparation for the trans meridian travel, an attempt
at preadaptation to the new routine of living anticipated upon arrival has
been recommended ( 140-142).
CHRONOBIOLOGY 703
Urine Volume
t--f
9·l ml
FIG. 9. Cosinor summary o f the circaseptan rhythms i n 1 7-ketosteroid excretion

and urine volume of a healthy man. Rhythms in both variables are synchronized with
societal 7·day routine during all of the time span analyzed (urine volume) or during
most of that span (17-ketosteroid) ; d. Figure 5 (1).
Third, reports abound on the phase shifting of rhythms in a fixed geo

graphic setting by the manipulation of environmental cycles such as the
regimen of light and darkness and/or the daily routine of activity and rest
( 1 5 3-160, 2 7 1-7 2 ; cf. 19) . Pittendrigh had suggested earlier that for many
species ( 1 64) the adaptation of a circadian rhythm to an altered synchronizer
schedule is faster following a synchronizer delay than after a synchronizer
advance. But for chaffinches kept in 12·hr light (250 lux) alternating with 1 2 ·
hr darkness (.5 lux) , Aschoff & Wever ( 1 65) found a faster adaptation when a
single span of light or darkness was shortened by 6 hr rather than lengthened
by the same amount. From a macroscopic study of chronograms, they con
clude that resynchronization following a lengthening by 6 hr of either the
light or the dark span lasts 4 to 5 days, whereas only half that time is
needed for resynchronization following an advance of rhythm by 90°,
Figure 10. The opposite behavior was found for rats (40 , 166) , Figure 1 1 ,
as well as for humans (40, 167) , Figure 1 2 , and even for monkeys ( 1 68)-fro m
the microscopic analysis of data in the classical study by Simpson & Gal-
704 HALBERG
PHASE SHIFTING OF ACTIVITY RHYTHM (A 'far)

in Fringilla coelebs L .
(From Aschoff a. Wever 1963) following different
kinds of manipulation of the lighting regimenfA 'fs}
=:�
-2 - 6 D (hours)
=!�
o n=9
+2
2 - 6 L (hours}
""' 0 . n=9
�
�
+2
� " " " 1 " , , ,.
'-
I.. 0 � � 72 96 120 hours
.J!. +6
<I +4
+2
o --1>i��
-2
:��
+2
-2
o ��i'"
o
1 1 /1 1/ 1 1 11 /1 1 1/ 1 1
� 96 1�� 192 hours
Time
FIG. 10. Rhythm adaptation in chaffinches following a change in synchronizing
regimen of alternating light (250 lux) and darkness (.5 lux). Macroscopic interpreta
tion of data : adaptation following advance of synchronizer faster than following de
lay (165).
braith ( 1 2 1 ) . This problem deserves further scrutiny under controlled con

ditions ; special attention should be paid to individual differences in various
aspects of circadian rhythm adaptation following changes in synchronizer
or adherence to unusual routines. Such studies pertain to work hygiene-
even to the performance of healthy subjects on odd routines-quite apart
from bearing upon adaptation following transmeridian flights. Since such
flights result in a shift of the synchronizer as well as in a geographic dis-
BY 90· ADVANCE
Phose Shifting
of 24 -h- synchronized Circadian Rhythm
in Intraperitoneal Temperatllre
of Female MSD Rots

BY 90· 1ill:!! OF LIGHTING REGIMEN

.
00-, -36(h I �......
N of rats c 8
I
I ()
I ::r:
:;0
I
. I
...:m·:..·..·_·....·_·..··..··..·.._·l·-
a:
'& IS" -270 '''- IS' o
I z
l!I" :c
I
I o
�
.!!
� � I I
�= Acrophcse = Cresl- Phose of
tx:I
b I Rhythm
� L
N�
�!
�
I
I
I
6(/)5= Cl'longe in Phose of Synchr onizer,
where SynChronizer = LD 12:12
(3
t
O
<.) I
"t 6(/)R= Cha nge in Phose of Rhythm
f
�
�
j � I
I
I
L i < 201= Incondescent l i gh t . -- 20
Inte rval for c n o l ysis = I day
LUI[ "
><
L .. 1� -1eO-j
�\.i 12" -180 .
! r!
.. r.... .. . ._......... ..__._. .._ .._ ... .._
" .. .. . .. ..
ABRUPT SYNCHRONIZER SHIFT
: I : GRADUAL SHIFT OF RHYTHM
11 �J}�.;:,
__ r�donee
Span of" 60R Acrophase Span of 6 0 R +
Relatively Shot! . '"ter�1 (from coslnor\ Relatively Long
06"� "9<>;1:
GMT (heta given) .6hrs .. locol time (CST)
I I I � j iI � I I I ;J; I I
...� .ole; 01.. "'�
• I 06" -90 "
).0 ,
, �
o cf! rl cJ'
�,... �}o..' !\'� �+ 0(\"" �,� �:,. t.t:"" f/I''fl ",•
• '0 (): 0
• • 0
,,,,V-
O IQ 0
,"
TIME (DATE) -..)
o
FIG. 1 1 . Rhythm adaptation in inbred female Minnesota Sprague-Dawley rats is faster following a delay of tTl
synchronizing lighting regimen than following an advance (40, 166).

PHASE S H I FTING OF CI RCADIAN R H YTHM IN O RA L
TEMPE RATURES O F 5 HEALTHY ADULT W H I TE MALES
E-W w-E
- 6 ¢S ';' t +6 ¢ S
f--- Minnesota. U.S.A. --- -Jo p o n - -Minnesota, u.S.A. -!
- Time (CST)
�
U.SA. Japan Time
Degrees 1 Hours Hours
t 0 600
I
, In terval for Analysis ,:: 5 days
, ,0
60s by single 26-h
span o f wake fulness
�
II\ aConfidenC� (from casinor J
AcropnOS91U/ orc
2.S5. unless otherwis@ indicated
"Anticipated"
..
" Postflight
-e. Meon ¢ a ·377D
w
(f)
«
I
(L
o
0:
(.)
«
z
« -270
o
« ::1:��6
�
Mean SE
· ·242' !:3°
(3 'I I
,I I
'I I
·1 I
II I
II
II I
II I
I I I
¢k� Acrophose :: Crest - Phase of Rhythm I I I
6 0s :: Change in Phose of Synchroni.zer, II I
6
wl1ere Syncl1ronizer =24-:h societal scheriIJle
¢R = Chonge in phase of Rhythm
tbS"0:&
Spanof - 6 ¢
SS_
Span
J§'J
of +L:::. � R
R
Relatively short Relatively long
*'----+---'oc---:>---:'t-
o� 0 ...�'" 0...� ....;,. �'\
-90
..0
••
0 0
·of)'O'& e
�.o� �)(J- 0�}.
0
..
\�" TIME ( D ATE )
FIG. 12. Rhythm adaptation following a flight from east to west, involving social
synchronizer delay, seems to be faster than that following a flight from west to east
involving synchronizer advance--despite the circumstance that rhythm advance is
associated with return to familiar home setting (40, 167).
placement, one should control each of these two factors, preferably on sepa
rate groups of subjects studied concomitantly.
Rhythms also continue to be studied in unusual environments, such as
the Arctic ( 1 6 1-162) , caves (29, 67, 78-80, 163, 1 7 1-173, d. 28) , or extra
terrestrial space ( 170) . The question remains open whether on unusual work
routines there is rhythm alteration and decrement in preformance. Holm-
CHRONOBIOLOGY 707
quest, Retiene & Lipscomb (169) studied male rats living on a regimen in
which light and dark were randomly presented over a span of 40 days.
Body weight, endocrine organ weight, adrenal function, and gross motor
activity were recorded. I n comparison with control animals living on a regu
lar LD regimen, the group rhythms in motor activity and adrenal steroid level
were apparently altered, but no effects of the random regimen on the animals'
health were noted.
No untoward effects had been reported earlier by Holmgren & Swensson
(335) who subjected rats to repeated i nversions of a 24-hr LD regimen at
intervals of 4 days over the course of 16 weeks (cf. 19, 284) .
Plasma corticosteroids in subjects on unusual schedules have been
macroscopically studied by Orth, Island & Liddle (204). In discussing their

results they i ndicate that a "single day (on an abnormal schedule) does not
disrupt the 1 7-0HCS (rhythm) for that day" and also that "several individ
uals on 19 and 33-hour sleep-wakefulness schedules appeared to exhibit
two 17-0HCS (cycles) per sleep-wake cycle" (204) , yet they conclude that
the pituitary-adrenal cycle is a function of the duration of the subject's
sleep-wakefulness cycle. This inference must be qualified, since the prom
inent rhythm in urinary 17-0HCS excretion and in certain other variables of
human subjects isolated in a cave for a span of 3 to 4 months continues to
exhibit a circadian frequency desynchronized from the 24-hr local time,
even though spectra of sleep-wakefulness data from the same subjects
exhibit frequencies lower than one cycle in 28 hr (29, 67, 78-80) . Further
more, microscopic studies (206) reveal prominent circadian components
with a period near 24 hr persisting in the urinary corticosteroid excretion of
subj ects living on a 2 1-hr day in the Arctic (161).
Such studies are the more interesting since it will be important to deter
mine the extent to which the societal 24-hr schedule should be altered in the
artificial environments of certain cities of the future---now actually on
drafting boards-in vehicles for extraterrestrial space, or in u nderwater
environments. In several such milieus, alterations of schedule may be
logistically desirable yet they also should be physiologically acceptable ;
one should ascertain whether prolonged life on non-24-hr routines might
lead to a detriment in performance or health, notably to deficits in resistance
to potentially noxious agents. It also has been suggested that certain acute
concomitants of phase shifting, such as insomnia, may be prevented if shift
workers would adopt a 25-hr day-the daily working span being prolonged
from 8 hr to 8 hr and 20 min in this case and the resting span accordingly to
16 hr and 40 min. With such a system, Eranko, who has studied shift work
problems with Kihlberg (205) , wished to achieve a schedule whereby work
for a given individual began 1 hr later each calendar day-day work thus
changing only gradually (rather than abruptly) into night work and vice
versa, with a full cycle being completed in 2S days. The i mplications of
rhythms are of obvious interest also to those involved in the global move
ment of personnel on various schedules (337, 338).
Intergroup - 6 in 1> 0 . 5 1 h± .03 5
-"'-
� �
X " 23.49 ± .033� Meon ± I S. f. - X · 13994 ± .01 4
! I 19") 1 50")
SHAM-
BILATERAL OP]!9 ENUCLEATION OPERATION
.- -.. Mode
Mo� Median
Meqion
--
Mean
I
I
I Mean
II II
o 4 I ,
"
I I
I I
" 3
I I
6 ,.,
z
I I
I I
I I
I I
I
I II
'-t , I I II
I
1 :1: :i
o
23.2 23.3 23.4 23.5 23.6 237 23.8 23.9 24.0 24, 1
"'(( Period ; hours 1
FIG. 13. Circadian period of rectal temperature in 14 blinded and 18 sham-operated

CBC mice (1953-Series), determined by least-square spectrum. "Circadian" denotes
periods of blinded and sham-operated animals (see Appendix A). Circadian synchro
nization requires objective validation of a period dispersion < ± .1 hr. Sham-operated
controls exhibit a 24-hr-synchroni.zed circadian rhythm. Period of blinded mice devi
ates from 24 ± .1 hr length-we are dealing with a presumably free-running circadian
rhythm desynchronized from 24-hr "solar" and 24.8-hr "lunar" day. In many cases
such a fine resolution is a priori not practicable inter alia because of insufficient length
of available time series. [Summary of data collected every 4 hr from mice kept in
light from 06°° to 18°0 alternating with darkness, originally described at the 4th Con
ference of the International Society for the Study of Biological Rhythms in Basle,
Switzerland, Sept. 18-19, 1953. Pergressive analyses in Figure 2. Amplitude-damping
of �3 1 % in blinded mice during observation span of 48 days-May-June 1963 (14).1
RHYTHMS IN EXPERIMENTAL ORGANISMS
Models of rhythms with various frequencies continue to attract interest

(219-246), partly as a follow-up of some older models (247-252). A number
of these papers, but by no means all of them, at least refer to biologic data,
and in a few instances a model in the form of an oscillating circuit (219) or an
oscillator (220) is actually formulated with reference to biologic data. At
the other extreme, purely mathematical and statistical papers also are avail
able (245). Winget et al., apart from con trib u ti n g a s eries of studies on deep
body temperature and heart rate among other rhythms of nonhu m an pri
mates and chickens (1 18, 253-255), also address themselves to the important
task of evaluating the waveform of a rhythm by " microscopic" procedures.
Stroebel ap pl i es vari a n ce s pe ct ra to t he s t udy of circad ia n rhythms i n
behavioral parameters of experi m en tal animals. H e studies features of
conditioned emotional responses as a function of circadian system phase (119)
and explores learning rates of rats in vario us circa dian system p hase s,
advocating a controlled biologic rhythm approach to psychiatric problems
(256) . Controlled stu dies on rhy th ms and behavior presented by Randall
APPENDIX A
TERMS FOR RHYTHMS IN A DO�AIN OF MEDIAL FREQUENCIES'

[Adjectives and by zero change nouns for the tentative designation of the frequency or period of certain biologic rhythms (d. 1)J
Derivations Pronunciation Physiologic spectral region

Term all
from Latin spoken accentb phonetic notation· description limitsd
Ultradian ultra, beyond ultradian ul tra' de �n Certain frequencies From 1 cycle/ l hr to

dies, day higher than 1 in 19.9 hr/l-
-anuS" circadian 21 horanf
(")
Circadian circa, about circadian sftr ka' de ;m From 1 cyc1e/20 hr to ::c
1 cycle in about 24 hr :::0
dies, day or 1 cycle in 1 in 27.9 hr/2D- o
Z
-anus precisely 24 hr 28 horan o
to
Infradian
(d. Fig. 13)
infra, below
dies, day
in/radian in fni' de �n Certain frequencies
lower than
From 1 cycle/1.166 d to
1 in 5.999 d/29 §
-anus circadian horan to 5 dian �
• As compared to 1 . the much higher frequencies exhibited, among others, by rhythms that are more specific for the nervous, circu
latory and respiratory system, e.g., by action potentials of brain or heart; or to 2. much lower frequencies, e.g., of menstrual and circ
annual cycles.
b Italicized syllable indicates spoken accent.
e Spoken accent is indicated by the symbol of the written accent (') placed at the end of the syllable intended to be the prominent
one. Separations indicate syllables. Phonetic notation is used according to Webster's New International Dictionary, Springheld, Mass .,
1961. Thus, one should pronounce "a" as in add; "fl." as in arm; /la" as in ace; /Ie" as in end ; "e" as in even ; "i" as in it; "u" a s in
up; "ii" as in fuse; ";)" as in silent. Limits of spectral regions are tentative and subject to revision.
d hr= hour or hours; d = day or days; yr = year or years.
e
Adjective-forming suffix. --l
o
f From hora, hour, and -anus. \0
710 HALBERG
(257-258) also stand out by virtue of the experimental approach employed.

In contrast to others publishing on "clocks" after experimental manipulation,
Randall & Littschwager (257) include control animals in their work ; they
explore circannual changes and higher frequencies by a combination of
Fourier analysis and analyses of variance (257) . The adrenal gland continue:s
to be studied by investigators of intrinsic aspects of rhythms (259, 260) , as
is the pineal gland (261-264, 273, 291, 304, 3 12) ; reports on extrinsic factors
continue to be contributed by Brown (265, 266). The synchronization of
biologic rhythms (267) and the role of automation in biologic rhythms (268)
are discussed by Soli berger. Menaker (278) reports on rhythm synchroniza
tion in the sparrow by extraretinal light perception.
The amenability to phase shifting of mitotic rhythms in the epithelium

of rodent skin (3) is confirmed by Alov (293) and extended to rhythms in the
epithelia of cornea, tongue, and esophagus (293) ; variations in mitotic

counts after thyroidectomy and adrenalectomy in the rat are given ap
parently without ascertaining the extent of adrenal insufficiency by deter
minations of corticosterone or by other means (cf. 294) .
C herkovich(295) subj ects three monkeys (Papio hamaeryas) to varia
tions in lighting regimen ranging from (a) illumination by day, over (b)
illumination by night and rest and darkness by day. (e) 6-hourly alternations
of light and darkness followed by (d) such 6-hr "days" and "nights" dis
placed along the 24-hr scale by 6 hr, to (e) continuous illumination for 24 hr,
(f) continuous darkness for 24 hr, "and so on". After 2 months of such
"systematic interference" with illu mination and feeding, all three monkeys
reportedly developed a neurosis with severely deranged conditioned reflex
activity and the appearance of somatic pathology, including coronary i n
sufficiency and micronecroses in the heart of one monkey.
Ulcer production in monkeys subjected to 12-hr cycles involving 6 hr
of forced activity alternating with 6 hr of rest is under continued study by
Brady (296, 297) ; his findings are extended to the rat by Rice (298) . The
chronopathology of gastric ulcers is a subject of experim ental (305) and
clinical interest (306) , as remains the mapping of rhythms in a variety of <,
variables (299-304, 322-332, 340, 341) including the so-called hours of
changing resistance (33, 107, 307-3 10, 313) . Suggestions on statistical design
and analysis also are available (42, 43, 47, 48, 52, 61-63, 3 1 1 , 314, 3 1 5) .
The time relation between the development o f rhythmicity o n the one
hand and its synchronization with environmental factors on the other hand
is a topic of continuing interest (316-318), as are problems more generally
related to the development of circadian rhythms (3 16-321). In a moth

Pectinophora gossypiella, rhyth micity of a population is elegantly induced by
Minis & Pittendrigh with a single stimulus, the manipulation of environ
mental temperature or lighting (316). Conceivably the time at which a
circadian rhythm can be induced in the moth may be " microscopically"
found to precede by a few hours if not by a day the time at which the
rhythms can be coupled to environmental stimuli, unless, as is equally
CHRONOBIOLOGY 711
possible, there be an important difference in this connection between the
moth and human beings. For several human infants fed on self-demand, the
occurrcnce of a desynchronized circadian period for considerable spans of
time-weeks or months-prior to the actual societal synchronization of the
circadian system has been macroscopically ascertained (3 17, 318).
CONCLUSION
In an attempt to determine whether a given value is "normal" or "ab

normal", clinicians as well as biologists customarily study many rhythmic
variables on the basis of single samples-without qualifying such values in
terms of the phases of the various rhythms contributing to the variable
sampled, even though it has been pointed out that a single datum can
meaningfully be qualified as to circadian system phase if the conditions of

study are standardized (269) . This review indicates that from relatively few
samples-some of variables extensively utilized by biologists and cIinicians

reasonably reliable new and potentially useful endpoints of rhythms can be
obtained by rhythmometry.
This "chronobiologic" endeavor to acquire new endpoints from the study
of rhythms as yet relates to investigative biology and medicine rather than
to clinical practice.
It is pertinent that, as shown in the Tables included with this review :
(a) the acrophases (crest-phases) of certain circadian rhythms in blood, in
urine, and i n systemic functions of healthy human beings, as well as i n cer
tain experimental animals, can be objectively and readily determined by
electronic computation-as will be the rhythm-adjusted level, the amplitude,
and the waveform of a rhythm-and that (b) these acrophases agree re
markably well in studies carried out by different investigators working
many years and miles apart with differing biophysical, biochemical, or
behavioral methodology, under dissimilar standardization of the conditions
chosen for observation and of the kind and extent of sampling. Such agree
ment among endpoints allows me to conclude this review with the suggestion
that the time is ripe for the planning, at the international level, of conditions
and techniques that may be adopted generally for obtaining standardized
time series on rhythmic variables and for checking these out in different
laboratories around the world, with a view toward a subsequent, broader
scale study of rhythm modifications in biology and medicine (lOS.)
In concluding his review of a related problem-annual reproductive
cycles-A. C. Giese in 1959 wrote that "a tremendous amount (of work) is
still undone which can provide a lifetime of problems for those who are
challenged by them" (270) . I n 1968 there still remains a lifetime of work for
students of rhythmometry ; they face the challenges of obtaining new biologic
characteristics from the study of rhythms and of applying these endpoints
toward an understanding of underlying factors, in different forms of life (339) .
712 HALBERG
LITERATURE CITED
1 . Halberg, F., Engeli, M., Hamburger, 15. Biologische Rhythme1t, Nachr. A kad.
C., Hillman, D. Spectral resolution Wiss. Giittingen (Birukow, G.,
of low-frequency, small-amplitude Rensing, L., Eds., Vandenhoeck &:
rhythms in excreted ketosteroid; Ruprecht, Gilttingen, 1967)
probable androgen-induced circa 16. Photoperiodism and Related Phenom
septan desynchronization. A cta En ena in Plants and A nimals
docrinol. Suppl. 103, 54 pp. (1965) (Withrow, R. B., Ed., Pub!. #5.5
2. Halberg, F. Resolving power of elec AAAS, Washington, D. C., 903
tronic computers in chronopathol pp., 1959)
ogy-an analogy to microscopy. 1 7 . Reinberg, A., Ghata, J. Biologica.l
Scientia, 101, 412-19 (1966) Rhythms (Walker, New York, 1 3 8
3. Halberg, F. Physiologic 24-hour pe pp., 1964)
riodicity ; general and procedural 18. BUnning, E. The Physiological Clock
considerations with reference to the (Springer-Verlag, Berlin, 145 pp.,

adrenal cycle. Z. Vitamin- Hormon 1964)
Fermentforsch., 10, 225-96 (1959) 19. Menzel, W. Menschliche Tag-Nacht
4. Circadian Clocks, Proc. Feldafing Rhythmik und Schichtarbeit (Benno

Summer School (Aschoff, J., Ed., Schwabe, Basel/Stuttgart, 189 pp.,
North-Holland, Amsterdam, 479 1962)
pp., 1965) 20. Soliberger, A. Biological Rhythm Re
5. Biological Clocks, Cold Spring Harbor search (Elsevier, New York, 461
Symp. Quant. Bioi. (Long Island pp., 1965)
BioI. Assoc., New York, 524 pp., 2 1 . Cloudsley-Thompson, J. L. Rhythmic
1960) A ctivity in A nimal Physiology and
6. Circadian Systems, Rept. 39th Ross Behavior (Academic Press, New
Conf. Pediat. Res. (Fomon, S. F., York, 236 pp .• 1961)
Ed.. Ross Labs. Columbus. Ohio, 22. Harker, J. E. The Physiology of
93 pp., 1961) Diurnal Rhythms (Cambridge Univ.
7 . Rhythmic Functions in the Living Sys Press, London, 1 14 pp., 1964)
tem, Ann. N. Y. A cad. Sci. (Woif, 23. Goodwin, B. C. Temporal Organiza
W., Ed., New York, 1326 pp., tion in Cells (Academic Press, New
1962) York, 163 pp., 1963)
8. Photo-Neuro-Endocrine Effects in Cir 24. Danilevskii. A. S. Photoperiodism and
cadian Systems, with Particular Seasonal Development of Insects
Reference to the Eye, Ann. N. Y. (Oliver & Boyd, Edinburgh, 283
A cad. Sci. (Hague, E. B., Ed., pp., 1965)
New York, 645 pp., 1964) 25. Richter, C. P. Biological Clocks in
9. Interdisciplinary Perspectives of Time, Medicine and Psychiatry (Thomas,
Ann. N. Y. A cad. Sci. (Fischer, Springfield, m., 1 09 pp., 1965)
R., Ed., New York, 9 1 5 pp., 1967) 26. Lunedei, A .• Cagnoni, M., Fantini, F.,
10. Symposium on Rhythms, in Verhandl. Tarquini, B., Morace, G., Maiello,
Deut. Ges. Inn. Med. 33rd Kongr., M., Panerai, A., Scarpelli, P. T.,
886-994, 1 1 1 6- 1 7 (Bergmann, Toccafondi, R. Sindromi Dien
MUnchen, 1967) cefaliche (Problemi in discussivne)
1 1 . Proe. 1st Intern. Symp. Biorhythms in (L. Pozzi, Roma, 413 pp., 1967)
Expel. CUn. Endocrinol., Florence, 27. Kleitman, N. Sleep and Wakefulness
May 30-31, 1 966. Rass. Neurol. (Univ. Chicago Press, Chicago,
Veget. 552 pp., 1965)
12. Symposium on Rhythms, in Proc. 4th 28. Mills, J. N. Human circadian rhythms.
Panam. Symp. Pharmacol. Therapy, Phys. Rev. , 46. 128-71 (1966)
Mexico City (Excerpta Med. 29. Halberg, F., Reinberg, A. Rythmes
Found., Amsterdam, 1968) (In circadiens et rythmes de basses
press) frequences en physiologie humaine.
13. La Photoregulation de la Reproduction J. Physiol. (Paris) , 59, 1 1 7-200
chez les Oiseaux et les Mammiferes, (1967)
Colloq. Intern. CNRS, Montpellier, 30. Kayser, C., Heusner, A. A. Le rythme
1967 (Benoit, J., Assenmacher, I., nycthemeral de la dcpense d'ener
Eds., CNRS, Paris. in press) gie. Etude de physiologie comparee.
14. Biological Cycles and Psychiatry. 3...• J. Physio!. (Paris) , 59, 3-1 1 7
Symp. Bel-A ir (Dick, R., Ed.) (1967)
CHRONOBIOLOGY 713
31. Biological Rhythms. Environmental 44. Brazier, M. A. B., Casby, J. U. Cross
Biology, 565-607 (Altman, P. L., correlation and autocorrelation
Dittmer, D. S., Eds., Fed. Am. studies of EEG potentials. Elet
Soc. Exptl. Biol., Bethesda, Md., troenceph. Clin. Neurophysiol., 4.
694 pp., 1966) 201-11 (1952)
32. Bibliography on Time Series and 45. Brazier, M. A. B., Barlow, J. S. Some
Stochastic Processes (Wold , H., Ed., applications of correlation analysis
Oliver & Boyd, Edinburgh, 5 1 6 to clinical problems in electroen
pp., 1965) cephalography. Electroenceph. Clin.
33. Reinberg, A. The hours of changing Neurophysio/., 8, 325-31 (1956)
responsiveness or susceptibility. 46. Halberg, F. Temporal coordination of
Perspect. Bioi. Med., 11, 1 1 1 -2 6 physiologic function. Cold Spring
(1967) Harbar Symp. Q uant Bioi., 289-310
34. Malek, J., Gleich , J., Maly, V. C har (1960)
acteristics of the daily rhyth m of 47. Blackman, R. B., Tukey, J. W. The
Measurement of Power Spectra
menstruation and labor. Ann.

N.Y. Acad. Sci., 98, 1042-55 (1 962) (Dover, New York, 190 pp., 1958)
35. Kaiser, 1. H., Halberg, F. Circadian 48. M ercer, D.M.A. Analytical methods
aspects of birth. Ann. N. Y. A cad. for the study of periodical phe
Sci., 98, 1 056-68 (1962) nomena obscured by random fluc

36. Frey, S. Der Tod des Menschen in tuations. Cold Spring Harbor Symp.
seinen Beziehungen zu den Tages Quant. Bioi., 73-86 (1960)
und Jahreszeiten. Deut. Z. C hir., 49. Halberg, F., Panofsky, H. 1. Thermo
218, 366-69 (1929) variance spectra; method and clini
37. McFarland, R. A. Human Factors in cal illustrations. Exptl. Med. Surg.,
Air Transportation ; Occupational 19. 284-309 (1961)
Health and Safety (McGraw-Hill, 50. Panofsky, H., Halberg, F. II. Thermo
New York, 830 pp., 1953) variance spectra; simplified com
38. Hal ber g, F. Physiologic 24-hour putational example and other meth
rhythms: a determinant of response odology. Ibid., 323-38
to environmental agents. I n Man's 5 1 . Sato, K., et aI. On the physiological
Dependence on the Earthly A tmo significance of the average time
sphere, 48-89 (Schaefer, K. E., Ed. and frequency-patterns of the
Macmillan, New York, 1962) electroencephalogram. Electroen
39. Halberg, F., Kunkel, H. Ansatze zu ceph. CUn. Neurophysiol., 8, 325-3 1
einer "mi kros kop ischen" Rhyth (1956)
mometrie in der N eurologie. 52. Klinkel, H. Die Periodik der paroxys
Fortschr. Med. , 86, 85-90 ( 1 96 7 ) malen Dysrhythmie im Elektroen
40. Halberg, F., Nelson, W., Runge, W., zephalogramm (Habilitationsschrift,
Schmitt, 0., Pitts, G., Reynolds, Freie Univ. Berlin, 1966)
0., Tremor, J. Tests of circadian 53. Halberg, F., Stein, M., Diffley, M . ,
rhythm characteristics-design Panofsky, H., Adkins, G . Computer
evaluation by results on rodents techniques in the study of biologic
and men. SPace Sci. rhythms. Ann. N. Y. A cad. Sci.,
4 1 . Halberg, F. Rhythmic interactions of 1 15, 695-720 ( 1964)
steroidal and neural functions. In 54. Adey, W. R., Walter, D. O. Analysis
Hormonal Steroids, 966-79 (Mar of brain-wave generators as mul
tini, L. et al. Eds., Excerpta Med. tiple statistical time se ries. IEEE
Found., Amsterdam, 1967) Trans., BME-12, 8-13 (1965)
42. Halberg, F., Tong, Y. L., Johnson, 55. Walter, D . O., Adey, W. R. Spectral
E. A. Circadian system phase-an analysis of electroencephalograms
aspect of temporal morphology; recorded during learning in the cat,
procedures and illustrative ex before and after su bthal amic le
amples. In The Cellular A sp ects of sions . ExpU. Neural., 7. 481-501
Biorhythms, 20-48 (Maye rsbach , (1963)
H. v., Ed., Springer, Berlin, 198 56. Walter, D. O., Adey, W. R. Spectral
pp., 1967) analysis for electroencephalograms:
43. Batschelet, E. Statistical methods for mathematical determination of neu
the analysis of problems in animal rophysiological relationships from
orientation and certain biological records of limited duration. Ibid.,
rhythms (ArBS, Washington, D.C., 8, 1 5 5-81
1965) 57. Adey, W. R. , Walter, D. O. Applica-
714 HALBERG
tion of phase detection and averag schen bei volliger Isolation. U111-
ing techniques in computer analysis schau Wiss. Tech., 12, 378-83
of EEG records in the cat. Ibid., 7, (1966)
1 86--209 72. Aschoff, J. Human circadian rhythms
58. Halberg, F. Periodicity analysis-a in activity, body temperature and
potential tool for biometeorologists. other functions. Life Sci. Space Res.,
Intern. J. Biometeorol., 7, 167-91 5, 159-73 (Brown, A. H., Favor
(1963) ite, F. G., Eds., North-Holland,
59. Schuster, A. On the investigation of Amsterdam, 1967)
hidden periodicities with applica 73. Aschoff, J. Significance of circadian
tion to a supposed 26-day period of rhythms for space flight. In Bio
meteorological phenomena. Ter astronautics and the Exploration 0/
restr. Mag., 3, 13-41 1898) Space, 465-84 (Bedwell, T. C . , Jr.,
60. Koehler, F., Okano, F. K., Elveback, Strughold, H., Eds., San Antonio,
L. R., Halberg, F., Bittner, J. J. Texas, 1964)
Periodograms for the study of 74. Aschoff, J., Gerecke, U., Wever, R.
physiologic daily periodicity in Phasenbeziehungen zwischen den

mice and in man. Exptl. Med Surg., circadianen Perioden der AktiviUtt
14, 3-30 (1956) und der Kerntemperatur beim
61. Enright, J. T. Accurate geophysical Menschen. Pjlilgers Arch., 295,

rhythms and frequency analysis. 1 7 3-83 (1967)
In Circadian Clocks (See Ref. 4), 75. Aschoff, J. Die minimale Wltrme
31-42 durchgangszahl des Menschen am
62. Bliss, C. 1. Periodic regression in Tage und in der Nacht. Fjlilgers
biology and climatology. Conn. Arch., 295, 1 84-96 (1967)
A gr. Exptl. Sta. Bull. 615 (1958) 76. Aschoff, J. Exogenous and endogenous
63. Chapman, S., Bartels, J. Geomag components in circadian rhythms.
netism, 2 vols. (Clarendon, Oxford, Cold Spring Harbor Symp. Quant.
1049 p., 1940) Biol., 25, 1 1-27 ( 1960)
64. Kunkel, H. Moderne Analysen pe 77. Aschoff, J. Physiologie biologischer
riodischer Vorgltnge in der Neuro Rhythmen. A rztl. Praxis, 18, 1569-
logie. Deut. Med. J., 9, 320-27 93 (1966)
(1968) 78. Halberg, F., Siffre, M., Engeli, M . ,
65. Haus, E., Lakatua, D., Halberg, F. Hillman, D . , Reinberg, A. Etude
The internal timing of several en libre-cours des rythmes cir..
circadian rhythms in the blinded cadiens du pouls, de l'alternance
mouse. Expel. Med. Surg., 25. 7-45 veille-sommeil et de I'estimation
(1967) du temps pendant lea deux mois de
66. Halberg, F. Body temperature, cir sejour souterrain d'un homme
cadian rhythms and the eye. Col adulte jeune. Camp t. Rend. A cad.
loq. Intern CNRS, Montpellier, Sci., 260, 1259-62 (1965)
July 11-22, 1967 (In press) 79. Reinberg, A., Halberg, F., Ghata, J"
67. Ghata, J., Halberg, F., Reinberg, Sillre, M. Spectre thermique
A., SHIre, M. Rythmes circadiens (rythmes de Ja temp erature rectal e)
desynchronises ( 1 7 -hydroxycortico d'une femme adulte avant, pendant
steroYdes, temperature recta1e, veille et apres son isolement souterain de
sommeil) chez deux sujets adultes trois mois. Compo Rend. A cad.
sains. Ann. Endocrinol., 29, 269-70 Sci., 262, 782-85 (1966)
(1968) 80. Siffre, M., Reinberg, A., Halberg, F.,
68. Hastings, J. W., Keynan, A. Molecular Ghata, J., Perdriel, G., Slind, R.
aspects of circadian systems. In L'isolement souterrain prolonge.
Circadian Clocks (See Ref. 4), 167- Etude de deux sujets adultes sains
82 avant, pendant et apreS cet isole
69. Aschoff, J., Gerecke, D., Wever, R. ment. Presse Med., 74, 9 1 5-19
Desynchronization of human cir (1966)
cadian rhythms. Japan. J. Physiol., 8 1 . Schaefer, K. E., Dougherty, J. H.
17, 450-57 (1967) Variability of respiratory functions
70. Aschoff, J., Wever, R. Spontan based on circadian cycles. Rept.
periodik des Menschen bei Aus 486 NASA (Naval Submarine
schluss a1ler Zeitgeber. Naturwissen Base, New London, Conn., 1966)
schaften, 15, 337-42 (1962) 82. Schaefer, K. E., Clegg, B. R., Carey,
71. Aschoff, J. Tagesrhythmus des Men- C. R. Dougherty, J. H., Weybrew,
CHRONOBIOLOGY 715
B. B. Effect of isolation in a con related rhythms(Ph.D. thesis, Univ.
stant environment on periodicity of Minnesota, June 1966)
of physiological functions and per 95. Curtis, G. C., Fogel, M., Zarate, C.
'
formance levels. A erospace Med., The effect of sustained affect on
38, 1002-18 (1967) the diurnal rhythm of adrenal cor
83. Hildebrandt, G. Rhythmus und Re tical activity. Psychosoma.t. Med.,
gulation. Med. Welt, Nr. 2, 73-81 28, 696-713 (1966)
(1961) 96. McClure, D. J. The diurnal variation
84. Golenhofen, K., Hildebrandt, G. Die of plasma cortisol levels in depres
Beziehungen des Blutdruck sion. J. Psychosomat. Res., 10, 189-
rhythmus zu Atmung und peri 95 (1966)
pherer Durchblutung. Pflilgers 97. Krieger, D. T., Krieger, H. P. Cir
A rch., 267, 27-45 (1958) cadian variation of the plasma 1 7-
85. Aschoff, J. Jahresperiodik der Fort hydroxycorticosteroids in central
nervous system disease. J. CUn.
pflanzung bei Warmblutern. Stud.

Gen., 8, 742-76 (1955) Endocrinol. Metab., 26, 929-40
86. Pye, K., Chance, B. Sustained sinus (1966)
98. Bridges, P. K., Jones, M. T. The
oidal oscillations of reduced pyr.

idine nucleotide in a cell-free ex diurnal rhythm of plasma cortisol
tract of saccharomyces carlsber concentration in depression. Brit.
gensis. Proc. Nail. A cad. Sci., 55, J. Psychiat., 112, 1251-61 (1966)
888-94 (1966) 99. Knapp, M. S., Keane, P. M., Wright,
87. Halberg, F. Physiological rhythms. In
J. G. Circadian rhythm of plasma
I I-hydroxycorticosteroids in de
Physiological Problems in Space
Travel, 298-322 (Hardy, J. D., Ed.,
pressive illness, congestive heart
failure and Cushing's syndrome.
Thomas, Springfield, 111., 1964)
Brit. Med. J., 2, 27-30 (1967)
88. Aschoff, J. Adaptive cycles : their
100. Linquette, M., Fossati, P., Racadot,
significance for defining environ
A., Hubschman, B., Decoulx, M.
mental hazards. Intern. J. Bio
Les variations circadiennes de la
meterol., 1 1 , 255-78 (1967)
cortisolemie dans la maladie de
89. Aschoff, J. Circadian rhythms in
Cushing et les etats frontieres.
birds.In Proc. XIV Intern. Ornithol. Ann. Endocrinol., 29, 69-76 (1967)
Gongr., 81-105 (Snow, D. W., Ed.,
101. Cade, R., Shires, D. L., Barrow, M.,
Blackwell, Oxford, 1967)
Thomas, W. C. Jr. Abnormal
90. Aschoff, J., Saint Paul, U. v., Wever, duirnal variation of plasma cortisol
R. Circadiane Periodik von Fin in patients with renovascular hy
kenvogeln unter dem Einfluss pertension. J. CUn. Endocrinol.
eines selbstgewahlten Licht-Dunkel Metab., 27, 800-6 (1967)
Wechsels. Z. Vergleich. Physiol., 102. Gordon, R., Spinks, J., Dulmanis, A.,
58, 304-21 (1968) Hudson, B., Halberg, F., Bartter,
91. Bliss, E. L., Sandberg, A. A., Nelson, F. Phase relations of several circa
D. H., Eik-Nes, K. The normal dian rhythms in human plasma and
levels of 17 -hydroxycorticosteroids urine resolved by cosinor. GUn. Sci.
in the peripheral blood of man. J. (In press)
Glin. Invest., 32/3, 818-23 (1953) 103. Bartter, F., Delea, C. S., Halberg, F.
92. Migeon, C. J., Tyler, F. H., Mahoney, A map of blood and urinary
J. P., Florentin, A. A., Castle, H., changes related to circadian varia
Bliss, E., Samuels, L. T. The tions in adrenal cortical function in
diurnal variation of plasma levels normal subjects. Ann. N. Y. Acad.
and urinary excretion of 1 7-0HCS Sci., 98, 969-83 (1962)
in normal subjects, night workers 104. Haus, E., Halberg, F. Circadian
and blind subjects. J. GUn. En phase diagrams of oral temperature
docrinol., Iii, 622-33 (1956) and urinary functions in a healthy
93. Halberg, F., Frank, G., Harner, R., man studied "longitudinally". Acta
Matthews, J., Aaker, H., Graven. Endocrinol., 51, 2 1 5-23 (1966)
H., Melby, J. The adrenal cycle in 105. Halberg, F., Reinhardt, J. Bartter, F.,
men on different schedules of motor Delea, c., Gordon, R., Wolff, S.,
and mental activity. Experientia, Reinberg, A., Ghata, J., Hofmann,
17, 282 (1961) H., Halhuber, M., GUnther, R,
94. Doe, R P. A study of the circadian Knapp, E., Pena, J. C., Garcia
variation in adrenal function and Sainz, M. Agreement in endpoints
716 HALBERG
from circadian rhythmometry on L. T., Bowers, J. Z. Plasma 1 7-hy

healthy human beings living on droxycorticosteroid levels and leu
different continents. Experientia cocyte values in the Rhesus mon
(In press) key, including normal variation
106. Halberg, F., Simpson, H. Circadian and the effect of A CTH. Am. J.
acrophasea of human 1 7-hydroxy Physiol., 182, 462-68 (1955)
corticosteroid excretion referred to 1 1 7. M ason, J. W., Harwood, C. T,
midsleep rather than midnight. Rosenthal, N. R. Influence of some
Human Bioi., 39, 405-13 (1967) environmental factors on plasma
107. Reinberg, A., Zagula-Mally, Z. W., and urinary 1 7-hydroxycorticoster
Ghata, J., Halherg, F. Circadian oid levels in the Rhesus monkey.
rhythms in duration of salicylate Am. J. Physiol., 190, 429-33 (1957)
excretion referred to phase of ex 118. Winget, C. M., Card, D. H., Hether
cretory rhythms and routine. Proc. ington, N. W. Circadian oscilla
Soc. Exptl. Med. Bioi., 124, 826-32 tions of deep-body temperatu re and
(1967) heart rate in a primate (Cebus al

108. Gunther, R., Knapp, E., Halberg, F. bafrons) . A erospace }.fed., 39, 350-
Circadiane Rhythmometrie mittels 53 (1968)
elektronischer Rechner zur Beurtei 1 19. Stroebel , C. Behavioral aspects of

lung von Kurwirkungen. In Kurver circadian rhythms. In Comparative
laufs- una Kurerfolgsbeurteilung, Psychopathology, 1 58-72 (Zubin, ].,
106-1 1 (Teichmann, W., Ed., Hunt, H., Eds., Grune & Strattoll,
Sanitas-Verlag, Bad Worishofen, New York, 1967)
1968) 120. Honjo, S., Fujiwara, T., Takasaka, M,
109. Ceresa, F., Angeli, A., Gaidano, G. P., Suzuki, Y., Imaizumi, K. Observa
Boccuzzi, G., Molino, G. P., tions on the diurnal temperature
Perotti, L. Aspetti della regolazione variation of Cynomolgus monkeys
della secrezione corticotropa nell' (Macaca irus) and on the effect of
obesita. Atti XIIo Congr. Soc. changes in the routine lighting upon
Ital. Endocrinol. (1968) this variation. Japan. J. Mea. Sci.
1 10. Marotta, S. F., Linwong, M . Excre Bioi., 1 6, 189-98 (1963)
tion of urinary 1 7-ketosteroids and 1 2 1 . Simpson, S., Galbraith, J. J. Observa
1 7-ketogenic steroids. 1 . Effects of tions on the normal temperature of
age, time of day and season. the monkey and its diurnal varia
Chiengmai Mea. Bull., 5, 167-81 tion, and on the effect of changes in
(1966) the daily routine on this variation.
111. Krieger, D. T., Krieger, H. P. Cir Trans. Roy. Soc. Edinburgh, 45, 65-
cadian patterns of urinary elec 104 (1905�6)
trolyte excretion in central ner 1 2 2 . Halberg, F . Rhythms and the adrenal
vous system disease. Metabolism, cortex. Proc. 4th Panam. Symp.
16, 815-23 (1967) Pharmacol. Therapy, Mexico City
1 1 2. Reinberg, A., Ghata, J., Sidi, E. Noc (Excerpta Med. Found., Amster
turnal asthma attacks: their re dam, 1968)
lationship to the circadian adrenal 123. Halberg, F. Organisms as circadian
cycle. J. A llergy, 34, 323-30 ( 1 963 ) systems; temporal analysis of their
1 1 3. Sakai, M. Diurnal rhythm of 1 7- physiologic and pathologic re
ketosteroid and diurnal fluctuation sponses, including injury and death.
of depressive affect. Yokohama Med. In Medical A spects of StreSS in the
Bull., 1 1 , 352-67 (1960) Military Climate, 1-36 (Walter
1 14. Vestergaard, P., Leverett , R. Ex Reed Army Inst. Res., Washing
cretion of combined neutral uri ton, D. c., 1964)
nary 1 7-ketosteroids in short term 124. Ungar, F., Halberg, F. Circadian
collection periods. A study of spon rhythm in the in vitro response of
taneous variability. Acta Endo mouse adrenal to adrenocortico
erinol., 25, 45-53 (1957) tropic hormone. Science, 137, 1058-
1 1 5. Vestergaard, P., Leverett, R., Doug 60 (1962)
las, W. R. Spontaneous variability 125. Ungar, F., Halberg, F. In vitro dem
in the excretion of combined neutral onstration of circadian rhythm in
17 -ketosteroids in the urine of adrenocorticotropic activity of C
chro nic schizophrenic patients. Psy mouse hypophysis. Experientia, 19,
chiat. Res. Rept. 6, 74-89 (1956) 158-59 (1963)
1 1 6. Migeon, C. J., French, A. B., Samuels, 1 26. Haus, E., Halberg, F. Der circadiane
CHRONOBIOLOGY 717
AdrenalzykJus und seine Bedeutung variation in body temperature.
fiir die Reaktionsbereitschaft der Proc. Soc. Exptl. Bioi. Med., 1 15,
Nebennierenrinde. Wien. Z. Inn. 1 1 29-31 (1964)
Med., 8, 361-70 (1962) 140. Strughold, H. Physiological day-night
1 2 7 . Andrews, R. V., Folk, G. E. Circadian cycle in global flights. A viation
metabolic patterns in cultured Med., 23, 464-73 (1952)
hamster adrenal glands. Compo 141. Strughold, H. Day-night cycling in
Biochem. Physiol., 1 1, 393-409 atmospheric flight, space flight and
(1964) on other celestial bodies. Ann.
128. Andrews, R. V., Folk, G. E., Hedge, R. N. Y. A cad. Sci., 98, 1 109-15 (1962)
Metabolic periodicity in adrenal 142. StrughoId, H. Temporal coordination
glands cultured from Arctic rodents. of day-night cycle after intercon
Fed. Proc., 24, 508 (1965) tinental flight. Symp. Circadian
129. Gibsou, R. B. The effects of transposi Systems, Univ. Minnesota, June
tion of the daily routine on the 4-7, 1961
rhythm of temperature variation. 143. Thomas, Lowell. Keep an eye on your

Am. J. Med. Sci., 129, 1048-59 inner clock. Reader's Digest, 61-64
(1905) (August 1966)
130. Ogata, K., Sasaki, T. On the causes of 144. Report. "Aspects nouveaux du som
diurnal body temperature rhythm meil normal et pathologique (1).
in mall, with reference to observa Rappel de Ia physiologie du som
tions during voyage. Jap an. J. meil. Les rythmes nycthemeraux.
Physiol., 13, 84-96 (1963) Electroencephalogramme ct phases
1 3 1 . Ogata, K., Sasaki, T. Diurnal varia du sommeil. " A ctualite de la vie
tion in body temperature with medicale, Suppl. bi-mensuel Vie
special reference to observation Med. [presumably 1966]
made during a sea-voyage. Intern. 145. Juin, G. Les decalages horaires
J. Biometeorol., 7, 75-80 (1963) (leurs aspects et leurs consequences
132. Bugard, P., Henry, M . Quelques as dans I'aviation commerciale). A rch.
pects de la fatigue dans I'aviation Mal. Pro/., 24, 1 13-17 (1963)
de transport. Presse Med., 69, 146. Lavernhe, J. Rythme de vie et
1903-6 (1961) changements rapides de fuseaux
133. Burton, A. C. The clinical importance horaires au cours des voyages
of the physiology of temperature aeriens. Presse Med., 72, 2623-26
regulation. Can. Med. Assoc. J., (1964)
75, 7 1 5-20 (1956) 147. Juin, G. Une enquete sur la fatigue
134. Flink, E. B., Doe, R. P. Effect of a bord des "jets". Presse Med., 69,
sudden time displacement by air 1 104 (1 9 61 )
travel on synchronization of ad 148. Klein, K. E., Briiner, H., Ruff, S.
renal function. Proc. Soc. E%ptl. Untersuchungen zur Belastung des
Bioi. MerJ., 100, 498-501 (1959) Bordpersonals auf Fernfliigen mit
135. Gerritzen, F. The diurnal rhythm in DUsenmaschinen. Z. Flup;wiss., 14,
water, chloride, sodium and potas 109-21 (1966)
sium excretion during a rapid dis 149. Chemin, P. Les rythmes biologiques
placement from east to west and chez l'homme application d l'avia
vice versa. J. Aerospace Med. , 33, tion et d la cosmonautigue (These
697-701 (1962) Doctorat Med., Univ. Bordeaux,
136. Gullett, C. C . Jet planes and the 1967)
circadian cycle. J. Am. Med. A ssoc., 150. LaFontaine, E., Lavernhe, ]., Couril
197, 935 (1966) lon, J., Medvedeff, M . , Ghata, J.
137. Hauty, G. T., Adams, T. Phase shifts Influence of air travel east-west
of the human circadian system and vice-versa on circadian rhythms
and performance deficit during the of urinary elimination of potas
periods of transition: I. East-West sium and 1 7-hydroxycorticoster
flight. Aerospace Med., 37, 668-74 oids. A erospace Med., 38, 944-47
(1966) (1967)
138. Hauty, G. T., Adams, T. Phase shift 1 5 1 . Hauty, G. T., Adams, T. Phase
ing of the human circadian system. shifts of the human circadian sys
In Circadian Clocks (See Ref. 4), tem and performance deficit dur
413-25 ing the periods of transition: II.
139. Sasaki, T. Effect of rapid transposi West-East flight. Aerospace Med.,
tion around the earth on diurnal 37, 102 7-33 (1966)
718 HALBERG
152. Hauty, G. T., Adams, T. Phase shifts in daily rhythms. Proc. Natl. A cad.
of the human circadian system and Sci., 44, 965-73 (1958)
performance deficit during the 165. Aschoff, J., Wever, R. Resynchronisa
periods of transition : III. North tion der Tagesperiodik von Vogeln
South flight. Ibid., 1257-62 nach Phasensprung des Zeitgebers:.
153. Perkoff, G. T., Eik-Nes, K., Nugent, Z. Vergleich. Physiol., 46, 321-35
C. A., Fred, H. L., Nimer, R. A., (1963)
Rush, L. Samuels, L. T., Tyler, 166. Halberg, F., Nelson, W., Runge, W.,
F. H. Studies of the diurnal varia
Schmitt, O. H. Delay of circadian
tion of plasma 1 7-hydroxycorti rhythm in rat temperature by
costeroids in man. J. CUn. Endo phase-shift of lighting regimen is
crinol., 19, 432 (1959)
faster than advance. Fed. Proc.,
154. Sharp, G. W. G. Reversal of diurnal 26, 599 (1967)
leucocyte variations in man. J. 167. Haus, E., Halberg, F., Nelson, W.,
Endocrinol., 21, 107 (1960)
Hillman, D. Shifts and drifts in
155. Sharp, G. W. G., Slorach, S. A., phase of human circadian system

Vipond, J. Diurnal rhythms of following intercontinental flights
keto- and ketogenic steroid excre and in isolation. Fed. Proc., 27,
tio� and the adaptation of changes 224 (1968)

of the activity-sleep routine. J.
168. Halberg, F. Summarizing discussion. In
Endocrinol., 22, 377-85 (1961)
Symposium on Circadian Rhythms
156. Sharp, G. W. G. Reversal of diurnal
in Non-Human Primates (Rholes,
rhythms of water and electrolyte
F. H., Ed., Karger, Basel, 1969)
excretion in man. J. Endocrinol. ,
169. Holmquest, D. L., Retiene, K., Lips
21, 97 (1960)
comb, H. S. Circadian rhythms in
157. Yokobori, S., Miyasaka, T., Shiraishi,
rats : effects of random lighting.
A., Tanase, N., Nakagi, S., Tanaka,
Science, 152, 662-64 (1966)
M., Inoue, S., Naoi, F., Sakio, H.,
Okazaki, K. Fatigue and the 1 70. Dietlein, L. F., Vallbona, C. Experi
adrenal cortex. J. Ind. Med. ment M-4, injlight phonocardio
gram-measurements of the dura
(Tokyo), 2, 15-23 (1960)
tion oj the cardiac cycle and its phases
158. Yurugi, R., Totsuka, T., Naba, K.,
during the orbital jlight of Gemini IT,
Iizuka, M., Akiyama, T., Kimura,
K. Experimental studies on the ef 397-402 (Gemini Midprogram
fects of reverse day-night life cycle Conf., including Expt. Results,
upon the twenty-jour-hom' rhythm
NASA, Washington, D. C., 1966)
of living junctions (Aero- M ed.
171. Mills, J. N. Circadian rhythms during
Lab., March 1961) and after three months in solitude
159. Saito, H., Takamatsu, M� Experi underground. J. Physiol., 174, 2 1 7-
mentelle Studien uber die Beein 31 (1964)
flussung von Inversion der Zeit 172. Mills, J. N. Sleeping habits during
phasen von taglichen Arbeit, mit four months in solitude. Ibid., 189,
besonderen Berucksichtigung von 30-31 (1966)
rhythmischen Veranderungen der 1 73. Mills, J. N. Keeping in step--away
Blut and Hambeschaffenheiten from it all. New Scientist, 9, 350-51
wl1hrend Tag und Nacht. Rept. (1967)
Ins!. Sci. of Labour No. 477 (1953) 1 74. Clark. C. S., Kripke, D. F., Merritt,
160. Saito, H. Hours oj work, pauses for J. A., Physiological data processor·
rest, shift system (Inst. for Sci. of IEEE Conference Record, 5th Ann·
Labour, Tokyo, 285 pp., 1966) Rocky Mountain Bioeng. Symp.,
161. Simpson, H. W., Lobban, M. C. Ef May 6-8, 1967, 88-92
fect of a 2 1-hour day on the human 1 75. Cartwright, N., Kripke, D. F., Cook,
circadian excretory rhythms of 1 7- P. Statistical reduction of hand
hydroxycorticosteroids and elec staged sleep analysis. 6571st Aero
trolytes. A erospace Med., 38, 1205- med. Res. Lab. Rept. ARL-TR-68-5,
13 (1967) 44 pp. (June 1968)
162. Lobban, M. C. Daily rhythms of 1 76. Reimann, H, Periodic Diseases (F. A.
renal excretion in arctic-dwelling Davis, Philadelphia, 1963)
Indians and Eskimos. Quart. J. 177. Bryson, R. W., Martin, D. F. 1 7-
Exptl. Physiol., 52, 401-10 (1967) ketosteroid excretion in a case of
163. Siffre, M. Beyond Time (McGraw manic-depressive psychosis. Lancl1t,
Hill, New York, 228 pp., 1964) 2, 365-67 (1954)
164. Pittendrigh, C. S., Bruce, V. G., Kaus, 1 78. Rizzo, N. E., Fox, H. M., Laidlaw,
P. On the significance of transients J. c., Thorn, G. W. Concurrent
CHRONOBIOLOGY 7 19
observations of behavior changes trol of reproductive cycles in birds.
and of adrenocortical variations in a Am. Scientist, 52, 137-56 (1964)
cyclothymic patient during a period 192. Gwinner, E. Wirkung des Mond
of 12 months. Ann. Intemal Med. , lichtes auf die Nachtaktivitat von
41, 798-81 5 (1954) Zugvogeln. Lotsenversuch an Rot
179. Jenner, F. A., Gjessing, L. R., Cox, kehlchen (Erithacus rubecula) und
J. R., Davies-Jones, A., Hullin, Gartenrotschwanzen (Phoenicurus
R. P., H anna , S. M. A manic phoenicurus) . Experientia, 23, 227
d epressive psychotic with a per (1967)
sistent forty-eight hour cycle. 193. Gwinner, E. Circannuale Periodik der
Brit. J. Psychiat., 1 13, 895-9 10 Mauser und der Zugunruhe bei
(1967) einem Vogel. Naturwissenschaften,
180. Harding, G., Jeavons, P. M., Jenner, 54, 447 (1 9 67 )
F. A., Drummond, P., Sheridan, 194. Gwinner, E. Circannuale Periodik
M., Howells, G. W. The electro als Grundlage des jahreszeitlichen
encephalogram in three cases of Funktionswandels bei Zugvogeln.

periodic psychosis. Electroenceph. J. Ornithol., 109, 70-95 (196 8)
CUn. Neurophysiol., 2 1 , 59-66 195. Pengelley, E. T., Fischer, K. C. The
(1966) effect of temperature and photo

1 8 1 . Rey, J. H., Will cox, D. R. C., Gib period on the yearly hibernating
bons , J. L., Tait, H., Lewis, D. J. behavior of captive golden-mantled
Serial biochemical and endocrine ground squirrels (Citellus laleralis
investigations in recurrent mental tescorum). Can. J. Zool., 41, 1 103-
illness. J. Psyc/losomat. Res., 5, 20 (1963)
1 55-69 ( 1 9 6 1 ) 196. Pengell ey, E. T., Kelly, K. H. A
1 8 2 . Crammer, J. L. Water and sodium in "circannian" rhythm in hibernat
two psychotics. Lancel, 1 1 22-26 ing species of the genus Citellus
(30 May 1959) with observations on their phys.
183. Crammer, J. L. Rapid weight-changes iological evolution. Camp. Biochem.
in mental patients. Lancet, 259-62 Physiol., 19, 603-17 (1966)
(10 Aug. 1957) 197. Lofts, B. Evidence of an autonomous
184. Gjessing, R., Gjessing, L. Some main reproductive rhythm in an equator
trends in the clinical aspects of ial bird (Quelea quelea) . Nature,
periodic catatonia. A cta Psychol. 201, 523-24 (1964)
Stand., 37, 1-13 (1961) 198. Merkel, F. W. Untersuchungen fiber
1 85. Goodwin, J. C., Jenner, F. A., Lob tages- und jahreszeitliche Akti
ban, M. C., Sheridan, M. Renal vitiitsanderungen bei geldifigten
rhythms in a patient with a 48- Zugvogel n. Z. Tierpsychol., 13,
ho ur cycle of psycho sis during a 278-301 (1956)
period of life on an abnormal time 199. Merkel, F. W. Long-term effects of
routine. J. Physiol., 176, 16-17 constant photoperiods on European
(1965) Robins and Whitethroats. Proc.
186. Scarpelli, P. T., Fantini, F., Boccuni, XIII Intern. Ornithol. Congr.
M., Cagnoni, M. Le Malattie Ithaca, 950-59 (1963)
Periodiche. Problematica nosolo 200. Wolfson, A. Role of light and darkness
gica ed etiopatogenetica. Rass. in the regulation of the annual
Neural. Veg., 22, 5-23 (1968) stimulus for spring migration and
187. Reiss, Max. Neuroendocrinology and reproductive cycles. Proc. XII
Psychiatry (A critical assessment Intern. Ornithol. Congr. Helsinki,
of the present status) . Intern. J. 758-89 (1960)
Neuropsychiat., 3, 441-63 (1967) 201. Wolfson, A. Regulation of annual
1 88. Benoit, J., Assenmacher, 1., Brard, E. periodicity in the migration and
Etude de l'evolution testiculaire du reproduction of birds. Cold Spring
canard domestique soumis tres Harbor Symp. Quant. Biol., 25,
jeune a une eclairement permanent 507-14 (1960)
pendant deux ans. Campt. Rend. 202. Wolfson, A. Environmental and neuro
A cad. Sci., 242, 3 1 1 3- 1 5 (1956) endocrine regulation of annual
189. Farner, D. S. The annual stimulus for gonadal cycles and migratory be
migration. Condor, 52, 104-22 havior in birds. Recent Progr. Hor
(1950) mone Res., 22, 1 7 7-244 (1966)
190. Farner, D. S. Northward transequa 203. Zimmerman, J. L. Effects of extended
torial migration of birds. Sci. Rev., tropical photoperiod and temper
12, 29-30 (1954) ature on the Dickcissel. Condor,
191. Farner, D. S. The p h�toperiodic con- 08, 377-87 (1900)
7 20 HALBERG
204. Orth, D. N., Island, D. P., Liddle, The Earth-Moon System (Plenum.
G. W. Experimental alteration of Press, New York, 288 pp., 1966)
the circadian rhythm in plasma 2 1 9. Halberg, F., Halberg, E., Barnum"
cortisol (1 7-0HCS) concentration C. P., Bittner, J. J. Physiologic
in man. J. Clin. Endocrinol. 24-hour periodicity in human being!!
Metab., 27, 549-55 (1967) and mice, the lighting regimen and
205. Erankti, O. 2 5 -h o ur day : o ne solution daily routine. In Photoperiodism
to the shift-work problem. Intern. and Related Phenomena in Plants
Congr. Occup. Health, 3, 1 34 (1957) and Animals (See Ref. 16), 803-78
206. Simpson, H. W., Lobban, M. C., Hal 220. Pittendrigh, C. S., Bruce, V. G. An
berg, F. Near-24-hour rhythms in oscillator model for biological
subjects living on a 2 1 -hour routine clocks. In Rhythmic and Syntheti"
in the arctic summer at 7SoN-re Processes in Grawth, 75-109 (Prince
vealed by circadian amplitude ton Univ. Press, 1957)
ratios. Rass. Neurol. Veg. 2 2 1 . Korein, J., Tick , L. J., Zeitlin, R. A.,
207. Lamar, D. L., M erifield, P. M. Cam
Randt, C. T. Linear and nonlinear

brian fossils and origin of Earth spectral analytic techniques applied
Moon system. Geol. Soc. Am. Bull. to the human electroencephalogram.
78, 1359-68 (1 9 6 7) Bull. N. Y. A cad. Med., 44, 1 126·-

208. Wells, John W. Coral growth and 28 (1968)
geoch ronometry. Nature, 197, 948- 222. Pittendrigh, C. S., Bruce, V. G.
50 (1963) Daily rhythms as coupled oscil
209. Goreau, T. F. The physiology of lator systems and their relation to
skeleton formation in corals. L A thermoperiodism and photoperiod
method for measuring the rate of ism. In Photoperiodism and Re
calcium deposition by corals under lated Phenomena in Plants and A n
different conditions. Bioi . Bull., imals (See Ref. 1 6) , 475-505
1 1 6, 59-75 (1959) 223. Pittendrigh, c. S., Minis, D . H. The
210. Goreau, T. F., Gareau, N. I. The entrainment of circadian oscilla
physiology of skeleton formation in tions by light and their role as
corals. II. Calcium deposition by photoperiodic clocks. A m . Natural
hermatypic corals under various ist, 98, 2 6 1 -94 (1964)
conditions in the reef. Bioi. Bull., 224. Pittendrigh, C. S. The circadian
1 1 7, 2 39-50 (1959) oscillation in Drosophila pseudo
2 1 1 . Runcorn, S. K. Changes in the Earth's obscura pupae: a model for the
moment of inertia. Nature, 204, photoperiodic clock. Z. Pflanzen
823-25 (1964) physiol. , 54, 275-307 (1966)
212. Scrutton, C. T. Periodicity in Devo 225. Strumwasser, F. The demonstration
nian coral growth. Palaeontology, 7, and manipulation of a circadian
552-58 (1964) rhythm in a single neuron. In
Circadian Clocks (See Ref. 4),
2 1 3. Gebelein, C. D. Origin and growth
44 2-62
rate of subti dal algal stromatolites,
226. Wever, R. A mathematical model for
Bermuda. The Geological Society of
circadian rhythms. In Circadian
A merica A nnual Meeting, 75 (1967)
Clocks (See Ref. 4), 47-63 ; Pendu
214. McGugan, A. Possible use of algal lum versus relaxation oscillation,
stromatolite rhythms on geochron 74-83
ology. The Geological Society of 227. Wever, R. Possibilities of phase COIl
A merica A nnual Meeting, 145
trol, demonstrated by an electronic
(1967)
model. Cold Spring Harbor Symp.
2 1 5. Pannella, G., MacClintock, C. Biolog Quant. Bioi., 25, 197-206 (1960)
ical and environmental rhythms re 228. Wever, R. Zum Mechanismus der
flected in molluscan shell growth. biologischcn 24-Stunden-Periodik.
J. Paleontol. , 42, 64-80 (1967) Kybernetik, I, 1 39-94 (1962), 2 1 3-
2 1 6. Lamar, D. L., Mc-Gann-Lamar, J. V., 31 (1963) ; 2, 1 2 7-44 (1964)
Merifield, P. M. Age and origin of 229. Schmitt, O. H. Biophysical and math
Earth-Moon system. In Paleogeo ematical models of circadian
Physics (Runcorn, S. K., Ed., in rhythms. Cold Spring Harbor Symp.
press) Quant. BioI., 25, 207-10 (1960)
2 1 7 . M unk, W. H., MacDonald, G. J. F. 230. Wachholder, K. Die allgemeinen
The Rotation of the Earth (Cam physiologischen Grundlagen der
bridge Univ. Press, London, 323 Entstehung von Lebensrhythmen.
pp., 1960) Acta Med. Scand. Suppl. 307, 2 1-
2 1 8 . Marsden, B. G., Cameron, A. G. W. 31 (1955)
CHRONOBIOLOGY 721
231. Chance, B., Pye, K., Higgins, J. 246. Prigogine, I., Balescu, R. Phenomenes
Waveform generation by enzymatic cyc1iques dans la thermodynamique
oscillators. IEEE Spectrum, 4, des processus irreversibles. Bull.
79-86 (1967) Class. Sci. A cad. Ray. Beig., 42,
232. Ehret, C. F., Barlow, J. S. Toward a 256-65 (1956)
realistic model of a biological 247. Volterra, V. Theorie Mathematique
period-measuring mcchani$m. Cold de la Lutte de la Vie (Gautiers-Vil
Spring Harbor Symp. Quant. BioI., lars, Paris, 1931)
25, 2 1 7-20 (1960) 248. :'van der Pol, B. On " Relaxation-Oscil
233. Goodwin, B. C. An entminment lations". Phil. Mag., 2, 978-92
model for timed enzyme synthesis (1926)
in bacteria. Nature, 209, 479-81 249. van der Pol, B., van der Mark, J.
(1966) The heartbeat considered as a re
234. Ehret, C. F., Trucco, E. Molecular laxation oscillation, and an electri
models for the circadian clock. I. cal model of the heart. Phil. Mag.,
The chronon concept. J. Theoret. 6, 763-75(1928)

BioI., IS, 240-62 (1967) 250. Lotka, A. J. Theorie analytique des
235. Kalmus, H., Wigglesworth, L. A. associations biologiques. In Exposes
Shock excited systems as models de Biometrie et de Statistique

for biological rhythms. Cold Spring Biolocique, IV (Hermann et Cie . .
Harbor Symp. Quant. Bio!., 25, Paris, 1934)
2 1 1-16 (1960) 2 5 1 . Lotka, A. J. Analytical note on cer
236. Chance, B., Higgins, J. J., Garfinkel, tain rhythmic relations in organic
D. Analogue and digital computer systems. Proc. Nail. Acad. Sci., 6,
representations of biochemical pro 410-15 (1920)
cesses. Fed. Proc. , 21, 75-86 (1962) 252. Lotka, A. J. Undamped oscillations
237. Higgins, J. A chemical mechanism for derived from the law of mass ac
oscillation of glycolytic interme tion. J. Am. Chem. Soc., 42, 1595-
diates in yeast cells. Biochemistry, 99 (1920)
51 , 989-94 (1964) 253. Winget, C. M., Card, D. H . , Pope,
238. Biinning, E., Zimmer, R. Zur Deutung J. M. Circadian oscillations of
der Phasenverschiebungen und three parameters at defined light
"Transients" nach exogener Sto intensities and color. J. Appl.
rung endogener Rhythmen. Planta, Physiol., 24, 401-6 (1968)
59, 1-14 (1962) 254. Winget, C. M., Card, D. H. Daily
239. Winfree, A. T. Biological rhythms rhythm changes associated with
and the behavior of populations of variations in light intensity and
coupled oscillators. J. Theoret. color. Life Sci. Space Res., 5,
Bioi., 16. 1 5-42 (1967) 148-58 ( 19 6 7)
240. Spangler, R. A., Snell, F. M. Sustained 255. Winget, C. M., Fryer, T. B . Telem
oscillations in a catalytic chemical etry system for the acquisition of
system. Nature, 191, 457-58 (1961) circadian rhythm data. A erospace
241. Higgins, J. Theory of oscillating re Med., 37, 800-3 (1966)
actions. Ind. Eng. Chem., 59. 18-62 256. Stro..bel, C. F. Biologic rhythm ap
(1967) proach to psychiatric treatment. In
242. Frenkel, R. Reduced diphosphopy Proc. 7th IBM Medical Symp.
ridine nucleotide oscillations in (Steinbeck, H . , Ed., I B M Corp.,
cell-free extracts from beef heart. Yorktown Heights, N.Y., 1967)
Arch. Biochem. Biophys., 1 1 5 , 1 12- 257. Randall, W., Littschwager, J. The
21 (1966) relationship between cyclic changes
243. Vanden Driessche, T. The nuclear in thyroid function and behavior
control of the chloroplasts' cir of cats with brain stem lesions. J.
cadian rhythms. Sci. Progr. Oxford, Psychiat. Res., 5, 39-58 (1967)
55, 293-303 (1967) 258. Randall, W., Lakso, V. Body weight
244. Vanden Driessche, T., Bonotto, S. Le and food intake rhythms and their
rythme circadien de la teneur en relationship to the behavior of
inuline chloroplastiqu.. de A uta cats with brain stem lesions.
bularia mediterranea. Arch. Intern. Psychcm. Sci., 1 1 , 3 3-34 (1968)
Physiol. Biochim., 76, 205-6 (1968) 259. Rapoport, M. I., Feigin, R. D.,
245. Hurwicz, L. Basic mathematical and Bruton, J., Beisel, W. R. Circadian
statistical considerations in the rhythm for tryptophan pyrrolase
study of rhythms and near activity and its circulating sub
rhythms. Ann. N. Y. A cad. Sci., strate. Science, 153, 1 642-44 (1966)
98, 85 1-57 (1962) 260. Reinberg, A. Rythmes des fonctions
722 HALBERG
corticosurrenaliennes et systemes sparrow? Science, 160, 1125-27
circadiens. In Symposium Inter (1968)
national sur la Neuro-Endocri 274. Butler, P. W. P., Besser, G. M .
nologie, 75-89 (Expansion Sci. Pituitary adrenal function i n severe
Fran!:., Paris, 1966) depressive illness. Lancet, 1, 123·1-
261. Axelrod, J., Wurtman, R. J. The 36 (1968)
pineal gland : a biological clock 275. Lohrenz, F. N., Fullerton, D . T.,
(See Ref. 260), 201-12 Fahs, H., Wenzel, F. J. Adrenocor
262. Quay, W. B. Photic relations and tical function in depressive states-
experimental dissociation of cir study of circadian variation in
cadian rhythms in pineal composi plasma and urinary steroids. In
tion and running activity in rats. tern. J. Neuropsychiat . , 4, 21-25
Photochem. Photobiol., 4, 425-32 (1968)
(1965) 276. RUbin, R. T., Young, W. M., Clark,
B. R. 1 7-hydroxycorticosteroid and
263. Quay, W. B. Circadian and estrous

rhythms in pineal and brain vanillylmandelic acid excretion in
serotonin. Progr. Brain Res., 8, a rapidly cycling manic-depressive.
61-63 (1964) Psychosomat. Med., 30, 1 62-71
264. Quay, W. B. Regional and circadian (1968)

differences in cerebral cortical 277. Halberg, F., Vestergaard, P., Sakai,
serotonin concentration. Life Sci., M. Rhythmometry on urinary 1 7-
4, 379 (1965) ketosteroid excretion by healthy
265. Brown, F. A., Jr., Park, Y. H. As men and women and patients with
chronic schizophrenia; possible
sociation-formation between photic
and subtle geophysical stimulus chronopathology in depressive ill
patterns-a new biological concept. ness (In press, memorial volume in
honor of Professor Jacques Benoit)
Bioi. Bull., 132, 3 1 1-19 (1967)
278. Menaker, M. Extraretinal light per
266. Brown, F. A., Jr., Park, Y. H . Synodic
ception in the sparrow, 1. Entrain
monthly modulation of the diurnal
ment of the biological clock. Proe.
rhythm of hamsters. Proc. Soc.
Natl. A cad. Sci., 59, 4 1 4-21 (1968)
Exptl. B io!. Med., 125, 7 12-15
279. Fenyo, E., Hasznos, T. Periodic EEG
(1967)
Complexes in subacute panenceph
267. Soil berger, A. Biological measure
alitis : reactivity, response to
ments in time, with particular
drugs and respiratory relation
reference to synchronization mech
ships. Electroenceph. Clin. Neur()
anisms. Ann. N. Y. A cad. Sci.,
physiol., 16, 446-- 5 8 (1964)
138, 561-99 (1967)
280. Poole, E. W. Nervous activity in
268. Soliberger, A., Apple, H. P., Green relation to the respiratory cycle.
way, R. M . , Kind, P. H., Lindan, Nature, 189, 579 (1961)
0., Reswick, J. B. Automation in 281. Poole, E. W. Periodic EEG complexes
biological rhythms research with in subacute panencephalitis: re
special reference to studies on activity, response to drugs and
Homo. I n The Cellular Aspects of respiratory relationships. Electro
Biorhythms, 1 84--9 8 (Springer-Ver enceph. CUn. Neurophysiol., 16,
lag, N. Y., 1967) 446--5 8 (1964)
269. Halberg, F. Some aspects of biologic 282. Hobson, J. A. Respiration and EEG
data analysis; longitudinal and synchronization in the frog. Nature,
transverse profiles of rhythms. In 213, 988-89 (1967)
Circadian Clocks (See Ref. 4), 13-22 283. Hobson, J. A., Goldfrank, F., Snyde r,
2 70. Giese, A. C. Comparative physiology: F. Respiration and mental activity
annual reproductive cycles of marine in sl eep. J. Psychiat. Res., 3, 79-90
invertebrates. Ann. Ref!. Physiol., (1965)
21, 547-76 (1959) 284. Bjerner, B., Holm, A., Swensson, A.
2 7 1 . Saito, H. Some considerations on re Diurnal variation in mental per
duction of working hours in Japan formance ; a study of three shift
from view-point of science of labour. workers. Brit. J. Ind. Med., 12, 103-
J. Sci. Labour, 40, 469-86 (1964) 10 (1955)
272. Saito, H. Biochemicalaspect of fatigue, 285. Garcia Sainz, M., Halberg, F. Mitotic
with special reference to physical rhythms in human cancer, reeval
and mental burden of work. Ibid., uated by electronic computer pro
42, 427-47 (1966) grams--evidence for temporal path
273. Gaston, S., Menaker, M. Pineal func ology. J. Nail. Cancer Inst., 37,
tion : The biological clock in the 2 79-92 (1966)
CHRONOBIOLOGY 723
286. Nkhols, C . T., Tyler, F. H . Diurnal fluctuation (circadian and ultra
variation in adrenal cortkal func dian) in biogenic amines of the rat
tion. A nn. Rev. Med., 18, 3 1 3-24 brain. A m. J. Physiol., 2 1 4, 1 66-73
(1967) (1968)
287. Bunney, W. E., Hartmann, E . L. 300. Scheving, L. E., Pauly, J. E . Circadian
Study of a patient with 48-hour phase relationships of thymidine-
manic depressive cycles. A rch. Gen. 3H uptake labeled nuclei, grain
Psycho!., 12, 61 1-25 (1965) counts, and cell division rate in
288. Jenner, F. A., Goodwin, J . C., rat corneal epithelium. J. Cell
Sheridan, M . , Tauber, 1. J., Lob Bioi., 32, 677-83 (1967)
ban, M. C. The effect of an altered 301. Scheving, L. E., Pauly, J. E . Daily
time regime on biological rhythms rhythmic variations in blood coag
in a 48-hour periodic psychosis. ulation times in rats. Anat. Record,
Brit. J. Psychiat . , 1 14, 2 1 5-24 1 5 7, 65 7-65 (1967)
(1968) 302. Wurtman, R. J., Rose, C. M., Chou,
289. Bryson, R. W. Psychoendocrinology
C., Larin, F. F. The daily rhythms

(M.D. thesis, Glasgow Univ., in the concentrations of various
1954) amino acids in human plasma. New
Engl. J. Med., 279, 1 7 1-75 (1968)
290. Cookson, B. A., Quarringtou, B.,

Huszka, L. Longitudinal study of 303. Wurtman, R. J., Chou, C., Rose,
periodic catatonia. J. Psychiat. C. M. Daily rhythm in tyrosine
Res., 5, 15-38 (1967) concentration in human plasma:
291. Quay, W. B . Epiphyseal responses to persistence on low-protein diets.
light and darkness in birds and Science, 1 58, 660-62 (1967)
mammals. In La Photoregulation 304. Wurtman, R. J., Axelrod, J., Sedvall,
de la Reproduction chez les Oiseaux G., Moore, R. Y. Photic and neural
et les Mammiferes (See Ref. 13) control of the 24-hour norepineph
292. The Cellular Aspects of Biorhythms rine rhythm in the rat pineal
Symp. Rhythmic Res., VIII Intern. gland. J. Pharmacol. Exptl. Therap.,
Congr. A nat., Wiesbaden (von 157, 487-92 (1967)
Mayersbach, H. v., Ed., Springer, 305. Ader, R. Gastric erosions in the rat :
Berlin, 198 pp., 1967) effects of immobilization at dif
293. Alov, I . A. The mechanism of the ferent points in the activity cycle.
diurnal periodicity of mitosis. Bull. Science, 1 45, 406-7 (1964)
Exptl. Bioi. Med., 48, 1418-23 306. Tarquini, B., Della Corte, M.,
(1959) Orzalesi, R. Circadian studies on
294. Scheving, L. E., Pauly, J. E . Effect of plasma cortisol in subjects with
adrenalectomy, adrenal medullec peptic ulcer. J. Endocrinol., 38,
tomy and hypophysectomy on the 475-76 (1967)
daily mitotic rhythm in the corneal 307. DeVries, K., Goel, J. T., Booy-Noord,
epithelium of the rat. In The Cel H., Orie, N. G. M. Changes during
lular Aspects of Biorhythms (See 24 hours in the lung function and
Ref. 292), 1 67-74 histamine hyperreactivity of the
295. Cherkovich, G. M. The experimental bronchial tree in asthmatic and
production of a neurosis in man· bronchitic patients. Intern. A rch.
keys by changing the diurnal A llergy, 20, 93-101 (1962)
rhythm. Bull. Exptl. Bioi. Med., 308. Reinberg, A., Sidi, E., Ghata, J.
47, 935-38 (1959) Circadian reactivity rhythms of
296. Brady, J . V. Ulcers in "executive human skin to histamine or allergen
monkeys". Sci. Am., 199, 95-103 and the adrenal cycle. J. A llergy,
(1958) 36, 273-83 (1965)
297. Brady, J. V. Experimental studies of 309. Reinberg, A. Hours of changing re
psychophysiological responses to sponsiveness in relation to allergy
stressful situations. In Symposium and the circadian adrenal cycle. In
on Medical A spects of Stress in the Circadian Clocks (See Ref. 4), 214-
Military Climate, 271-89 (Walter 18
Reed Army Inst. Res., Washing 3 10. Matthews, J. H., Marte, E., Halberg,
ton, D. C., 1964) F. Fluothane toxicity in mice
298. Rice, H. K. Responding-rest ratio in studied by indirect periodicity
the production of gastric ulcers in analysis. In Toxicity of Anesthetics,
the rat. Psycho! . Record, 13, 1 1-14 197-208 (Fink, B. R., Ed., Wil
(1963) liams & Wilkins. Baltimore. 1968)
299. Scheving, L. E., Harrison, W. H., 3 1 1 . McHugh, R. B. Validity and ef.
Gordon, P., Pauly, J. E . Daily ficiency in the design of transverse
7 24 HALBERG
physiologic peliodicity experiments. H. Periodische Einf!ilsse auf die
In The Cellular A spects of Bio indiv id uale IIaufigkeit cereb ral er
rhythms (See Ref. 292), 61-86 Anfalle. Arch. Psychiat. Z. Ges.
312. McGeer, E. G., M c Geer, p. L. Cir Neurol., 206, 29.1-308 ( 1 9 64)
cadian rhythm in pineal tyrosi ne 325. Yoshimura. H. Seasonal changes in
hydroxylase. Science, 143, 73-74 human body fluids. Japan. J.
(1966) Physiol., 8, 1 65-79 (1958)
313. Haus, E. Periodicity in response a nd 326. Sueda, T. Schwankungen im 24-St.un
suscepti bil it y to envi ronmental den Rhythmus bei maniseh··de
stimuli. Ann. N. Y. A cad. Sci., pressiven Kranksein- Pathophy
1 17, 292-319 ( 19 M) siologic des manisch-depressiven
314. Bl iss, C. I., Bl evins, D. L. The analy Krankseins. Psychiat. Neurol. Ja
sis of seasonal variation in measles. pan., 9, 1449-85 (1962)
Am. J. Hyg., 70, 328-34 (1959) 327. Tamura , A. Changes of diurnal
3 1 5. Bliss, C. 1., Fleischer, D. A. The rhythm of Na-, K- and Ca-exere
analy sis in angles of a microbial tion in urine with disorders in

experiment. Biometrics, 20, 883-91 brai n. Psychiat. Neural. Japon., 5,
(1964) 405-23 (1965)
3 1 6. M inis, D., Pittend ri gh . C . Ci rcadian 328. Watanabe, G.-I., Huyama, T. Cli

oscill ation controll ing hatchi ng : matic effect on the alkaline phos
ontogeny during embryogenesis of phatase activity in human serum,
a moth. Science, 159, 5 34-36 (1968) Japan. J. Med. Progr. , 43, 480-89
3 1 7. H ell briigge, T., Lange , J. E., Ruten (1956)
franz, J., Stehr, K. Circadian
329. Rutenfranz, J., Singer, R. Unt.er
periodicity of physiological func
suchungen zur Frage einer Ab
tions in different stages of infancy
h1ingigkeit der Alkoholwirkung von
and childhood. Ann. N. Y. A cad. der Tageszeit. Intern. Z. A n gew.
Sci. , 1 17, 361-73 (19M)
Physiol., 24, 1-1 7 (1967)
318. Hellbriigge, T. Zeitliche Strukturen
330. Hayashi, K., Ota, M., Kato, M . •
in der kindlichen Entwicklung.
Ch iba , Y., Narita, A. Seasonal and
Monatsschr. Kinderheilk., 1 13, 252-
diurnal activities of bi ti ng insect
62 (1965)
attacking grazing cattle, with
319. H ellbriigge ,T. Uber tageszeitliche
special reference to repellent-spray
Ver1inderu ngen der ph ysiologisch en
ing. Japan. J. Zootech. Sci., 38,
Leistungsbereitschaft bei Schul
376-84 (1967)
kindern. Fortschr. Med., 78, 4 1-44
(1960) 331. Hildebrandt,G. Rhythmus und Re
320. Hellbriigge, T., Pechstein, J., Ullner, gulation unter besonderer Beriick
R., Reindl, K. Zum Verst1indnis sichtigung der Blutdruckregula

der Periodik-Analyse in der Medi tion. Z. Ges. Inn. Med., 22, 206-13
zin. For/schr. Med., 7 , 2 89-9 5 (1967) (1967)
321. Martin-du-Pan, R. L'apparitio n du 332. Kaiser, I. H . Effect of a 2 8-h our day
rythme circadien des 17-hydroxy on ovulation and reproduction in
mice . Am. J. Dbstel. Gynecol., 99,
steroldes chez Ie nourrisson. Sa
modification sous l'effet de la Con 7 72-84 (196 7)
sommation de corticosteroides . 333. Mohler, S. R. Fatigue in aviation ac
Praxis, 56, 138-44 (1967) tivi ties. A erospace Med., 37, 722-32
322. Frazier, T. W., Rummel, J. A., Lips (1966)
comb, H. S. Circadian variability 334. Mohler, S. R., Dille, J. R., Gibbons,
in vigilance performance. A erospace H. L. The time zone and circadian
Med., 39, 383-95 (1968) rhythms in relation to aircraft occu
323. Baillaud, L. Variations d'une periodi pants taking long-distance flights.
cite endogene normalement cir Am. J. Public Health, 50, 1 404-9,
cadienne affectant Ie degagement (1968)
des entre-noeuds de la Bryone, 335. Holmgren, H . , Swensson, A. Der Ein
Bryonia dioica, en fanction de fluss des Lichtes auf den 24-Stundell
facteurs agissant sur la vitesse de Rhythmus der Aktivit1it, des
croissance. Z. Pjlanzenphysiol., 57, Leberglykogens und der Korper
203-5 (1967) temperatur. A cta Med. Scand.
324. Helm chen, H . , Kilnkel , H . , Selbach, Suppl. 278, 7 1-76 (1953)
C H RONOBIOLOGY 725
336. Jurkevich, 1. Non-linear regression ing& Reproduction Ltd., London,
analysis and anlysis of variance of 1967)
periods defined by irregular obser 339. Cu mming, B. G., Wagner, E . Rhyth
vations. NASA Pub!. NASA-CR- mic processes in plants. Ann. Rev.
465 (1966) Plant Physiol. , 19, 381-416
337. Kovarov, F. I., Zakharov, L. V., (1968)
Lisovskii, V. A. Sutochnyi Ritm 340. Lungu, AI. Orologiile biologice (Edi
(Circadian rhythm of man's physio tura Stiintifica, Bucure§ti, 237 pp.,
logical functions in health and dis 1968)
ease) (Leningrad : Meditsina, 200 341. Szczepanska, E., Preibisz, J., Drze
pp.,1966) wiecki, K., Kozlowski, S. Studies
338. Behavioral Problems in A erosp ace Medi on the circadian rhythm of varia
cine, Conf. Proc. 25 of A dvisory tions of the blood antidiuretic hor
Group jor A erospace Research & mone in humans. Polish Med. J.,
Development, NATO (Tech. Edit- 7, 5 1 7-23 (1968)

(1969) Halberg CHRONOBIOLOGY PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

(1969) Halberg CHRONOBIOLOGY PDF

Uploaded by

Copyright:

Available Formats

ANNUAL

metering of body functions and from advances in electronic computer

than was heretofore possible; their contribution to the study of biologic

certain diseases. Answers to these questions may eventually be provided by

COMMENTS ON TERMS USED

Rhythms, synchronizers, and bio rhythms Whether they are viewed

" macroscopically" or " microscopically" (see below) , rhythm s can be defined

w is the angular frequency and t = time) as sketched in Figure 1 .

rhythm in intraperitoneal temperature telemetered at 10' intervals from 6

with food freely available at 24 ± .5° C environmental temperature in light

the temporal characteristics of biologic phenomena, leading to an objective

(34, 35) or death (36, 37) in populations of humans or rodents (38).

tistical point and interval estimations.

stemming from unidentified or unevaluated sources and interfering with the

Electroencephalogram Responses to drugs

in: Urinary variables In all regions Indicated

SYMBOL [ILLUSTRATIVE PHASE

body core temper- ]

to Intraperitoneal Temperatures (x) of on Adult Female MSD Rqt.

Telemetry at N 30' intervals for 24 hours

u.u -co + C cos (wl+.p) Key:

CLASSICAL "MACROSCOPIC" "MICROSCOPIC"

In the service of medicine, it is particularly worthwhile to attempt to

CIRCADIAN RHYTHM OF HUMAN PLASMA 17-HYDROXYCORTICOSTEROlD IN SAMPLES OF

* Total span of study 24 h for all subjects. Co and C in ",g/100 m!.

indicated with (t) sign.

(.95 confidence limits)

Mexico 1(20) .05(.04to .06) -159°(-145 to -173) Pelia (105)

France 12(1) .07(.05 to .09) -138° (-121 to -155) Reinberg(105)

Italy 31 (1) .17(.15to.19) _134° (-12410 -1 43) Ceresa (109)

Australia 8 (1) .06(.03 to .09) -103°(- 85 to -133) Gordon et aI. (102)

• T= 24 h =360°; 1 h = 15°.<I> r eference =middle of habitua l slee p span.

N ofs ub je cts N oise -to- P

.. T=24 h=3600; 1 h= 15° . <1>= mi ddle of habit ua l s el e p s pa n. 0\

t Am plitu de ex pressed i n me q/hr . 00

• T=24 h=360o; I h=15°. cI> reference=middle of habitual sleep span.

Moreover, most of the information summarized in Tables IV to XIII is

Let us assume, first, that observations covering many cycles of a rhythm

10 (25) [1.5, 10] <.01 3.6 Gunther et a!.

• T = 24 h =360°, 1 h = 15°. $ reference =middle of habitual sleep span.

S pecit; s* . . Cir cadi an N oi. se - to-

Blood C ons ti tue nts

Ouabain; .5 mg/. 2 cc/20 g

Librium; 5 . 4 mg/20 g b.wt.;

Ouabain; .15mg/ . 2 cc;

* Animals maintained on regularly alternating light/dark cycle [L(060L 1800)/D

In principle, all curves can be accounted for by harmonic analysis, and

CIRCADIAN PARAMETER ESTIMATIONS ON VARIABLES

Circadian amplitude C* Circadian acrophase '"

Gross motor activity 65 (23 to 107) -160° (-123 to -198)

Depression of pinnal mitoses 44 (26 to 62) -201° (-179 to -223)

* C given as % of mean. '" from mid-L. Mice maintained on regularly alternating

Circadian acrophase (.95 confidence arc)

from mid-L from serum corticosterone '"

Serum corticosterone 66° (- 42 to - 89)

* L(06°0-1800): D(18oo-06M); T fitted=24 hr=3600; 1 hr=15° (see 123-126, also

should be determined objectively. In this context, objectivity requires that:

4. Statistical dispersion indices should be sought for each endpoint.

Ph ase-drift of Desyn chronized Circadian Rhythm

Group-mean �_f:��;���:;otion ---� �O'"-- &: ..

FIG. 2. Reproducibility of circadian desynchronization following blinding in

effects at certain predictable times. This possiblility of a p redictab ly re­

FIG. 3. Time relations of circadian rhythms in liver glycogen, serum corticoster­

Group-mean �_f:��;��:;otion ---� �O'"-- &: ..

effects at certain predictable times. This possiblility of a p redictab ly re

FIG. 3. Time relations of circadian rhythms in liver glycogen, serum corticoster

FIG. 4. Phase relations of circadian rhythms in the urinary excretion of 1 7-hy

synchronization; alterations in period length of these two spectral compo

Third, reports abound on the phase shifting of rhythms in a fixed geo

braith ( 1 2 1 ) . This problem deserves further scrutiny under controlled con

In an attempt to determine whether a given value is "normal" or "ab

samples-some of variables extensively utilized by biologists and cIinicians

Sci., 98, 1 056-68 (1962) nomena obscured by random fluc

from circadian rhythmometry on L. T., Bowers, J. Z. Plasma 1 7-hy

(1967) heart rate in a primate (Cebus al

elektronischer Rechner zur Beurtei 1 19. Stroebel , C. Behavioral aspects of

(1966) effect of temperature and photo

3 1 6. M inis, D., Pittend ri gh . C . Ci rcadian 328. Watanabe, G.-I., Huyama, T. Cli