Faculty of Medicine • Masaryk University • Brno • Czech Republic
Department of Physiotherapy and Rehabilitation
Department of Functional Diagnostics and Rehabilitation
PROCEEDINGS
SYMPOSIUM
NONINVASIVE METHODS IN CARDIOLOGY
Edited by: Halberg F., Kenner T., Fišer B., Siegelová J.
2008
Faculty of Medicine Masaryk University Brno Czech Republic
Department of Physiotherapy and Rehabilitation
Department of Functional Diagnostics and Rehabilitation
PROCEEDINGS
SYMPOSIUM
NONINVASIVE METHODS IN CARDIOLOGY
Edited by: Halberg F., Kenner T., Fišer B., Siegelová J.
2008
2
The Symposium takes place under the auspices of
Prof. PhDr. Petr Fiala, Ph.D., Rector of Masaryk University Brno
Prof. MUDr. Jan Žaloudík, CSc., Dean of Faculty of Medicine Masaryk
University Brno
Ing. Petr Koška., MBA, Director of the St. Anna Teaching Hospital in Brno
MUDr. Marie Košuli ová, Director of National Centre of Nursing and Other
Health Professions
ISBN 978-80-7013-481-8
3
CONTENTS
ROLE AND CLINICAL IMPORTANCE OF THE EVALUATION
OF ARTERIAL PULSES Kenner T..................................................................................................... 5
QUO VADIS CHRONOMICS 2008:
MEASURING VARIABILITY IN US, AMONG US AND AROUND US Halberg F....................... 16
CIRCADIAN STAGE-DEPENDENT INFRADIAN-MODULATED CHANGES
IN A MENTAL FUNCTION DURING AGING Halberg F.............................................................. 26
THE COSMOS IN A EUKARYOTIC UNICELL Halberg F............................................................ 32
SOLAR SIGNATURES IN AUSTRALIAN SUICIDE INCIDENCE:
GENDER DIFFERENCES IN PROMINENCE OF PHOTIC VS.
NONPHOTIC SPECTRAL COMPONENTS Halberg F.................................................................. 44
REASONS FOR A PROTOCOL FOR RADIATION TREATMENT
AIMED AT EXPLOITING WEEKLY RHYTHMS Halberg F.......................................................... 63
BRÜCKNER-EGESON-LOCKYER (BEL) CLIMATE CYCLE
IN ORIGINAL BRÜCKNER’S, LOCKYER’S AND FOLLOW-UP
DATA Halberg F................................................................................................................................ 74
SHOULD 7-DAY/24-HOUR CHRONOBIOLOGICALLY
INTERPRETED BLOOD PRESSURE MONITORING
REPLACESINGLE MEASUREMENTS BEFORE
CATARACT SURGERY? Cornélissen G........................................................................................... 90
BRÜCKNER-EGESON-LOCKYER (BEL) CYCLE
IN HELIOGEOMAGNETICS Cornélissen G................................................................................. 106
BODY MASS INDEX (BMI), PULSE PRESSURE (PP)
AND PREMETABOLIC SYNDROME Cornélissen G................................................................... 116
AURORAL AEOLIAN PERIODICITY DURING 1545-1724,
INCLUDING THE MAUNDER MINIMUM Cornélissen G.......................................................... 124
ON GAPS AND INTERPOLATION METHODS TO AVOID ERRORS
IN PERIOD ESTIMATION WITH CONVENTIONAL TIME SERIES
ANALYSIS Czaplicki J.................................................................................................................... 128
AMBULATORY PROFILE IN A NON-AMBULATORY SUBJECT:
A SPHYGMOCHRON WITH GAPS (WHEN WE SHOULD
MEASURE AGAIN, NOT INTERPOLATE) Hörmann H............................................................. 137
C-ABPM REVEALS SOLAR CIS-HALFYEAR AND TRANSYEAR
SIGNATURES IN HUMAN DIASTOLIC BLOOD PRESSURE Katinas S................................. 144
PAIN AND THE CARDIOVASCULAR SYSTEM REVISITED
IN A LONG-TERM MONITORING Katinas S.............................................................................. 147
HARM VS. BENEFIT FROM LOSARTAN WITH
HYDROCHLOROTHIAZIDE AT DIFFERENT CIRCADIAN
TIMES IN MESOR-HYPERTENSION OR CHAT Watanabe Y.................................................... 149
TIME-SPECIFIED NORMS REVEAL FULL SYSTOLIC BUT
INCOMPLETE DIASTOLIC EARLY MESOR-HYPERTENSION,
MH Watanabe Y............................................................................................................................... 168
DIFFERING FAR-TRANSYEAR/CALENDAR YEAR AMPLITUDE
RATIOS IN BLOOD PRESSURE VS. HEART RATE
IN ADOLESCENCE Watanabe F................................................................................................... 177
4
TRANSYEARS, NO CALENDAR-YEAR IN BLOOD PRESSURE
DECADES BEFORE MESOR-HYPERTENSION:
NORMAL OR ABNORMAL? Watanabe Y......................................................................................184
CHRONOMICS: ANXIETY DISORDER IN ADOLESCENCE
AND HEART RATE ASYNCHRONIZED WITH WEEKLY
SCHEDULE Watanabe Y................................................................................................................189
A TRANSTRIDECADAL CYCLE IN HUMAN HEART RATE:
SELECTIVE INFRADIAN, NOTABLY MULTIDECADAL
SOLAR-PHYSIOLOGIC BEL CONGRUENCES Sothern R.........................................................204
EFFECTS OF PHASE II CARDIAC REHABILITATION
ON INSULIN RESISTANCE AND MYOCARDIAL REMODELLING
IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION Kohzuki M..................................214
ARTERIAL STIFFNESS DETERMINED BY PRESSURE WAVE
VELOCITY, AORTIC COMPLIANCE AND CARDIO-ANKLE
VASCULAR INDEX Fišer B............................................................................................................227
AMBULATORY ARTERIAL STIFFNESS INDEX IN PATIENTS
MONITORED FOR 6 CONSECUTIVE DAYS Siegelová J...........................................................233
PHYSICAL ACTIVITY AND 24-HOUR PROFILE
OF BLOOD PRESSURE Havelková A...........................................................................................238
INTERVAL AND CONTINUOUS TRAINING IN CARDIOVASCULAR
REHABILITATION IN MEN AFTER ACUTE MYOCARDIAL INFARCTION:
INFLUENCE ON AEROBIC CAPACITY AND PERFORMANCE
ON THE LEVEL OF ANAEROBIC THRESHOLD Chludilová V.................................................244
BAROREFLEX SENSITIVITY IN MULTIPLE SCLEROSIS Konečný L....................................251
EFFECTIVITY OF PHYSIOTHERAPY IN STROKE
IN ACUTE PHASE Tarasová M.....................................................................................................262
MUSCLE STRENGTH EXAMINATION OF HAND AND MOTOR
SKILLS OF HAND IN PATIENTS WITH CEREBRAL
PALSY Drlíková L...........................................................................................................................272
QUALITY OF LIFE AFTER CARDIOVASCULAR REHABILITATION
IN CHRONIC ISCHEMIC HEART DISEASE Pochmonová J......................................................279
AUTONOMIC NERVOUS SYSTEM IN PARKINSON’S
DISEASE Pospíšil P.........................................................................................................................288
PATIENTS WITH STROKE: RESULTS OF PHYSIOTHERAPY
AND OCCUPATIONAL THERAPY Bártlová B.............................................................................298
5
ROLE AND CLINICAL IMPORTANCE OF THE EVALUATION OF ARTERIAL
PULSES
Thomas Kenner
Physiologisches Institut, Graz
Dedication
This short and incomplete review of some own interests and some outlooks is dedicated to
Bohumil Fiser
who, together with all members of the “Brno-team” organized and stimulated so many
interesting ideas and meetings, and who together with all friends in this city made Brno to a
meeting point, where all of us love to come together.
It seems to me that many ideas and plans, on which all of us sometime started to work and
which then were forgotten or neglected, suddenly come up again, so that even some historical
parameters recently receive a kind of scientific medical OSCAR, which is titled “ GOLD
STANDARD”.
I would say, that exclusively Bohumil and all members of the "Brno Team" deserve such a
“Gold Standard” title.
Below I will try to present my opinion that I have doubts about the validity of all other “gold
standard” titles in medical science.
Remarks
The choice of words, which are used in order to express certain thoughts, gives insight into
unconscious trends of brain activity.
I am astonished about the increasing abundance of expressions like „gold standard“ in
medicine and medical research. One interesting explanation of using such an expression can
be found in Sigmund Freud’s book on “jokes and their relation to the unconscious”.
There appear to me two main considerations for an analysis. At first the jealous association of
medicine with gold and money may play a role. In fact, this is in agreement with the
observation of a present trend in clinical medicine towards business-like industrialization
(Lüscher, 2008). On the other hand it seems surprising that in the current time of financial and
banking crisis, the rather slippery and variable gold value is chosen for the description of
biological norms and standards. Perhaps unconsciously the word gold expresses the wish that
life should not be associated with the uncertainties of international oil corruption.
One such “gold standard” supposedly is the value of the pulse wave velocity for the
estimation of the stiffness along the aorta as measured between carotid and femoral artery (see
T. Weber 2008).
Introduction
The time course of functional processes in a dynamic system – like the CV-system - depends
on the structure of the system. Therefore, one can state that the observation of functional
processes can be used to extract diagnostic information about structure and function.
The functional processes of the CV-system are related to flow and pressure in the vascular
channels.
This trivial introduction aims to the question how to extract relevant diagnostic information,
and how to analyze and present this information.
Any time-dependent signal – like arterial pulses – can be analyzed and described in terms of
time domain or in terms of frequency domain.
The time sequences of arterial pressure and flow are described mathematically by a pair of
transmission equations. These equations have been used already in the 19 th century by E.H.
Weber, by A.I. Moens and by J. v. Kries.
When I read about hemodynamic recordings, interpretations and calculations I have the
feeling that experiments and descriptions should be revisited, which Wetterer and Kenner
have published in 1968 in a book, which had the disadvantage to be written in German and
which in addition is unavailable since many years. These experiments and explanations were
easy to understand and were intended to present some basic knowledge about developments
in analysis of arterial pulses in a simple form.
The following is the attempt to review and to explain some fundamental facts, which seem to
me essential for application in diagnostic procedures.
6
7
TIME DOMAIN
Pulse wave velocity
The pulse wave velocity is an essential term in these equations. The equation, which describes
the pulse wave velocity as a function of the physical properties of an elastic tube and the
contained fluid bears the name Moens’ equation:
c = Eh/2r
c: pulse wave velocity, E: elastic modulus, h: wall thickness, r: radius of the tube,
: density of the fluid
The pulse wave velocity in a tube increases with increasing elastic modulus (a measure of
stiffness) and with wall thickness. c decreases with increasing radius and increasing density of
fluid (blood).
Due to the tissue properties, distension of arteries – by increasing blood pressure – inceases
the elastic modulus and consequently the pulse wave velocity.
Characteristic impedance
For illustration of the behavior of pulse waves in an artery Wetterer and Kenner used a model
system consisting of a pump and an elastic tube, which on its distal end is adjusted with an
outflow resistance. In the example of Fig. 1 the pump generates a flow pulse. The pressure
reacts with a pressure pulse. As will be shown below, such a pump like a normal ventricle
may be called a “hard” pump. During the diastole the outflow valve is closed, consequently
no central flow can be seen during this period.
The relation between the amplitude of the pressure pulse (dp) and the flow pulse (dq) is
described by the so called characteristic impedance
Z = dp/dq
Z can be determined by the following relation:
Z = c /r2
The stiffer the artery and the higher the pulse wave velocity, the higher is the pressure
amplitude – in relation to a given flow amplitude.
8
Pulse wave reflection
Pressure and flow waves run along a fluid filled tube with velocity c. On a location where the
characteristic impedance increases or decreases or where a resistance is located, wave
reflection takes place. The reflected part of a wave then runs into the reverse direction. In the
arterial system the main peripheral reflections are positive, thus the pressure wave returns
without changing sign, as in the simple example of fig. 1 (from Wetterer and Kenner p. 28).
If a reflected wave reaches the closed outflow (e.g. aortic) valves, then total reflection takes
place – as can be seen in fig. 1. As long as the valve is open through systole, the reflection
factor may be reduced. The reflection factor k indicates the sign and magnitude of the
reflected part of the wave as related to the incoming magnitude. The following equation
describes the reflection factor at the location of resistance.
k = (R – Z)/(R + Z)
The equations include the description of the reflection of both, pressure and flow waves. It
was Ph. Broemser who recognized the fact, that the returning reflected pressure wave may
influence the ejection of the corresponding ventricle. He was the first to discuss the possibility
of an optimal matching between heartbeat and the structure of the vascular system.
Pressure-flow relation and wave reflection
A resistance R is defined as the quotient of pressure gradient and flow gradient. From the
observation of a typical pressure-flow relation it can be concluded that at any point of the
function shown in fig. 2 (from Wetterer and Kenner p. 316), that – according to the given
definition – R may have a different value for different pressure values. It was to my
knowledge R. Ronniger (1955) who recognized that for the peripheral reflection of a wave the
steepness of the pressure-flow relation in the range of the pressure amplitude is essential:
Rdiff = dp/dq
The fact that the pressure-flow relation is not proportional, but may be nonlinear and may be
described by a non-proportional line, is important for the actual values of systolic and
diastolic pressure as indicated in fig. 2. It can be concluded that the reflection factor and the
magnitude of peripheral reflection is not necessarily related to the value of the total peripheral
resistance.
9
Negative reflection
There are two interesting conditions where negative reflection takes place.
One condition is present when – e.g. in the upper extremity – a reflected wave runs towards
the branching point at the aorta. At this point the reflected wave finds – entering the aorta - a
marked decrease of the characteristic impedance. Therefore, this wave is negatively reflected.
– It returns in distal direction after changing sign.
Another condition is artificially produced by the inflation of a cuff during the classical
measurement of blood pressure. The location of the artery, which is occluded by the inflated
cuff, has an effect as a positive reflection site. During the following reduction of the cuff
pressure, the arterial pressure wave may suddenly open the occluded artery, thus generating
an effect which corresponds to a sudden shift from positive to negative reflection at this
location (see Kenner 1979). In any location and/or condition of the body where arteries are
compressed by outside pressure, similar phenomena may be present.
Hard (flow) and soft (pressure) pump
Fig. 3 (from Wetterer and Kenner p. 185) explains the difference between extreme types of
pumps. A normal strong ventricle generates flow pulses even against increasing outflow
resistance. It rather corresponds to a “hard pump”. In contrast, a ventricle in a state of
decompensation reacts markedly towards changes of outflow resistance. It rather can be
compared to a soft pressure pump. In the case of a hard pump retrograde incoming waves,
which arrive at the root of the aorta during systole are reflected positively. In the case of a soft
pump, during systole the reflection factor is reduced or even a negative central reflection can
be expected.
These considerations explain the fact that the properties of the heart muscle have a
characteristic effect on the central aortic pulse contour.
FREQUENCY DOMAIN
Resonance and transfer function
If, into the elastic-tube model, instead of periodic pulses of a certain frequency, sinusoidal
flow oscillations of variable frequency are generated by the pump then, resonance phenomena
can be observed as shown in fig. 4 (from Wetterer and Kenner p. 60).
10
It is evident, that a peripheral pressure contour has a different shape a central (aortic) pressure
pulse.
In the case of sinusoidal pressure variations, the shapes of flow and pressure are always and
everywhere sinusoidal. Besides by the frequency, central as well as peripheral oscillations can
be characterized 1. by amplitude and 2. by phase.
In fig. 4 only amplitudes can be recognized, which vary in characteristic manner as function
of the frequency.
The importance of calculations in terms of frequency domain can be explained by the fact –
mentioned above – that any signal can be transformed from time domain into frequency
domain by so called Fourier transform. An example in Fig. 5 (from Wetterer and Kenner p.
258) will be explained below.
The relation, which permits to determine the connection between two pulses describes the
frequency dependence of the relation between amplitudes and phases, and thence between the
pulse contours, is called transfer function. Recently the transfer function between radial and
aortic pressure pulses is quite often mentioned. This transfer function supposedly permits to
calculate the shape of the aortic pressure pulse from recorded pressure pulses at the radial
artery (O’Rourke 1996).
Input impedance and extended analysis of cardiovascular control
The relation between pressure and flow pulses can – in the frequency domain – be described
by a transfer function. The amplitudes (“modulus”) of this function, which depends on the
frequency has the dimension of a resistance. In order to illustrate this function, fig. 5 shows
the frequency dependence of this function from measurements by O’Rourke and Taylor in a
dog (taken from an illustration in Wetterer and Kenner 1968). Dogs have a marked respiratory
arrhythmia, which is shown as an insert; this simplifies the estimation of the data shown in
fig. 5. The function which describes the frequency dependence of the input impedance is
characterized by a U-shape with a marked minimum.
In a study published nearly 40 years ago (Kenner 1972) it was shown, that there are two
components of information in the input impedance. The part above the heart rate contains
information about the arterial system as discussed above. The second part of lower
frequencies, which can not easily be measured, contains information about cardiovascular
control; e.g. baroreceptor reflex and autoregulatory control of blood flow and blood pressure.
11
The observation of input impedance in the region of frequencies below the heart rate, depends
on the presence of slow pressure-, flow-, or heart rate- variations. In the example of fig. 5 the
spontaneous arrhythmia was useful. Also, experimentally generated variations, which
influence blood pressure and flow like e.g. tilting may be used.
In the paper mentioned (Kenner 1972), a simple method for the description and examination
of the overall control properties of the circulatory system was derived and discussed. The
objective of the study was, to present an overlook over the behavior of the whole circulation
in response to disturbances in the low frequency region. Therefore, approximated transfer
functions were used to describe the circulatory control properties.
The low frequency input impedance (frequency region between about 0.0005 Hz and heart
rate) is shown to be a very useful magnitude to examine the closed loop behavior of the
system.
The term closed loop condition indicates the presence of feedback within the system. In
contrast, open loop is an experimental condition if the sensors (e.g. baroreceptors) can be
stimulated isolated without feedback.
It is found that the basic control mechanisms in local arterial beds as well as in the whole
circulation can be described by pressure and flow control loops, both having first order
transfer properties. Considering the circulation as a whole, the fact has to be taken into
account, that the system, including the heart as an amplifier, is a mechanical feedback system.
Onto this system the autoregulatory and neural (baroreceptor) control loops exert their
influence.
A set of equations was established which permits to describe the dynamic properties of the
circulatory system under closed loop condition and under a variety of open loop conditions.
The effect of blood volume variation, infusion of vasoactive drugs, and the role of a time
delay into a control circuit can be demonstrated. The equations in addition yield a simple and
powerful stability criterion, which permits to predict under which conditions instability and
pathologic oscillations of blood pressure, blood flow and also of respiration may be
generated.
12
Summary
Quite some time after the periods of Otto Frank, Philipp Broemser and Erik Wetterer – whom
I can call my teacher and who wrote a book on the arterial pulse together with me – the
interest in arterial hemodynamics appeared not really of importance in medicine.
Recently fluid dynamics of the cardiovascular system and in particular, the generation of
arterial pressure and flow pulses gain more and more interest. Parameters and mathematical
variables were rediscovered or reinvented and several types of indices were constructed. The
computerization finally permitted easily to estimate and calculate parameters and indices. And
of course, competition between different types of instrumentation plays a role, even as far as
normal values of parameters and indices are concerned. Funny enough, as a consequence,
certain parameters and measurement techniques are being revalued as “gold standard”.
In this short study it is attempted to summarize some basic facts of cardiovascular fluid
dynamics. Furthermore it is attempted, as short as possible to explain the two ways to
describe signals: in the way of time domain and in the way of frequency domain.
Supported by grant MSM 0021622402
Literature
Freud S.: Der Witz und seine Beziehung zum Unbewussten.
Verlag Fischer, 8. Aufl. (2006)
Kenner T.: Dynamic control of flow and pressure in the circulation.
Kybernetik 9: 215-225 (1971)
Kenner T.: Physical and mathematical modeling in cardiovascular systems.
In: N.H.C. Hwang, D.R.Gross, D.J.Patel (eds.): Quantitative cardiovascular studies.
Clinical research applications and engineering principles. pp 41 - 109
University Park Press, Baltimore 1979
Lüscher T.F.: Ist die Medizin ein Business? Neue Züricher Zeitung Nr. 193, 20. 8. 2008
O’Rourke M.F.: Perspective for the 21st
century – Overview
Z. Kardiol. 85: Suppl 3: 143 145 (1996)
Ronniger R.: Zur Theorie der physikalischen Schlagvolumenbestimmung.
Arch. Kreislaufforschung 22: 332-373 (1955)
Schneditz D., Kenner T.: Noninvasive assessment of vascular function.
In: Ronco C, Brendolan A, Levin NW (eds): Cardiovascular Disorders in Hemodialysis.
Contrib. Nephrol. Basel, Karger, 2005, vol 149, pp 306-314
13
Weber T. et al.: Pulswellengeschwindigkeit, zentraler Blutdruck und ugmentationsindex –
“neue” parameter zur Beschreibung eines Endorganschadens der arteriallen Strombahn bei
Hypertonie.
J. Hyperton. 12, 7 – 13 (2008)
Wetterer E., Kenner T.: Grundlagen der Dynamik des arteriellen Pulses.
Springer-Verlag, Berlin-Heidelberg-New York (1968)
Fig, 1
Central flow pulse (bottom) and positive end-reflection of pressure pulses i flow, M pressure
(central, middle, end of tube).
Fig. 2
Non-proportional pressure (p) – flow (Q) – relation In an anesthetized dog. C control, A after
Adrenalin-infusion
14
Fig. 3
“hard” flow pump
“soft” pressure pump
Fig. 4
Resonance of pressure oscillations. From left to right the frequency of the flow-input
increases from 0.7 Hz to 6 Hz.
Arrows: resonance frequencies at 2.22 Hz and 4.44 Hz.
i flow, M pressure (central, middle, end of tube)
15
Fig. 5
Input-impedance of a dog-aorta.
(after O’Rourke and Taylor 1966).
See text.
All figures are taken from Wetterer and Kenner (1968)
16
Quo vadis chronomics 2008:
Measuring variability in us, among us and around us
Franz Halberg, Germaine Cornélissen and Othild Schwartzkopff
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
The project on The BIOsphere and the COSmos (BIOCOS) works toward change from a health
care based on spotchecks in care providers' offices to a more thorough cost-effective selfsurveillance
based on monitoring. For instance, the chronomics of blood pressure (BP) and heart rate
(HR) detect vascular variability disorders (VVDs) and their combinations in vascular variability
syndromes (VVSs). 7-day/24-hour chronobiologically interpreted ambulatory monitoring has been
ongoing at Masaryk University, the leading European academic institution for chronobiology, in
Brno. The time series thus obtained lend themselves to monitoring the sun, specifically space
weather, unseen but important, accounting for novel differences between life and death.
1. VARIABILITY ACCOUNTS FOR THE DIFFERENCE BETWEEN LIFE AND DEATH
Genetics, the study of diversity in space, in inbred mice enabled the development of
chronobiology, the study of diversity in time.
Both are important since:
In response to the same stimulus such as noise,
- one audiogenically susceptible inbred strain of mice may respond with convulsions and
death; but
- another audiogenically resistant strain may not respond to the same noise and will
survive
as studied by genetics (not shown)
In response to the same stimulus such as noise,
- one group of audiogenically susceptible mice may respond with convulsions and death
when exposed at a vulnerable time; but
- another group of the same audiogenically susceptible mice can be prevented from
convulsions and death and will survive, when exposure is targeted at a resistant time; i.e.,
by shielding in time
as studied by chronobiology
Next, nonphotic cycles were found to characterize
- sudden cardiac death, suicide, crime, war and terrorism,
as studied by chronomics
2. ORIGINS:
- Study of the quantitative rules of plant hybridization began in a pea patch in Brno, now in
the Czech Republic, and developed into genetics
- Study of the quantitative and inferential rules of variability in blood eosinophil counts in
inbred mice began in Minneapolis, USA, and developed into chronobiology
- These sciences study diversity:
- genetics in space
- chronobiology in time
The diversity of the cosmos embedded in us led to chronomics, the study of aeolian yet
congruent transdisciplinary time series around us, e.g., by chronobiologically interpreted
7-day/24-hour and much longer multidecadal, physiological and archival monitoring
implemented in Brno, Minneapolis and the broader project on The BIOsphere and the
COSmos, BIOCOS
17
These differences, first encountered in chronobiology, then extended to chronomics,
complement genetics, led to the recognition that our genes have coded the information not only ~24hour
rhythms but also about infradians with periods, , ranging from 0.5 week to s shorter and
longer than 0.5 year and to s beyond 1, 2, 3 or 5 decades. Some of these cycles discussed long ago,
forgotten and surfacing again because of biological counterparts, are detected for HR and/or mental
function (1, 2).
BIOCOS contributes papers to this volume dealing with BP (4-6) as a densely sampled variable
in order to avoid "flying blind" with respect to diagnostics, therapeutics and space weather (7-12). A
truly individualized health care starts when, in addition to a reference standard derived from peers of
the same gender and age, a sequential test also provides a reference refined for the given subject at
the given time (3). Monitoring is not a luxury when, as shown in Figure 1, the same currently
popular drug Hyzaar can do harm in a patient (Su) in the morning, but is very beneficial when taken
in the same dose by the same person in the evening some weeks later. In Su, Figure 1, described in
detail in these proceedings by Prof. Watanabe (3), medication was changed systematically, on a
usual routine of living with diurnal activity and nocturnal rest. In the morning the medication raised
the circadian amplitude of BP to an extent of exacerbating or inducing a circadian overswing or
CHAT, whereas at another time it lowered both the circadian amplitude and MESOR, and offered
benefit, Figure 1.
Figure 1 © Halberg
Earlier, Figures 2 and 3, a student (TT), in whom a high BP was just diagnosed and in whom
the administration time, as in Su, had also been systematically varied around the clock to find the
optimal treatment time, we found differences as a function of time. The optimal time differed
between patients Su and TT. More specifically, we show in Figure 2 how medication was changed in
one and the same newly diagnosed patient: the same dose of the same treatment at certain times,
such as at 12:00, did not lower the BP MESOR further (fifth column headed " Rx 12"). When we
tried the same treatment time again, (11th
column), we found that it failed. In Figure 3, we also find
that at certain times, such as at 20:00, the treatment raises the circadian amplitude of BP in TT.
18
-17.6
-13.2
-8.8
-4.4
0.0
4.4
9/26/04 10/10/04 10/24/04 11/7/04 11/21/04 12/5/04 12/19/04 1/2/05 1/16/05 1/30/05 2/13/05 2/27/05
Time (calendar date)
CUSUM
Effect
detected
Estimated
time effect
took place
(from back-
tracking)
: No Rx to Rx at 00:00
Rx Time
(clock hour): None Rx 00 Rx 04 Rx 08 Rx 12 Rx 16 Rx 20 00 04 08 12 16
Increase
Decrease
Decision
Interval
Figure 2. Changing timing of medication ( Rx) during consecutive spans shows efficacy of treatment. An
empirical approach to chronotherapy: immediately after diagnosis, one should ascertain that the treatment
is effective. Optimization of treatment effects by timing can be achieved for the individual patient by
systematically changing, e.g., advancing the time of treatment. Successful treatment of MESORhypertension
assessed by a self-starting cumulative sum control chart (Cornélissen et al. 1997). To
optimize his hypotensive treatment (Rx), a just-diagnosed 24-year-old individual (TT) switched his Rx first
every 17 days by 4 hours and then mostly at shorter intervals. Note statistically significant decrease in
MESOR, evidenced by the breakout outside the decision interval of the negative CUSUM line. With
continued Rx, the blood pressure MESOR leaves the decision interval, indicating a statistically significant
decrease in overall blood pressure. © Halberg
-17.6
-13.2
-8.8
-4.4
0.0
4.4
9/26/04 10/10/04 10/24/04 11/7/04 11/21/04 12/5/04 12/19/04 1/2/05 1/16/05 1/30/05 2/13/05 2/27/05
Time (calendar date)
CUSUM
Effect detected in retrospect
(at time of summary after
end of recording)
Estimated time
effect took place
(from backtracking)
: No Rx to Rx at 00:00
Rx Time
(clock hour): None Rx 00 Rx 04 Rx 08 Rx 12 Rx 16 Rx 20 00 04 08 12 16
Increase
Decrease
Decision
interval
Figure 3. Changing timing of medication ( Rx) during consecutive spans shows risk of iatrogenic CHAT.
An empirical approach to chronotherapy: immediately after diagnosis, one should ascertain that one does
not induce circadian hyper-amplitude-tension (CHAT) by inappropriate timing of anti-hypertensive
medication. In this 24-year old man (TT) who advanced the time of treatment by 4 hours every 17 days
initially and at shorter intervals thereafter, treatment in the evening was associated with iatrogenic CHAT,
raising the question whether the risk of MESOR-hypertension may not have been traded for the even
higher risk of stroke that CHAT represents (see p. 30 of Halberg et al. 1995). Iatrogenic circadian CHAT,
induced by treatment at 20:00 daily, was silent to office visits. TT may have traded benefit (lowering of the
MESOR of blood pressure, Fig. 2) for something worse (circadian overswinging of BP). This danger applies
to some hypertensives (who tend to have a large circadian amplitude of BP) to whom treatment time is not
specified by the care provider, as was the case for TT (or is specified for bedtime). A few others who took
hypertensive medication at bedtime were also found to have CHAT. The figure also shows the assessability
of otherwise undetected harm by as-one-goes sequential analysis. © Halberg
19
Clearly, we need continued surveillance since we cannot predict when the lesson of Figure 1
may apply; the monitors are still slightly obtrusive and costly, but are affordable in BIOCOS with an
80% price reduction for use on a family-and-friends basis. We have the software to analyze
treatment and other effects objectively, but we need computer routines to bridge gaps for special
problems of research. To get this job done in a temporal microscopy and telescopy, when often the
data present themselves with gaps; these problems are overcome by least-squares up to a point.
Hence, methods to deal with unequally spaced data are of special concern to Prof. Jerzy Czaplicki
(13), and we are glad to have his contribution included herein.
The task remaining is that of the education of the public first and foremost, and of medical
students upstream and of care providers, of course, to the extent possible. To cite a historical
example, surgeons found it a terrible burden when it was suggested that they scrub before surgery. It
will take more cases, such as that of fulminating CHAT (Figure 11 in [4]), to convince the public of
the necessity to diagnose and treat vascular variability disorders, VVDs, notably when two or more
VVDs coexist in vascular variability syndromes, VVSs, Figure 1.
In this volume, we deal further with cancer, which also poses the task of marker rhythms
monitoring so as to individualize the timed treatment, but as a compromise to practicality, a simple
protocol is advocated (14) to convince the profession that the results already in hand in terms of
circadian optimization need extension. In another paper, at the level of the eukaryotic unicell (15),
we find again, as in the circulation, signatures of the cosmos, as we do when chronomics aligns
suicides with the terrestrial and solar environment (16). Prof. George Katinas finds two of the solar
beat periods in his diastolic BP (5), and we find that same ~0.42-year period in the 17-KS excretion
and in urine volume of a late friend who monitored his steroid excretion for 15 years, Figure 4,
whether he stayed at home in Copenhagen, visited Haile Selassie, the emperor of Abyssinia (now
Ethiopia), or lectured at the Royal Society (he always took a volumetric along and saved a sample of
his 24-hour urine) for determining the breakdown products of steroids, hormones essential for
survival and reproduction. Moreover, the time course of 17-KS at the ~0.42-year period mimics that
of the planetary geomagnetic index Kp, Figure 5 (17), and we find that the same ~5-month solar
period is globally congruent in period also with the volume of urine in which the steroids were
determined, Figure 6, but the time course of urine volume (not shown) mimics that in the cycle of
Zürich numbers, a measure of solar activity also gauged by proxies such as aurorae (18). BIOCOS
and the broader chronomics welcome the cooperation of Prof. Jarmila Siegelova in the spirit of
Mendel and hope that her initiative in BP and HR monitoring will not have to wait (as long as
Mendel had to) to see the fruits of her endeavors. This hope is justified since by contrast to Mendel,
who was denied the right to teach, Jarmila is teaching us even as emerita. With her, we reanalyze the
original data of Brückner and Lockyer, and follow-up information that became available in the
interim (19) validating by chronomics the pioneers' time-macroscopic scholarship.
In summary, we have tools for monitoring BP and HR that are somewhat cumbersome and
costly, but are cost-effective and will be further improved as the demand for them increases. We
have computer programs for a chronobiologic diagnosis and, what seems critical, for a
chronobiologic optimization of the timing of treatment and for surveillance of its maintained
efficacy. What is needed most is the recognition by the public and the medical student that a good
drug at the wrong time can do harm, whereas at the right time it serves well. If a system with a
website now being built becomes a reality, it can serve not only the user's individualized health care,
but will also monitor the sun and its associations that include sudden cardiac death, suicide and the
greatest societal ills affected by the cosmos, crime, war and terrorism, and thus the course of history.
Figures 7 and 8 should emphasize the need to store, analyze and use data; Figure 9 shows a plan for
doing so.
20
Figure 4. Urinary 17-ketosteroid recorded over 15 years in CH, a clinically healthy male scientist 49 years
of age at start of study. Chronobiologic serial section showing, on top, the daily excretion of 17ketosteroids;
in the next row the MESOR, M, as the lower curve and the cis-half-year (0.42-year) amplitude,
A, as the distance between the two curves in the second row; dots below the lower and above the upper
curves indicate the standard deviations of the Ms and As. Acrophases in the third row are shown with dots,
corresponding to their CIs (95% confidence intervals) when results are statistically significant, P-values for
the rejection of the "no 0.42-year" amplitude are shown in the fourth row and are mostly below the dashed
horizontal line indicating the 5% level. The time course of cis-half-year acrophases in this figure mimics
when the no 0.42-year amplitude assumption can be rejected the time course in Figure 5 of the acrophases
of the cis-half-year of the planetary geomagnetic index, Kp. Urine volume is congruent overall in period
globally with the former two variables, but its phase behavior is transiently congruent only with relative
sunspot (Zürich) numbers differing in its time course from that of the phase of 17-KS and Kp (not shown).
The two biospheric variables differ in terms of their environmental phase synchronization. © Halberg.
21
Figure 5. A chronomic serial section of the planetary geomagnetic index Kp from October 23, 1948, to
October 29, 1963, with the fit of a 0.42-year cosine curve shows a similar time course of acrophases as that
of the 17-KS in Figure 4. Note that statistical significance is lost toward the end of the record for Kp in this
figure, but not for 17-KS in Figure 4. Note further at the beginning the lack of statistical significance in Kp,
but not in 17-KS may be driven by Kp, but this is not suggested by the behavior of the As that are quite
large for 17-KS at the end of the record in Figure 4, while the cis-half-year is not statistically significant in
Kp and its amplitude decreases with time. Time courses of intermittently congruent environmental periods
concurrent with the persistence of a previously or subsequently congruent period in the biosphere (when
the previously congruent environmental period is not detected) serve to resolve partial endogenicity in
cosmic-biospheric associations, preferably when all data series are equidistant and are the longest
available matching data series at a given time. Problems arise when at least one series is unequidistant
because of artifacts that can simulate a periodicity when none exists and vice versa can obscure a real
periodicity to the point that it is no longer detected. © Halberg.
22
Figure 6. Global spectral window with a predicted ~154-day (0.42-year) component in both the excretion of
certain breakdown products of steroidal hormones (the 17-ketosteroids, 17-KS) (top) and in the volume of
urine excreted by a clinically healthy man (CH) (bottom). The ~0.42-year component is also found in two
related but not identical environmental variables, the geomagnetic index (Kp) (Figure 5) and solar activity
(Zürich relative sunspot numbers, not shown). © Halberg.
23
Figure 7. Failure to store, analyze and use routine
cardiovascular, e.g., blood pressure, heart rate or
other ECG monitoring for both further medical
research in the light of long-term outcomes and the
transdisciplinary study of solar variations recall the
tall tale of Baron Münchhausen's horse, which was
cut in two by the town gate as it closed: when the
head of the horse subsequently drank at the well,
the water poured of its severed midsection onto the
ground. Similarly, much information from within the
physiologic range (the indispensable water in our
analogy) is lost today but may be usefully recycled
tomorrow. Illustration by Martin and Ruth KoserMichaels
from Münchhausen: Des Freiherrn
Wunderbare Reisen und Abenteuer, Droemersche
Verlagsanstalt, Munich, © 1952, facing p. 32.
Reproduced with permission of the publisher.
Figure 8. The alternative to the status quo is recycling, in a website in Figure 9. © Halberg.
24
Figure 9. The Phoenix Group of volunteering electrical and electronic engineers from the Twin Cities
chapter of the Institute of Electrical and Electronics Engineers (http://www.phoenix.tcieee. org) is planning
on developing an inexpensive, cuffless automatic monitor of blood pressure and on implementing the
concept of a website (www.sphygmochron.org) for collection and analysis of data collected with these
instruments. © Halberg.
25
1. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F. BrücknerEgeson-Lockyer
(BEL) cycle in heliogeomagnetics.
2. Halberg F, Cornélissen G, Sothern RB, Otsuka K, Revilla M. Circadian stage-dependent infradianmodulated
changes in a mental function during aging (MTE).
3. Watanabe Y, Cornélissen G, Halberg F, Beaty L, Siegelova J, Bakken EE. Harm vs. benefit from
losartan with hydrochlorothiazide at different circadian times in MESOR-hypertension or CHAT.
4. Cornélissen G, Halberg F, Kaufman SC, Sanchez de la Peña S, Otsuka K, BIOCOS project. Should 7day/24-h
chronobiologically interpreted blood pressure monitoring replace single measurements before
cataract surgery?
5. Katinas GS, Halberg F, Cornélissen G, Sanchez de la Peña S, Czaplicki J, Siegelova J, BIOCOS project.
C-ABPM reveals solar cis-halfyear and transyear signatures in human diastolic blood pressure.
6. Watanabe F, Cornélissen G, Watanabe Y, Siegelova J, Czaplicki J, Halberg F, BIOCOS project.
Differing far-transyear/calendar year amplitude ratios in blood pressure vs. heart rate in adolescence.
7. Watanabe Y, Cornélissen G, Katinas GS, Watanabe F, Halberg F. Chronomics: anxiety disorder in
adolescence and desynchronization of heart rate from weekly schedule.
8. Watanabe Y, Cornélissen G, Halberg F, Hillman D, Czaplicki J, Sothern RB, Otsuka K, Siegelova J,
BIOCOS project. Transyears, no calendar-year in blood pressure decades before MESOR-hypertension:
normal or abnormal?
9. Watanabe Y, Cornélissen G, Otsuka K, Revilla M, Czaplicki J, Schwartzkopff O, Siegelova J, BIOCOS
project. Time-specified norms reveal full systolic but incomplete diastolic early MESOR-hypertension,
MH.
10. Cornélissen G, Siegelova J, Abramson J, Sundaram B, Mandel J, Holley D, Halberg F. Body mass index
(BMI), pulse pressure (PP) and premetabolic syndrome.
11. Hörmann H, Cornélissen G, Halberg F. Ambulatory profile in a non-ambulatory subject: a
sphygmochron with gaps (when we should measure again, not interpolate).
12. Katinas GS, Cornélissen G, Halberg F, Sanchez de la Peña S, Czaplicki J, Siegelova J, BIOCOS project.
Pain and the cardiovascular system revisited in a long-term monitoring.
13. Czaplicki J, Cornélissen G, Halberg F. On gaps and interpolation methods to avoid errors in period
estimation with conventional time series analysis.
14. Halberg Francine, Cornélissen G, Halberg F, Ulmer W, Sanchez de la Peña S, Siegelova J,
Schwartzkopff O, BIOCOS project. Reasons for a protocol for radiation treatment aimed at exploiting
weekly rhythms.
15. Halberg F, Cornélissen G, Katinas GS, Hillman D, Berger S, Woolum JC, Sanchez de la Peña S,
Siegelova J. The cosmos in a eukaryotic unicell.
16. Halberg F, Wolff C, Cornélissen G, Berk M, Dodd S, Henry M, Wetterberg L, Nolley E, Beaty L,
BIOCOS project. Solar signatures in Australian suicide incidence: gender differences in prominence of
photic vs. nonphotic spectral components.
17. Sothern RB, Katinas GS, Cornélissen G, Halberg F. A transtridecadal cycle in human heart rate:
selective infradian, notably multidecadal solar-physiologic BEL congruences.
18. Cornélissen G, Halberg F, Revilla M, Siegelova J, Schwartzkopff O, Czaplicki J, Sanchez de la Peña S,
Schröder W, BIOCOS project. Auroral aeolian periodicity during 1545-1724, including the Maunder
minimum.
19. Halberg F, Cornélissen G, Czaplicki J, Prabhakaran Nayar SR, Siegelova J. Brückner-Egeson-Lockyer
(BEL) climate cycle in original BEL data.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM 0021622402
26
Circadian stage-dependent infradian-modulated changes in a mental function during aging
Franz Halberg1
, Germaine Cornélissen1
, Robert B. Sothern1
, Kuniaki Otsuka2
, Miguel Revilla3
Jarmila Siegelova4
, Bohumil Fiser4
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
University of Valladolid, Valladolid, Spain
4
Masaryk University, Brno, Czech Republic
RBS, a clinically healthy man, started estimating 1 minute by counting at 25 years of age: he
continued such estimations 2-7 times/day on the average 5 times/day, until the age of 60, with very
few interruptions. The data are here separated into 3-hourly bins, providing 8 data sets for 8
fractions of the 24-hour day, i.e., 00:00-03:00, 03:00-06:00, 06:00-09:00 ..., 21:00-00:00. The mean
and standard error (SE) were determined for each daily fraction on a yearly basis. Changes as a
function of age were assessed by linear regression of yearly means for each of the 8 3-hour
circadian stages. Results are shown in Figure 1.
Between 09:00 and 12:00, counting
to 60 takes statistically significantly less
time at 60 than at 25 years of age
(r=-0.802, P<0.001), whereas between
18:00 and 21:00, the opposite is true
(r=+0.400, P=0.016). The bin from 03:00-
06:00 is the least documented, by only 199
measurements; it is most irregular to
eyeballing, presumably due to the
relatively small number of tests. In the 7
other well-documented bins (N=2888-
10542), the data between 00:00 and 03:00
allow the naked eye to discern a
modulation by cycles with relatively long
periods, but any impression of one or the
other longer cycle is subjective. Table 1 is
objective and qualifies impressions.
Testing the estimation of one minute
for decades around the clock at different
times of the day corresponding to different
circadian stages (on a routine of diurnal
activity and nocturnal rest) thus reveals
diverse changes as a function of age. To
the unaided eye, these occur at some
circadian times, seemingly more or less
linearly, albeit in different, even opposite
directions, and/or at other times are overtly
modulated by infradian cycles. When
analyzed time-microscopically, such
modulations are not the same, Table 1.
If we conceive of a time structure
with a spectral element and an element of
trends, the latter including one with age, we find in Table 1 that the spectral element of a mental
function has several components, contributing in different ways to aging (1, 2). Above all, the
Figure 1. Different time course of aging in data
collected during various 3-hour spans of the day,
during 36 years of around-the-clock estimations of 1
minute. RBS, clinically healthy man, 25 years of age
at start of 1-minute estimations ~5 times a day for 36
years. © Halberg.
27
circadian rhythm's stage determines opposite effects that in their turn can be modulated further by
components that also differ with circadian stage, Table 1. Most surprising is that between 12:00 and
21:00, an about 34-year component is statistically significant as a putative signature of the
Brückner/Egeson/Lockyer cycle (3-6), also recently documented by Maravilla et al. (7) (35.6
years). Table 1 shows a few other periodicities as well in the same mental function, including about
15-year and about 9-year cycles, if not a circadecadal component, the former corresponding perhaps
to a global cycle (8), the latter perhaps a signature of the solar wind, both validated by these
analyses.
Table 1: Spectral components, including a Brückner/Egeson/Lockyer cycle of ~34 years,
modulating aging of a mental function revealed by separate analyses according to circadian
stage*
3-Hour
Bins of
time
Initial
Trial
period (y)
Convergent NLLS
Period [95% CI] (y) Amplitude [95% CI]
00-03 35 17.27 [13.65, 20.88] 1.55 [0.21, 2.89]
03-06 " 27.07 [17.50, 36.63] 4.54 NS
06-09 " 19.49 [14.64, 24.35] 1.73 [0.42, 3.04]
12-15 " 30.94 [16.37, 45.50] 0.87 [-.09, 1.82] BSS
15-18 " 33.53 [20.24, 46.81] 1.19 [0.11, 2.27]
18-21 " 33.63 [20.69, 46.58] 1.12 [0.16, 2.08]
21-24 " 18.66 [14.88, 22.44] 1.87 [0.62, 3.12]
03-06 15 19.31 [12.70, 25.92] 4.08 NS
09-12 " 17.57 [11.67, 23.46] 1.45 NS
12-15 " 14.29 [11.40, 17.17] 0.95 [0.04, 1.86]
15-18 " 13.95 [10.75, 17.15] 0.98 NS
18-21 " 14.27 [ 9.70, 18.84] 0.70 NS
12-15 10 9.09 [ 7.75, 10.43] 0.87 [-.05, 1.78] BSS
15-18 " 8.93 [ 7.49, 10.36] 0.96 [-.12, 2.05] BSS
18-21 " 8.92 [ 6.95, 10.89] 0.67 NS
Weekly
means
35, 25 or
11 y
25.92 [23.68, 28.16] 1.17 [0.90, 1.44]
*Results converge to nonlinear least-squares (NLLS) analyses of different clock-hour bins
approximating various circadian stages in RBS, a clinically healthy man 25 years of age at start of
estimations continued to the age of 60 years (and beyond). BSS = borderline statistically significant,
NS = not significant.
28
Figure 2. Opposite time course of aging during several
decades as a function of clock-hour of testing the
estimation of 1 minute. RBS, clinically healthy man, 25
years of age at start of 1-minute estimations ~5 times a
day for 36 years. © Halberg.
It is methodologically noteworthy that opposite effects can be seen at different circadian
stages, to a point that in the morning, time passes faster at age 60 than at the age of 25 years and the
opposite is true in the evening, Figure 2. Figure 1 and Table 1 also document that possible solar
infradians deserve consideration as circadian stage-dependent modulating entities. These
conclusions are in keeping with the detection (in SBS, the father of the subject here investigated), of
a prominent half-yearly spectral component in the evening, but not in the morning in his selfmeasurements
of blood pressure during 22 years (9). Melatonin concentrations tend to be higher in
the evening than in the morning. This may render a person more sensitive to geomagnetics in the
evening than in the morning. Geomagnetics that display a prominent component with a period of 6
months (10, 11) can actually be tested by follow-up analyses of the time courses of the solar and
biospheric variables involved to see whether subtraction and addition in waxing and waning
amplitudes of the half-year component in geomagnetics (or any other pertinent frequency more
generally) may have any coincident associations in the biosphere (12, 13).
Mental aging, dealt with by the axiom "use it or lose it" (14), may actually be qualified as
"improve it", perhaps more so by timing, i.e., by using any mental exercise at the best time for
optimization, a task for the future. For all students of aging, however, it seems clear that studies
29
done on a variable that changes its circadian amplitude with age such as a number of hormones do
(1, 15), will have to be repeated with a view of different circadian stages contributing differently to
the results (at circadian maxima and minima in opposite ways).
The reason can be readily understood: If the amplitude increases with age, there will be an
increase with age at the time of peak and a decrease at the time of trough, unless there is also a
change in daily mean (MESOR) and/or phase. Vice versa, again assuming no change in phase if the
circadian amplitude decreases with age, as in the case of circulating DHEA-S (15), there will be a
decrease at peak time and an increase at trough time, unless there is also a change in MESOR
and/or phase. As to Figure 1, the 09:00-12:00 span is probably associated with maximal cortisol
concentration in blood, which is considerably decreased in the evening hours: the hormone may
contribute to mental function. The span from 00:00 to 03:00 may be characterized by maximal
melatonin concentration.
Figure 3. While effects in opposite directions may contribute to canceling
any effect of aging on MESOR, the acrophase advance is statistically
highly significant, in keeping with similar findings for other variables
such as blood pressure and heart rate. RBS, clinically healthy man, 25
years of age at start of 1-minute estimations ~5 times a day for 36 years.
© Halberg.
30
Using the 8 3-hourly means computed for each year from 1971 to 2006, a 24-hour cosine
curve was fitted by least squares to yield estimates of the circadian MESOR, amplitude and
acrophase. These yearly imputations were linearly regressed as a function of age. Whereas no
change in MESOR is observed (r=0.020, P=0.908), there is a slight tendency for the circadian
amplitude to decrease with age, as anticipated (r=-0.197, P=0.249), and there is a marked circadian
acrophase advance (r=0.551, P<0.001), Figure 3. All three parameters are also characterized by an
about 19-year component, resolved nonlinearly. Period estimates (and 95% confidence intervals)
are 19.20 (15.25, 23.15) years for the MESOR, 18.99 (13.95, 24.04) years for the circadian
amplitude, and 19.91 (15.90, 23.93) years for the circadian acrophase, with respective amplitudes
(and 95% confidence intervals) of 1.55 (0.49, 2.62) s, 1.08 (0.10, 2.06) s, and 12.45 (4.99, 19.91)
degrees (with 360 degrees corresponding to 19.91 years), respectively.
In the presence of low-frequency cycles with periods of about 10 years or longer as found
herein, it is premature to speculate until accrual of more cases like RBS, and these added subjects
and RBS himself collect longer series, so that time series covering at least 2 replications/subject and
preferably more can be analyzed.
1. Halberg F, Sothern RB, Cornélissen G. Chronomics, human time estimation and aging. In
preparation.
2. Halberg E, Halberg J, Halberg Francine, Sothern RB, Levine H, Halberg F. Familial and
individualized longitudinal autorhythmometry for 5 to 12 years and human age effects. J
Gerontol 1981; 36: 31-33.
3. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
4. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
5. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
6. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
7. Maravilla D, Lara A, Valdés Galicia JF, Mendoza B. An analysis of polar coronal hole
evolution: relations to other solar phenomena and heliospheric consequences. Solar Phys
2001; 203: 27-38.
8. Markov VI, Sivaraman KR. New results concerning the global solar cycle. Solar Phys 1989;
123: 367-380.
9. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clockhour
in long-term investigation is no panacea. Proc., International Conference on the Frontiers
of Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 208-211.
10. Chapman S, Bartels J. Geomagnetism. 3rd ed. Oxford: Clarendon Press; 1962. 1049 pp.
11. Cornélissen G, Halberg F, Pöllmann L, Pöllman B, Katinas GS, Minne H, Breus T, Sothern
RB, Watanabe Y, Tarquini R, Perfetto F, Maggioni C, Wilson D, Gubin D, Otsuka K, Bakken
EE. Circasemiannual chronomics: half-yearly biospheric changes in their own right and as a
circannual waveform. Biomedicine & Pharmacotherapy 2003; 57 (Suppl 1): 45s-54s.
12. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
13. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
31
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
14. Recer P. The aging brain: use it or lose it. Cosmos Club Bulletin 2008; 61: 16-17.
15. Halberg F, Cornélissen G, Sothern RB, Wallach LA, Halberg E, Ahlgren A, Kuzel M, Radke
A, Barbosa J, Goetz F, Buckley J, Mandel J, Schuman L, Haus E, Lakatua D, Sackett L, Berg
H, Wendt HW, Kawasaki T, Ueno M, Uezono K, Matsuoka M, Omae T, Tarquini B, Cagnoni
M, Garcia Sainz M, Perez Vega E, Wilson D, Griffiths K, Donati L, Tatti P, Vasta M,
Locatelli I, Camagna A, Lauro R, Tritsch G, Wetterberg L. International geographic studies of
oncological interest on chronobiological variables. In: Kaiser H (ed.) Neoplasms—
Comparative Pathology of Growth in Animals, Plants and Man. Baltimore: Williams and
Wilkins; 1981. p. 553-596.
Supported by grant MSM 0021622402, GM-13981 (FH), University of Minnesota Supercomputing
Institute (GC, FH).
Prof. Franz Halberg, M.D., Dr. h.c. (Montpellier), Dr. h.c. (Ferrara), Dr. h.c. (Tyumen), Dr. h.c. (Brno),
Professor of Laboratory Medicine and Pathology, Physiology, Biology, Bioengineering and Oral medicine,
Director, Halberg Chronobiology Center, University of Minnesota, Mayo Mail Code 8609, Dept of
Laboratory Medicine, Minneapolis Campus
420 Delaware Street SE, Minneapolis, MN 55455, USA
32
The cosmos in a eukaryotic unicell
Franz Halberg1
, Germaine Cornélissen1
, George S. Katinas1
, Dewayne Hillman1
, Sigrid Berger2
,
John C. Woolum3
, Salvador Sanchez de la Peña4
, Jarmila Siegelova5
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Fakultät für Biowissenschaften (Botanik), Ruprecht-Karls-Universität Heidelberg, Heidelberg,
Germany
3
California State University, Los Angeles, CA, USA
4
Chronomic Res. Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City,
Mexico
5
Masaryk University, Brno, Czech Republic
This paper is dedicated to the memory of Hans-Georg Schweiger, who with one of us (SB)
maintained an artificial culture of unicellular giant cells of Dasycladales at the Max-Planck-Institut
für Zellbiologie after 1977 in Ladenburg bei Heidelberg, Germany. Hans-Georg realized that there
are more rhythms than circadians, focusing on about (~) 7-day cycles. We here add evidence of
~yearly and even longer spectral components as signatures of our cosmos at the unicellular level.
Abstract
Acetabularia (Ac) is a model for a broad spectrum of rhythms, some mapped in individual
unicells, others based on serially-independent sampling over a span of 14 years. We here
emphasize first and foremost, with the late Hans-Georg Schweiger, that ~7-day rhythms can freerun
in a unicell just as circadians do, desynchronized from a precise weekly schedule. The photic
circannual rhythm here mapped is shown to be neither the sole nor the largest peak in a spectral
window by the extended cosinor, a near- and a far-transyear can be documented in Ac as well as
circadecadals, suggesting that nonphotics have been coded in genes already ~500 million years
ago.
Acetabularia acetabulum
Ac is a eukaryotic giant unicellular alga with a nucleus that can be easily removed, a first
advantage. At least equally important, however, is that this atavistic organism has a spectral
element in its chronome (time structure), including inferentially statistically mapped ~24-hour
(circadian) (1), ~half-weekly (circasemiseptan) (2), ~7-day (circaseptan) (3), ~half-yearly
(circasemiannual) (4), yearly (circannual), longer-than-yearly -- near-transyearly (1.00 year <
[ {period} - CI {95% confidence interval}] < [ + CI] < 1.20 years} and far-transyearly (1.2 years
[ - CI] < [ + CI] < 1.9 years) (5) -- and ~10-yearly (circadecadal) (4, 5) cycles. This
combination of photic and nonphotic components in the spectral element of Ac's chronome makes
this organism unique among unicells. Much work has focused on Ac. acetabulum (formerly Ac.
mediterranea), but other species, including Acicularia schenckii, have also been cultivated and
investigated under laboratory conditions.
The relative prominence of circadian and circaseptan rhythms as spectral components in Ac.
acetabulum kept under conditions of light (L) and darkness (D) alternating at 12-hour intervals
(LD) and in continuous light (LL) is shown for oxygen production in Figure 1. A prominent 24hour
component in LD is very much reduced in amplitude in LL. This figure shows further in LD a
weekly (168-hour) component that is less prominent than the circadian and is likewise reduced in
amplitude in LL, but to a lesser extent, as compared to the circadian amplitude reduction in LL.
Accordingly, for oxygen production by Ac. acetabulum in LL, the circaseptan amplitude is larger
than the circadian amplitude, Figure 2.
33
0
10
20
30
40
50
60
70
80
RelativeAmplitude(LDMESOR=100%)
* Mean and 95% Confidence interval
OXYGEN PRODUCTION by ACETABULARIA
CIRCADIAN
ALL / ALD = 0.07
CIRCASEPTAN
ALL / ALD = 0.57
LD LL LD LL
168 24
RELATIVE PROMINENCE of 168 h and 24 h AMPLITUDE *
ON REGIMENS of ALTERNATING LIGHT and DARKNES (LD 12:12)
versus ON CONTINUOUS LIGHT (LL)
Fitting
PERIODS
Lighting
REGIMEN
N of algae 16 18 18 18
P < 0.0001P = 0.053
0
10
20
30
40
50
60
70
80
RelativeAmplitude(LDMESOR=100%)
* On regimens of light and darkness alternating at 12-h intervals
(LD 12:12) and in continuous light (LL); Mean and 95%
Confidence Interval.
168 24 168 24
LD LL
0.28
A168 / A24
RELATIVE PROMINENCE
of 168-h versus 24-h AMPLITUDE *
Fitting
PERIODS
OXYGEN PRODUCTION by ACETABULARIA
Lighting
REGIMEN
N of algae 16 18 18 18
P < 0.0001
2.33
P < 0.0003
Figure 1. Inhibition by LL after transfer from LD is
greater for a prominent circadian rhythm of
Acetabularia acetabulum than that for a less
prominent (in LD) circaseptan rhythm. © Halberg.
Figure 2. In keeping with Figure 1, a circaseptan
rhythm is more prominent than the circadian in LL
and less prominent in LD. © Halberg.
6.000
6.212
6.431
6.657
6.892
7.135
7.387
7.647
7.917
8.196
8.485
8.785
9.094
9.415
9.747
10.091
10.447
10.815
11.196
11.591
12.000
12.423
12.861
13.315
13.784
14.271
14.774
15.295
15.834
16.393
16.971
17.569
18.189
18.830
19.494
20.182
20.893
21.630
22.393
23.183
24.000
24.846
25.723
26.630
27.569
28.541
29.548
30.590
31.668
32.785
33.941
35.138
36.377
37.660
38.988
40.363
41.787
43.260
44.786
46.365
48.000
25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99 101 103 105 107 109 111 113 115 117 119 121 123 125 127 129 131 133 135 137 139 141 143 145 147 149 151 153 155 157 159 161 163 165 167 169 171 173 175 177 179 181 183 185 187 189 191 193 195 197 199 201 203 205 207 209 211 213 215 217 219 221 223 225 227 229 231 233
48
32
24
12
6
2 3 4 5 6 7 8 9 10
Time (days after release in continuous light)
ELECTRICAL POTENTIAL of ACETABULARIA ACETABULUM *
* Integrated over consecutive 2 minutes, averaged for 30 minutes, averaged further for 22
single cells at start, 8 cells at end, analyzed by a moving periodogram, presented
as a contour map, with the darkest shades corresponding to most prominent amplitudes.
16
8
Figure 3. Gliding spectral window reveals nonstationary nature of circadian rhythm in LL, waxing and
waning and drifting in frequency in LL. © Halberg.
34
-100
-50
0
50
100
150
0
SIGNAL-AVERAGED ELECTRICAL POTENTIAL
of ACETABULARIA ACETABULUM *;
TIME-MACROSCOPIC VIEWResidualsafterdetrending(arbitraryunits)
Time (days in LL)
0 2 4 6 8 10
* 20 single cells; Total number of observations: 38,578; experimental span:
376 days. Metaanalyzed data of Dr Sigrid Berger, Dr Luebbo von Lindern and
the late Dr Hans-Georg Schweiger.
Figure 4. The naked eye sees the greater aboutweekly
as compared to the about-daily swing during
the first 10 days in LL after prior synchronization in
LD. © Halberg.
LARGER ABOUT-WEEKLY THAN ABOUT-DAILY CYCLE IN ELECTRICAL POTENTIAL OF A
UNICELLULAR ALGA ACETABULARIA ACETABULUM EVOLVED 500 MILLION YEARS AGO*
* Nonlinear spectral analysis on signal-averaged data from 20 single cells, released (zero time) into continuous light
(LL), After prior standardization in light and darkness alternating at 12-hour intervals (LD12:12) for up to one week.
Total number of observations: 38,578; experimental span: 376 days. Note a more prominent amplitude (A) for a
component with a period near a week, than tha As of the about daily and about half-weekly components (all freerunning).
The circaseptan A is equated to 100 and the other As are expressed as percentage of the circaseptan.
Metaanalyzed data of Dr. Sigrid Berger, Dr. Luebbo von Lindern and the late Dr. Hans-Georg Schweiger.
Figure 5. Curve-fitting to data in Figure 4 shown as original values (dots) quantifies 3 spectral components
(right) with circaseptan prominence. © Halberg.
35
-30
-20
-10
0
10
20
30
0 24 48 72 96 120 144 168 192 216 240 264
DIFFERENT TIMING
of FREERUNNING CIRCASEPTAN COMPONENT
in OXYGEN PRODUCTION (OP), CHLOROPLAST
MIGRATION (CM) and ELECTRICAL POTENTIAL (EP)
in ACETABULARIA ACETABULUM *
* Released into continuous light (LL) after prior standardization in light and darkness
alternating at 12-hour intervals; period of 162.13 hours is average of presumably
free-running periods of 160.7, 162.2 and 163.5 hours, for OP, CM and EP, respectively.
Signal-averaged values of 20 - 24 single cells, each series detrended by 2nd or 3rd
order polynomial, depending on length of series ( < or > 14 days). Data from
Dr. Sigrid Berger, Dr. Luebbo von Lindern and the late Dr. Hans-Georg Schweiger.
Residualsafterdetrending(arbitraryunits)
Time (days in LL)
0 2 4 6 8 10
OP
CM EP
Acrophases and their 95% Confidence Intervals
Figure 6. Division of labor in time in LL in a
eukaryotic unicell, as shown by nonoverlapping
95% confidence intervals
displayed by the width of bracketed
horizontal lines on one of the peaks in each
of the 3 approximating functions. © Halberg.
CIRCADECADAL RHYTHM IN CIRCADIAN ACROPHASE (FRACTION OF CYCLE) OF
OXYGEN PRODUCTION OF ACETABULARIA MEDITERRANEA*
*Approximated by -0.6772 + 0.013 cos (2 t/11 y - 0.1375); tref = 2 Jan 1980; PR=10.2%; P<0.001; measurements in
LD12:12. Data kindly provided by Prof. Sigrid Berger.
Figure 7. Circadidecadal cycle in circadian acrophase in a population of unicells: putative signature of
Schwabe's cycle (in relative sunspot numbers). © Halberg.
36
Figure 3 shows the time course of the nonstationary circadian behavior in electrical activity
of a group of Ac cells (previously synchronized for up to a week with LD) for several days after
release from LD into LL. Signal averaging reveals, to visual inspection, time-macroscopically in
the first circaseptan cycle in LL, a circaseptan amplitude greater than that of the coexisting
circadian component, Figure 4. Curve-fitting quantifies an about half-weekly (circasemiseptan)
component as well (Figure 5), with an amplitude smaller than that of the circadian rhythm (6).
Figure 6 shows differences in phase among three presumably free-running variables investigated
in LL, oxygen production, electrical activity and chloroplast migration (7). Note from the nonoverlapping
CIs (horizontal lines around the peak) that the differences in timing of the 3 variables
are statistically significant, documenting a division of labor in time in a unicell. Figure 7
introduces a circadecadal rhythm in the circadian acrophase of oxygen production with a period of
~11 years. First circadian parameters in LD were assessed, and among these the circadian
acrophase was seen to exhibit a cycle associated with Zürich relative sunspot numbers.
Ac may have existed on earth ~500 million years ago (8). Hence it is a convenient object for
comparisons of phylogeny, notably of nonphotic circaseptans with corresponding features in
human ontogeny (9), demonstrating, at the unicellular level of chronomes (time structures) that
spectral components like the near-week are prominent in both early phylogeny and in the multicellular
human infant's early ontogeny, so that the latter can be modeled by the former (9). Several
infradian rhythms which are cycles in individual humans have been mapped as population rhythms
in Ac with serially-independent sampling as to individuals (4, 5) in Ac.
During the span of 1980-1991, 341 experiments were performed on the giant unicellular alga
Ac. acetabulum at the then Max-Planck-Institute for Cell Biology in Ladenburg, Germany. These
data are available online at http://www.mpizb-ldb.mpg.de/, linked to http://www.lvloldz.privat.tonline.de/deveppon.html,
courtesy of Dr. Lübbo von Lindern. We here analyze a longer set
obtained directly from Dr. Sigrid Berger, covering 14 years. Oxygen production, electrical
potential and/or chloroplast migration were recorded at 30-minute intervals for spans ranging from
19 to 109 days. In most experiments, the cells were first maintained for up to 7 days in the initial
span of light and darkness alternating at 12-hour intervals (LD12:12). When the circadian rhythm
was well expressed ad oculos, the cells were exposed to LL. In many experiments, after 7 to 18
days, different pulses were applied to the cells, such as dark pulses (for 8-24 hours), or a drug was
added to the medium (3-aminobenzamide, caffeine, geneticin, oligomycin, ouabain, pentanol,
ethanol, etc.), for spans of up to 97 days.
Each stage of each experiment was examined for validity of protocol by the actual times
originally recorded by computer in 341 experiments. Experiments ended as soon as the alga started
to form gametangia (sign of maturation), or their cap diameter reached a size filling the diameter
of the cuvette (sign of fast growth), or (less frequently) because of sudden cell death.
Two endpoints were examined herein, Table 1: the total duration of each study on a given
cell, and the duration of the initial span during which the cell was kept in LD12:12 conditions. The
duration of LD12:12 standardization spans was used as a primary check on algal behavior, since a
subjectively satisfactory behavior (rhythm) in LD12:12 was the condition for release into LL. For
comparison, data on two planetary indices of geomagnetic activity, Kp and Dst, were considered
over matching spans. In order to check against influences of artifacts, 100 noise series were
generated.
For each cell, the total study duration and the length of the LD12:12 span were assigned to
the calendar date of the mid-time of the corresponding span. These data were analyzed by leastsquares
spectra with periods ranging from 10.5 years to 2.5 months, followed by a nonlinear leastsquares
scrutiny of the periods found linearly with ordering statistical significance (without
37
Table 1: Estimates and 95% confidence limits of spectral components characterizing the
rhythms of two planetary indices of geomagnetic activity and the alga Acetabularia
Trial
period,
Geomagnetic indices Acetabularia
(span duration, in days)
(years) Kp Dst Study span LD12:12 spans
(arbitrary units)
10.5 8.013 (7.523, 8.535) 7.780 (7.192, 8.494) 10.017 (8.003, 12.031) 10.469(7.680,13.258)
A 0.43 (0.36, 0.50) 6.07 (4.50, 7.66) 5.75 (1.71, 9.79) 2.13 (0.73, 3.54)
5.25 3.282 (3.148, 3.431) 3.374 (3.257, 3.502) 4.563 (3.549, 5.904) 4.265 (3.758, 4.918)
A 0.20 (0.12, 0.27) 5.72 (4.16, 7.28) 3.56 2.10 (0.56, 3.65)
1.75 1.750 (1.713, 1.789) 1.739 (1.711, 1.769) 1.585 (1.481, 1.711) 1.848 (1.698, 2.058)
A 0.22 (0.14, 0.29) 5.79 (4.24, 7.35) 4.51 (0.93, 8.08) 1.30
1.0 1.316 (1.294, 1.340) 1.019 (0.999, 1.038) 0.902 (0.864, 0.941) 1.032 (0.996, 1.091)
A 0.19 (0.11, 0.27) 3.81 (2.22, 5.40) 5.10 (0.68, 9.53) 2.10 (0.54, 3.65)
0.5 0.499 (0.494, 0.503) 0.502 (0.500, 0.505) 0.485 (0.475, 0.498) 0.498 (0.402, 0.504)
A 0.21 (0.13, 0.28) 6.22 (4.66, 7.79) 5.07 (1.27, 8.88) 2.81 (1.28, 4.34)
A: amplitude. "Study span" and LD12:12 span are measures of vigor of the unicell in a total of 341 studies
during 1980-1991.
An About-Yearly Component is Neither the Sole nor the Largest
Infrannual Variation Characterizing Acetabularia 's Oxygen Evolution*
0.000
0.004
0.008
0.012
0.016
0 2 4 6 8 10 12 14 16
Frequency (cycles/14 years)
Amplitudeof24h(fractionofcycle)**
1.09 y
[1.13, 1.04]
9.24 y
[11.33, 7.16] 1.31 y
[1.36, 1.26]
Period = 1 year (y)
* In 14 years of experiments on these giant unicells kept in LD12:12, each cell contributing one of 279 estimates of the
circadian acrophase based on up to a week's recording analyzed by cosinor. From Max Planck Institute for Cell Biology
archives (HG Schweiger, director; courtesy of Sigrid Berger). Period lengths and 95% confidence intervals (CIs) assessed by
nonlinear least squares. **Indicating prominence of change in circadian acrophase ( ) at frequency shown on abscissa.
0.980 y
[1.013, 0.948]
Period (y): 7 3.5 2.33 1.75 1.4 1.17 1.0 0.875
Figure 8. Another demonstration, in the data underlying this figure, of a set of solar signatures, including
transyears, as well as components with a CI (95% confidence interval, given in parentheses) overlapping
the calendar year at one extreme (right) and the circadecadal Schwabe cycle at the other extreme (left) in a
population of unicells sampled with serial independence as to the individual alga. © Halberg.
38
CIRCASEPTAN (TOP) AND CIRCASEPTAN (BOTTOM) GROWTH RESPONSE
OF INTACT (TOP) OR ENUCLEATED (BOTTOM) Acetabularia
WITH FITTED MODEL (LEFT) AND COSINOR (RIGHT)
Scheme of schedule shifts of the light-dark regimen
A B
C D
Figure 9. Shifts of a regimen of light (L) and darkness (D) alternating every 12 hours carried out at intervals
ranging 2 to 15 days in unicells with and without a nucleus are associated with different patterns, allowing a
glimpse into the role of the nucleus in the genesis of about-weekly vs. about half-weekly cycles. Original
data from Schweiger et al. (3). © Halberg.
39
Table 2: Endpoints of linear-nonlinear rhythmometry of light transmission by Acetabularia
Estimates
—— Circadian —— — Circaseptan —
CS A
CD A
(%)Nucleus
present?
Period (h) 2A (AU) Period (d) 2A (AU)
1 (yes) 25.70 68.04 7.14† 26.34 38.71
2 (yes) 24.67 21.70 8.28 9.70 44.70
3 (no) 27.53 18.28 6.52 2.10 11.49
4 (no) 27.31 26.20 6.40 5.08 19.39
5 (no) 26.99 42.40 6.95 10.50 24.76
6 (no) 25.30 35.66 5.35 9.56 26.81
7 (yes) 24.84 10.34 8.13 5.54 53.58
8 (yes) 24.29 37.24 7.05 11.62 31.20
9 (yes) 24.48 7.20 7.25 10.94 151.94
10 (no) 26.09 53.78 6.44 6.22 11.57
11 (yes) 23.81 15.82 5.59 5.78 36.54
12 (no) 26.23 12.82 6.22 2.34 18.25
13 (yes) 22.47 27.28 8.88 17.42 63.86
2A=double amplitude. AU=arbitrary units. Estimates obtained by concomitant nonlinear fit of both circadian
(CD) and circaseptan (CS) components and linear trend.
†No trend included in model (CS not resolved with inclusion of linear trend in model).
correction for multiple testing). The same procedures were applied to a planetary (Kp) and an
equatorial (Dst) index of geomagnetic disturbance and to the 100 noise series matching the
sampling of the biological data.
Table 1 reveals congruence, i.e., overlapping 95% confidence intervals at a period of 6
months between the biological and geomagnetic variables. Table 1 shows that Ac shares with
terrestrial magnetism disturbance a precise half-yearly cycle, in two unusual endpoints that deal
with the vigor of the cell, namely the duration of a total of 341 studies as a whole and the span that
was required in LD. Figure 8 demonstrates, in addition to a yearly component, a near-transyear
and a far-transyear, with s of 1.09 (1.04, 1.13) and 1.31 (1.26, 1.36) years, respectively, in the
circadian acrophase of oxygen production in LD in 279 separate studies.
Ac's circadian, circasemiseptan and circaseptan rhythms have also been studied after
enucleation (3, 10, 11). Figure 9 shows that a circaseptan pattern can become circasemiseptan after
enucleation in Ac. acetabulum (3). By removing the nucleus, a normally subtractive (or rather
frequency-demultiplying) coupling in frequency of the circaseptan and circasemiseptan spectral
components may be uncovered. Figures 10a and 10b and Table 2 show the effect of enucleation of
Ac as a reduction of the circaseptan vs. circadian amplitude ratio, a hint of amplifying coupling
between the two rhythms' mechanisms, a possibility requiring follow-up because of the relatively
small number of cells involved, statistical significance notwithstanding.
There is the added finding in Ac. acetabulum that while enucleated cells are less vigorous
than intact cells, insofar as more enucleated cells die during a study (as compared to nucleated
ones) (3), the enucleated Ac's mortality can be greatly reduced by shifts of the lighting regimen (as
compared to the mortality of unshifted cells without the rhizoid containing the nucleus). Figure 11
shows that among many other laboratory models of phase-shifting (of LD), the greatest effect upon
the modification of lifespan, expressed as % of the mean, was found in Ac. acetabulum, as a
prolongation rather than as a shortening of life, as a potentially favorable effect (12, 13). Models
other than Ac are also useful (14). Changes with age are reported (15). The reader is further
referred to studies on Acicularia schenkii (16) and more generally to (1) and (8). Apart from the
opportunity to study enucleation effects, along with average trends, Ac has the thus-far broadest
spectral element mapped in a unicell.
40
Figure 10a. Circaseptan-circadian relations in the presence and absence of a nucleus displayed for the
unaided eye are analyzed in Table 2 and summarized in Figure 10b. © Halberg.
Figure 10b. Enucleation in
Acetabularia acetabulum changes
the circaseptan-to-circadian
amplitude ratio of light
transmission by Acetabularia kept
under constant environmental
conditions of light and
temperature. The circaseptan
prominence is reduced in a
relatively small sample of
individual unicells (dots)
investigated (cf. Table 2 and
Figure 11). * Data of J.C.
Woolum. © Halberg.
41
Figure 11. Manipulating the regimen of alternating light and darkness in Acetabularia acetabulum
without vs. with a nucleus (last column) allows insight into the role of the nucleus as a useful
putative synchronizer, replaced by the lighting regimen to the advantage of the enucleated cell. ©
Halberg.
42
1. Schweiger H-G, Hartwig R, Schweiger M. Cellular aspects of circadian rhythms. J Cell Sci
Suppl 1986; 4: 181-200.
2. Schweiger H-G, Halberg F. Can a unicell measure the week and an isolated cytoplasm
measure half a week? Notiz SIBioC 1982; 6: 525-526.
3. Schweiger H-G, Berger S, Kretschmer H, Mörler H, Halberg E, Sothern RB, Halberg F.
Evidence for a circaseptan and a circasemiseptan growth response to light/dark cycle shifts in
nucleated and enucleated Acetabularia cells, respectively. Proc Natl Acad Sci USA 1986;
83: 8619-8623.
4. Hillman D, Katinas G, Cornélissen G, Siegelova J, Dusek J, Jancik J, Masek M, Halberg F.
About-10-yearly (circadecennian) cosmo-helio-geomagnetic signatures in Acetabularia.
Scripta medica (Brno) 2002; 75: 303-308.
5. Halberg F, Cornélissen G, Faraone P, Schwartzkopff O, Regal P, Holley DC, Otsuka K. A
transdisciplinary near-transyear in Acetabularia validates its counterpart in the solar wind
and geomagnetics. 3, Proceedings, 5th International Workshop on Chronoastrobiology and
Chronotherapy, Matsubayasi K (Ed.), Division of Human-Nature Dynamics, Center for
Southeast Asian Studies, Nov 6, 2004. p. 43-51.
6. Halberg F, Cornélissen G, Katinas G, Hillman D, Schwartzkopff O. Season's Appreciations
2000: Chronomics complement, among many other fields, genomics and proteomics.
Neuroendocrinol Lett 2001; 22: 53-73.
7. Katinas G, Hillman D, Siegelova J, Dusek J, Svacinova H, Cornélissen G, Halberg F. Aboutweekly
changes in electrical potential, chloroplast migration and oxygen production in
Acetabularia grown under continuous exposure to light. Scripta medica (Brno) 2002; 75:
309-314.
8. Berger S, Kaever MJ. Dasycladales: An Illustrated Monograph of a Fascinating Algal Order.
Stuttgart: Thieme-Verlag; 1992. 247 pp.
9. Katinas G, Berger S, Cornélissen G, Hillman D, Woolum JC, Engebretson M, Syutkina EV,
Masalov A, Wang ZR, Wan CM, Bakken EE, Schwartzkopff O, Halberg F. Acetabularia
acetabulum: Unicellular model of neonatal vascular chronome. Neuroendocrinol Lett 2003;
24 (Suppl 1): 201-207.
10. Woolum JC, Cornélissen G, Halberg F. Chronometaanalysis: enucleation changes the
infradian-circadian amplitude ratio of Acetabularia. Abstract, 6° Convegno Nazionale de
Cronobiologia, Chianciano, Italy, November 27-28, 1998, p. 64.
11. Woolum JC, Cornélissen G, Hayes DK, Halberg F. Spectral aspects of Acetabularia's light
transmission chronome: effects of enucleation. Neuroendocrinol Lett 2003; 24 (Suppl 1):
212-215.
12. Berger S, Schweiger H-G, Halberg F. Lighting schedule shifts prolong survival of enucleated
Acetabularia. Progress in Clinical and Biological Research 1990; 341B: 699-705.
13. Cornélissen G, Halberg J, Halberg F, Nelson W, Schwartzkopff O, Stoynev A, Haus E.
Schedule shifts, cancer and longevity: good, bad or indifferent? J Experimental Therapeutics
and Oncology, in press.
14. Edmunds LN Jr. Circadian organization in the algal flagellate Euglena. In: Circadian
Rhythms, Eurekah Bioscience Database Eurekah.com/Landes Bioscience; 2005. p. 1-30.
http://www.eurekah.com/abstract.php?chapid=2504&bookid=140&catid=85
15. Lindern L v, Berger S. Decreasing period-length of the endogenous circadian period of
oxygen evolution in Acetabularia and its possible relation to aging. Chronobiology
International 1996; 13: 341-347.
43
16. Berger S, Lindern L v, Mergenhagen D. Lack of an endogenous circadian rhythm in oxygen
evolution by an ancient alga (Acicularia schenkii, Acetabulariaceae). Eur J Cell Biol 1995;
68: 339-344.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
44
Solar signatures in Australian suicide incidence:
gender differences in prominence of photic vs. nonphotic spectral components
Franz Halberg*, Germaine Cornélissen*,
Michael Berk‡, Seetal Dodd‡, Margaret Henry‡, Lennart Wetterberg§,
Ellis Nolley*, Larry Beaty*,Jarmila Siegelova, Bohumil Fiser, Charles Wolff•
And the broader BIOCOS Project
*Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
‡Department of Clinical and Biomedical Sciences -- Barwon Health, University of Melbourne,
Geelong, Australia
§Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
•Solar Physics Branch, NASA Goddard Space Center, Greenbelt, MD, USA
Abstract
Irrespective of gender in Australia, in a sample with many more males (50,169) than females
(15,859) and much more prominently in the undiluted sample of males only, the photic calendar
year is the largest component in spectra of the incidence of suicide. In the spectrum of suicide
incidence of Australian females, a period, , of about (~) 0.563 year, of putative solar origin
(insofar as it was identified as a beat period of solar rotation rates by one of us [CW]), happens to
predominate in the para-annual, including parasemiannual spectral regions over much lower
amplitudes at trial s of 1.00 (and 0.50) year, with the latter being very prominent in the incidence
spectrum of males committing suicide in Australia. The CI (95% confidence interval) of the ~0.56year
component (0.56-0.567 year) in the spectrum of women does not overlap the precise 0.50year
length, which in turn dominates the spectrum of suicide incidence in Minnesota, irrespective
of gender. These geographic and gender differences among spectra with too many, albeit some
predicted peaks should be complemented by more extensive data from many more locations.
Introduction
The built-in photic and societal signatures of the changes along the scales of 24 hours and of
the seasons have been of consistent interest to psychiatry (1), including the topic of suicide, Figure
1 (2; cf. 3). Spectra of the incidence of suicide also reveal putative nonphotic effects, such as those
of geomagnetics (4; cf. 5, 6). There are further nonphotic associations with (solar) weather in
space, which influences geomagnetics. The sun can also act directly via particle emissions from it,
the solar wind, which may in part penetrate the earth's magnetosphere. Any solar-terrestrial vs.
human associations can be gauged in incidence spectra of environmental cycles vs. those of
various epidemiological, psychophysiological and other biospheric time series (7-9).
Figure 1. Cosinor summaries by fit of a 1-year
cosine curve show circannual rhythms in the
incidence pattern of mortality from suicide,
cardiovascular diseases and accidents in
Minnesota during 1941 to 1967. Note
reproducibility of findings in consecutive spans.
Deaths from heart diseases peak in the winter,
suicides in June, and accidents somewhat later in
the year. Focus upon the photic seasons must not
detract from other nonphotic environmental
contributions resolved by the extended cosinor in
Figures 2, 5-7. © Halberg.
45
Suicides in Minnesota
Referred to Calendar Date of Death (1968 - 2002)
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
0 35 70 105
Frequency (cycles in 35 years)
Amplitude(N/day)
Trend
1.0 Year
(P=0.007)
0.5 Year
(P<0.001)
1.3 Year
(P<0.001)
1.07 Year
(P=0.006)
Suicides in England and Wales
Referred to Calendar Month of Birth
0
1
2
3
4
5
6
7
8
0 10 20 30 40 50 60 70 80
Frequency (cycles per 12 years)
Suicides(N/100,000Births)
1.0y 0.5y
~0.42y
~2.2y
0.73y*
~7.5y
Figure 2. Spectrum of the incidence of suicide in Minnesota, by calendar date of death (1968-2002),
irrespective of gender. Note prominent half-year component particularly related to geomagnetics (top);
below, spectrum of the incidence of suicide in England and Wales, by calendar date of birth (1955-
1966), irrespective of gender.
* Validated nonlinearly. Period = 0.727y (95% confidence limits: 0.703, 0.751y). © Halberg.
46
Congruence
Beyond the seasons (Figure 1) and associations of suicide with ambient electromagnetic
fields (6) and geomagnetic storms (4, 7), there is a putative signature of the solar wind, namely an
~1.3-year cycle in Minnesotans in the USA committing suicide (8, 9), Figure 2 (top). This ~1.3year
component was theoretically identified by CW (10) as a beat frequency of solar rotation rates
and was abundantly validated for diverse variables gauging solar activity (11-19). In the as-yet
relatively short time series stemming from satellite measurements during about 40 years in the
solar wind's speed, the sigma of its speed, and its proton density, the 1.3-year period is wobbly,
drifting, bifurcating and joining in frequency and waxing and waning in amplitude to the point of
being no longer detected, and in this sense of intermittency, spectral behavior in gliding spectra is
described as aeolian and accordingly broader spectral regions were dubbed a far-transyear (1.2
years [ - CI] < [ + CI] < 1.9 years), and thus tentatively separated from a near-transyear (1.00
year < [ - CI] < [ + CI] < 1.20 years). The latter was also found, among other variables (7), in
spectra of time series of suicide in Minnesota (8, 9). The far-transyear also characterized sudden
cardiac death in several locations (7, 20). In the incidence pattern of suicides in Minnesota (by the
day of death), the solar wind's ~1.3-year far-transyear was second in prominence overall and had
numerically the largest amplitude in the para-annual region, very slightly exceeding the
prominence of the also statistically significant seasons, Figure 2 (top). A near-transyear of 1.07
years had a slightly smaller amplitude than that of the calendar year component.
The relative prominence of cycles in the visible range, such as a calendar-year component as a
photic, thermic and social entity, vs. non-photic cycles has been taken as an approximate and
tentative gauge of the importance of their relative roles played in human health and broader affairs.
Thus, we assessed the roles of invisible weather in space and/or geomagnetic disturbance on the one
hand vs. the associations of seasonal changes of weather on earth on the other hand. These
associations of photic vs. nonphotic spectral prominence varied geographically for phenomena such
as suicide (8, 9) or sudden cardiac death (7, 20). The 10th
revision of the International Classification
of Diseases separated the diagnosis of sudden cardiac death from cardiac arrests associated with
myocardial infarctions, limiting it to electrical accidents of the heart, i.e., to cases with no history of
heart disease and no findings at autopsy (when this latter examination was possible; 7). In this ICD-
10, code I46.1, another prediction by CW, a spectral component of 0.42 year length has been found
in several geographic locations (7). These conditions may be influenced not only through any link
between helio- and geomagnetics, but also by other perhaps direct effects of particle emissions from
the sun, ultraviolet flux and gravitation, all associations summarized as nonphotic (to contrast them
with photic associations in the visible domain of the day and the calendar year).
A prominent half-yearly cycle in geomagnetics (4, 21-23), dominating the spectrum of
suicides by the day of death irrespective of gender in Minnesota, based on data over 35 years, had
the highest amplitude and the latter had thus been associated with geomagnetic activity.
Obviously, similar periods validated by an inferential statistical comparison of their CIs of s for
congruence or similarity, Figure 3, do not prove causality; they constitute a first basis for a followup
amplification or damping (addition or subtraction) remove-and-replace approach that examines
any association with the biosphere of time-varying environmental behavior, e.g., of an
environmental cycle, the subtraction including a failure to detect the cycle (removal). Thus far, the
behavior of the biospheric cycles examined by this approach showed damped persistence after
removal of the corresponding environmental spectral component (7, 24-26). This phenomenon,
dubbed bioresonance, can last for long spans after the environmental counterpart is no longer
detected.
47
Figure 3. Congruence vs. similarity vs. dissimilarity can be gauged by CIs (95% confidence intervals) of
characteristics such as the period or phase of a neighboring spectral component in two or more
concomitantly sampled time series of the same variables or of different variables within tissues, organs,
organ systems, individuals, populations, disciplines and, most interestingly, when they are transdisciplinary,
as are transyears or trans- and cis-half-years. Congruence implies overlying CIs (100%) or overlapping
ones (<100%), while similarity implies close CIs that do not overlap (0% congruence). The concept of %
congruence awaits elaboration. © Halberg.
Nonphotic prominence in Minnesota, England and Wales
There was also a clear spectral peak at a trial of 0.5 year in the spectrum of suicides by the
day of birth (rather than by that of death, the only kind of statistics analyzed from Minnesota and
Australia) in England and Wales (9), but in the latter location the most prominent component was
one with a period shorter than a year with a of ~0.73-year length, i.e., on this side (cis) of the
48
year, a cis-year. In the data from England and Wales, there was also a component of ~0.42 year
which, as noted, corresponds to another beat period of solar rotations, predicted as a result of a
decades-long modeling by CW (26-32). This cis-half-year is an abundantly documented (albeit in
relatively short series), highly variable (33-40) feature of solar activity and is also reflected in
increasing numbers of geographic locations in sudden cardiac death, Figure 4 (7, 20, 41-43).
Figure 4. Because of limited available data and many other inaccessible data, a curtain of uncertainty hides
any time- and geographic (geomagnetic or dip-magnetic) site-specificity of various spectral aspects in the
incidence of sudden cardiac death in many locations, with some exceptions recorded herein. Thus, as
compared to a far-transyear of about 16 months and with a cis-half-year of about 5 months (cY/2), but no
calendar year in Minnesota and in Tokyo, we find both a calendar year and a far-transyear in Arkansas and
in the Czech Republic. At the latter site a cis-half-year is detected after 1999, but not before. In some
locations the calendar year and the 0.5 year are the sole peaks in the para-annual and para-semiannual
region. © Halberg.
A 0.5 year peak dominating the spectrum of suicide incidence in Minnesota was also found
in England and Wales in statistics by the day of birth of those committing suicide. Geomagnetic
disturbance was thus putatively associated with suicide in all locations investigated, as were the
seasons. The 0.5-year peaklet in suicide incidence in Australia characterizes notably males.
Non-photic signature in female and photic in male and overall suicides in Australia
In incidence statistics by the day of death, the calendar year dominates in Australia overall,
Figure 5, and in males, Figure 6, but not in females, Figure 7. Transyears that were prominent in
Minnesota are also found in Australia at ~1.21 years in females, Figure 7, and at ~1.71 years in
males, Figure 6, that are both represented overall in Figure 5. When the data from Australia are
separated into those of males that were the majority (and had a trend removed), the impression
gained from all data in Figure 5 is supported by the prominence of the seasons in males, Figure 6,
yet there is also a peak, among others, at the presumably solar signature of an ~0.42-year and at
the putatively geomagnetic 0.5-year. In data from females in Figure 7, a (putatively solar) ~0.56-
year
49
Coexisting Photic and Non-photic Components in the Incidence Pattern of
Suicides in Australia (1968-2001)*
0.0
0.1
0.2
0.3
0.4
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6
Frequency (cycles/year)
Amplitude(N/day)
1.0 Year
0.5 Year 1/3 Year
0.394Y
[0.391, 0.396]
1.714Y
[1.681, 1.746]
1.212Y
[1.189,
1.234]
0.422Y
[0.419, 0.424]
1.006Y
[0.999, 1.012]
0.502Y
[0.498, 0.506]
9.14Y
[8.58, 9.71]
0.738Y
[0.730, 0.746]
3.30Y
[3.19, 3.40]
* Original data of Michael Berk. Data detrended (removal of linear trend). Number of cases:
66,028.
Figure 5. Suicide incidence (coded by day of death) in Australia shows a prominent photic year and nonphotics
such as a putative geomagnetic circasemiannual component and putative solar transyears and a
cis-half-year. © Halberg.
component is found. As already noted, it has been reported as a beat frequency of solar dynamics
(10), and is numerically more prominent than the yearly and half-yearly components.
The marked gender difference in Australia is based on a relatively smaller number of females
as compared to males, and deserves further study in other geographic locations. Two sites were
examined by the day of death (Australia and Minnesota) and one location by the day of birth: it
can be suggested, as in the case of sudden cardiac death (7, 20, 43), that photic and non-photic
components are present in all locations, irrespective of the kinds of statistics by day of death vs. of
birth. The seasons dominate in Australian males and in Australians overall (because of the larger
number of males), but not in Australian females and not in Minnesota, nor in England and Wales.
Among non-photics, the ~1.3-, 0.56- and 0.42-year components may be primarily solar and the
0.5-year component, partly terrestrial in origin. It remains to be elucidated why and how three of
the solar rotation's beat periods have biospheric signatures, but not the other seven thus far. How
do 1.33, 0.56 and 0.42 differ from the other beat periods in terms of physics? In evidence
accumulated thus far, the ~0.42-year component has a special place. With an also-present far- and
near-transyear, the cis-halfyear characterizes breakdown products of steroidal hormones critical to
survival and reproduction.
The broad-scale geographic mapping of factors underlying mood by focus on the extreme of
depression in the form of suicide remains a challenge. It is already known that negative affect has
both a solar and a geomagnetic component with a (non-photic) of 7 days, while positive affect is
predominantly circadian (44). With the new information on hand, the role played by the cosmos
50
Dominant Seasons in the Incidence Pattern of Suicides by Males in Australia
(1968-2001)*
0.0
0.1
0.2
0.3
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6
Frequency (cycles/year)
Amplitude(N/day)
1.0 Year
0.5 Year
1/3 Year
0.397Y
[0.394, 0.399]
1.718Y
[1.681, 1.754]
0.421Y
[0.418, 0.423]
1.004Y
[0.997, 1.010]
0.502Y
[0.499, 0.505]
9.16Y
[8.50, 9.82]
5.50Y
[5.18, 5.82]
1.99Y
[1.94, 2.03]
0.741Y
[0.734, 0.748]
* Original data of Michael Berk. Data detrended (removal of linear trend). Number of cases:
50,169.
Figure 6. Coexisting photic and nonphotic components in suicides by males in Australia. © Halberg.
Dominant Solar about 0.56-year Component in the Incidence Pattern of Suicides by
Females in Australia (1968-2001)*
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6
Frequency (cycles/year)
Amplitude(N/day)
1.0 Year
0.5 Year 1/3 Year
0.385Y
[0.382, 0.387]
1.214Y
[1.193, 1.236]
0.563Y
[0.560, 0.567]
9.19Y
[8.37, 10.01]
3.300Y
[3.188, 3.412]
0.685Y
[0.678, 0.692]
* Original data of Michael Berk. Number of cases: 15,859.
Figure 7. Nonphotic prominence in the incidence spectrum of suicides by females in Australia. © Halberg.
51
can be explored at likely built-in windows of new resonant frequencies to be investigated in
populations and in the few documented individuals by addition and subtraction up to a removeand-replace
approach where the amplification and damping of one or the other of the intermittent
environmental spectral components is done by the cosmos (7, 24, 25).
Certain frequency windows are identified for further study in the para-annual region of
spectra of the incidence patterns of suicide, such as the ~1.3-year far-transyear (7, 45) and three
windows that are very narrow in the parasemiannual region, since the s are close to each other. A
precise half-yearly component in circulating melatonin at middle latitudes by night (46) relates
putatively to geomagnetics. It has been mapped as a distinctly different entity (as far as CIs of the
s are concerned) as compared to ~0.56- and 0.42-year cycles, predicted as solar beat periods (10)
and found to have CIs not overlapping the precise half-year length.
To complicate the issue, when the circulating melatonin was determined with serial
independence as to individuals in 172 patients in blood drawn from each of them at 6 consecutive
4-hour intervals was analyzed as six separate series, each series consisting of data from a given
clock-hour, the CIs of the s all overlapped the 0.42-year (47). The CIs of s from analyses of
two more (related) series of circulating melatonin MESORs and circadian amplitudes of the
patients' set as a whole also overlapped the 0.42-year length (47). The resolution of the relative
prominence of cycles with periods of ~0.42-, 0.50- and 0.56-year, should they coexist concurrently
in some future study, will require very long series, notably if the time courses of these components
in the environment and, among others, in suicide are to be compared, as was done for the
biological week (25) and the far-transyear (7). Moreover, for the case of the same data on
melatonin circulating in the blood of 172 patients studied during several years, in which a cis-halfyear
is found by extended (linear-nonlinear) cosinor (47), a precise half-yearly component was
previously reported by a different (population-mean cosinor) approach (46).
Transdisciplinary discussions
It could be chance that in a 15-year series of daily 17-ketosteroid excretions, a predicted (10)
0.42-year period and transyears were found. Periods with CIs all covering the 0.42-year length
found in the melatonin circulating in the blood of 172 patients in Florence (47) could also be due
to random sampling error, yet somehow the 172 patients studied over several years had to be
synchronized and solar activity comes to mind as the synchronizer. With so many peaks in the
spectra demonstrated elsewhere and here in Figures 2 and 5-7, many if not all of them could come
about by the ever-present chance. But if the needed much longer series should become amenable
for analyses, the role of chance could be reduced. Also with respect to underlying mechanisms (46,
47), it seems pertinent that Monteleone et al. (48; cf. 49) found that bright light (2000 lux) applied
between 02:00 and 04:00 to human subjects depressed circulating melatonin by 40% more in
women as compared to men, in keeping with a stronger solar effect in females. This finding could
not be confirmed with exposure at an earlier time of night (50, 51), nor was a gender difference
relating to melatonin found by others (studying mean values only) (52-54). Melatonin reportedly
responds to magnetic fields (55) or magnetic storms (56-58) and is latitude-dependent (59); studies
of its chronome over years with serially-independent sampling as to many more individuals seem
highly desirable and may allow scrutiny of the results herein.
As to the degree of generality apart from suicides and from sudden cardiac death, the fartransyear
has been documented in terrorism (60-62), in Gallup Polls (63), in human natality in the
Philippines (64) and Brazil (65) and in epilepsy (66) and strokes (67) in Slovakia, but not in
natality in Japan (68) or Italy (69), another example of a geographic difference in the time
structure of epidemiological variations.
52
Figure 8. We need not ignore the many signatures of the cosmos with validated statistical significance of
anticipated periods that characterize:
a. dozens of decades-long time series of blood pressure and heart rate;
b. other physiology and psychology, including mental functions;
c. religious proselytism;
d. suicide;
e. sudden cardiac death;
f. terrorist activity for the past 39 years;
g. 2,556 years of international battles compiled by Raymond Holder Wheeler;
h. military expenditures for training in non-medical science;
i. degrees earned;
j. Gallup Polls; and
k. political and military actions in nearly 200 years, meta-analyzed from the much broader treasure of data
compiled by Alexander Leonidovich Chizhevsky.
While chance can never be ruled out, it would be further greatly reduced by systematic lifetime monitoring
of physiology in health, of pathology and disease, notably in archives to separate effects of sun and earth,
many of which are beneficial. Other effects such as extreme cold and heat or extreme light can be met by
countermeasures such as housing, heating and air conditioning. The task remains to develop
countermeasures to those nonphotic effects that can be documented as harmful. While the earth is the
immediate actor, and for that action the sun is the modulator, with the biosphere reacts to both terrestrial
and solar factors, the roles of actor, reactor and modulator are continuously changing. In the greenhouse
effect, organisms are the actors, as shown by a double-headed arrow (B2). There may be other more subtle
effects of synchronized human action upon the earth. Original drawing by Mary Sampson. © Halberg.
53
Figure 8 attempts to describe the status quo of ignorance. The invisible (except, e.g., for
northern lights) effects of space weather complement those of the visible light and of felt heat (and
cold). They play a role in psychiatry and far beyond, as does the broader cosmos, gauged, e.g., by
galactic cosmic rays (C, Fig. 8). The ~1.71-year far-transyear is also a characteristic of cosmic rays
(70-72). When exposure to environmental cycles (their aeolian nonstationary nature
notwithstanding) lasts for eons, they are eventually coded as bioresonance periods in the genes (
in Figure 8), yet are amplified or dampened by the continuing cosmic influences. But resonance
may also be found in the relations of earth and sun. When the latter ceases to display a given
period and then resumes it, such as an ~35-year cycle, the antipodal geomagnetic index aa may
continue to exhibit that cycle in the interim. A bidirectional arrow in Figure 8 indicates that the
biosphere changes the surface of the earth. The question whether the biosphere can substantially
influence its cosmic as well as the physical earthly environment is beyond the scope of available
evidence here summarized (73, 74). But the explanation of the status and of the origin of some
cycles shorter than the Schwabe period can be considered in the following.
Introduction to the origin of solar g-mode periodicities < 11 years
A number of solar periodicities shorter than a dominant 11-year Schwabe cycle in time have
been accepted as real at convincing probability levels, (for example, 40, 75, 76). But even these
strong signals are not seen all the time. Their amplitudes occasionally are within the noise in the
data, making them undetectable. Either they are still there, but weak, or they are gone and will be
re-excited later. We describe a model that can explain the first case. The other case (gone and reexcited)
may also be of interest to chronomics but it is more complicated and not discussed here.
a.) The Clockwork of Rotating g-Modes
This section summarizes the model (10, 31) operating deep inside the sun, Figure 9, which
causes a small fraction of the upward moving energy to vary, as if controlled by a series of clocks.
Although the clocks keep very good time, we shall see that the strength of each beat unavoidably
changes from one beat to the next. Upward flowing energy is the ultimate cause of phenomena
seen at the sun's surface and above (visible radiation, flares, mass ejections, solar wind, etc.). So
when this energy flow varies on some schedule, it should be detectable in many solar observables
and many biospheric variables influenced directly or indirectly by the sun.
The physical elements that can cause this are global oscillations of the sun called g-modes
(77, 78). Each mode involves about 90% of the solar mass in its motion; thus it has tremendous
stability even though its amplitude is small. The oscillation periods are of the order of hours but
that is not what regulates the solar clocks. Instead it is the rotation rates of the modes when
particular groups of them couple to form what is called a set (l), where l is an integer. Figure 9
shows how a set distorts the sun (highly magnified) as it oscillates. On the surface you can see that
the strongest oscillation amplitudes concentrate near the equator in a limited range of longitudes.
This is called a hot spot because that is where the set deposits the greatest amount of heat per unit
area, which it supplies from its own kinetic energy. A second hot spot is located symmetrically on
the other side of the sun. The hot spot extends to all depths inside the sun but its strength peaks at
the two radii shown in the cutaway section and then it declines exponentially toward the center and
toward the surface. Many more details on these sets are available in reference (31).
All sets rotate slightly slower than the solar mass in which they oscillate. There is a unique
rate for each value of l. For the lowest degree sets for which there is observational evidence, Table
1 shows the rotation periods apparent to an earthbound observer. Also, the rotation rate relative to
the fixed stars is given in nanohertz. These rates stand on three observational legs: A study of more
than two centuries of sunspot numbers (10), the internal solar rotation curve from helioseismology
(79), and a half century of 10.7 cm solar radio flux records (28).
54
A
B
Figure 9. This cutaway
sketch illustrates the set
of g-modes for l = 4
oscillating inside the sun.
Oscillatory power is
concentrated along a
straight line passing
through the origin and
intersecting the surface
near the equator but not
on it. We see only half of
the power concentration
since it extends to the
opposite side of the sun.
This structure rotates like
a rigid body about the
Sun’s spin axis at a rate
depending on l. When its
rotation causes its hot
spot to overlap with that of
another set, extra energy
is released, which affects
observables at the sun's
surface. Contour maps of
these power distributions
are available (31).
Table 1: Rotation rates of g-mode sets and their beat periods (28)
Rotation Beat Period (years)
L
Apparent
Period (days)
Absolute Rate
(nHz)
L' = 3 4 5 G
2 35.05 361.87 0.425 0.335 0.295 0.242
3 31.50 399.12 1.58 0.967 0.562
4 30.66 409.15 2.50 0.873
5 30.16 415.50 1.34
G 29.26 427.29
In addition to the low l values, the sunspot data also showed evidence for a strong feature at
considerably higher l. Since rotation rates for high l are too close to be resolved by existing data, it
is treated as one feature and called set(G). It had more impact on the sunspot data than any other
set and is presumably the strongest of them (10). On time scales shorter than the Sun’s 11 year
cycle, the sets in Table 1 are those that would most prominently affect events on the Sun.
b.) Rotational Beat Periods and their Heat Pulses
When the hot spot of a set such as Figure 9 rotates past the spot of another set, extra heat is
deposited at that place and time. The amount of heat is more than the simple sum of their separate
effects because the hot spots interact nonlinearly. This gives great significance to the frequency at
which two particular spots will overlap. In symbols, the beat period between two rotating sets is
P = [ (f1 - f2)k ]-1
55
where f1 and f2 are the rotation frequencies of the sets (e. g., Table 1). The factor k = 2 takes
account of the fact that each set has two hot spots per rotation. (For certain phenomena most
sensitive to latitude distributions, k =1.) The last few columns in the table show these beat periods.
They impose themselves on various events at the sun's surface and beyond because the sun can
utilize the extra energy made available at period P to magnify all the forms of solar activity (flares,
sunspots, radiation, etc.) and even the solar wind.
All beat periods in Table 1 have been calibrated with over two centuries of monthly mean
sunspot numbers and a half century of solar radio flux as mentioned above. Extra decimal places in
rotation frequencies are carried over from the theory to protect the difference frequencies (beats).
But the rotation frequencies contain an additive constant that is still uncertain to perhaps 2%. Beat
periods in the table are accurate to about 1%.
If two rotating sets were the only ones in the sun, then a beat would release the same amount
of heat every time. But there are other sets and sometimes they happen to be close to the region
where the hot spots of f1 and f2 are interacting. Thus the total amount of heat released at a certain
beat period will vary depending on what other hot spots happen to be nearby at that time. This
explains why these periodicities are strong some of the time and at other times are too weak to be
detected at the sun's surface.
Of the ten solar beat periods in Table 1, only three seem to have been found in the earth's
biosphere so far in the human circulation and other aspects of physiology, pathology and
sociology, including suicide. Two of them (1.34 and 0.56 yr) involve the set(G) which is the
strongest set, at least in its ability to influence the sunspot numbers (10). Since that set has the
smallest horizontal size (i.e., in latitude and longitude) it is supplying a very concentrated dose of
energy to small areas. That may be why it is observed so well in a highly local effect like a sunspot
or solar active region. But the strength of set(G) rather than its size is more relevant to the
biosphere where, e. g., a 1.34 yr period is detectible in each of 44 mostly decades long
physiological time series from of the order of a dozen subjects.
The third biosphere period, the cis-half-year (0.42 yr) is associated with the beat between two
solar sets with the lowest values of l. They are the sets that have the largest horizontal sizes. They
may have more effect on a larger scale effect like the solar wind. The details of how the g-mode
sets would affect a particular solar feature have never been worked out quantitatively. Many such
physical details of the Sun remain to be studied. Even more unknown, then, would be how
effective a solar beat period could be in affecting the biosphere and perhaps encoding itself into
DNA on Earth. Extensive future observations are far more likely to answer such questions than
theoretical modeling.
Conclusion and Epilogue
Systematically aligned physical and biospheric, in individuals lifelong monitoring is overdue
to complement the foregoing analyses of suicide and other much more extensive archival studies.
Individuals' monitoring must not be left to a very few highly motivated subjects, but should
proceed, preferably as family monitoring. One scientist, RBS, who started monitoring blood
pressure (BP) at 20 years of age, persuaded his father SBS to undertake BP monitoring when the
latter was in his sixties. RBS now has 41 years of around-the-clock data that complement 23 years
of data from SBS (80, 81). YW began monitoring his own BP at 35 years of age and now has 21
years of mostly half-hourly data; he monitored his son FW's BP from birth and has new data with
gaps up to 15 years of age (82, 83). A lifetime study or two may eventually thus be pieced together
by data from father and son.
Current spotcheck-based physiology and medicine will eventually include automatic wombto-tomb
monitoring in its scope, for which the technology is available in the experimental
56
laboratory, albeit not yet unobtrusively and noninvasively for the human. What Humboldt started
with Gauss and Sabine made into a magnetic crusade (84), which has proceeded to a systematic
monitoring of the environment near and far by satellite, should be complemented by surveillance
in the biosphere prospectively. A thorough analysis of the few accumulated longitudinal series that
cover around-the-clock up to 40 years retrospectively is equally overdue, and certainly the further
retrospective and prospective analysis of archives is desirable. Reference cycles in human
development and aging would then become available to replace imaginary baselines (85).
The planned extension of studies on suicides as a function of latitude and longitude is
overdue, but we are dealing with the consequence of extreme depression that originates from lesser
abnormalities in mood that need further scrutiny of their circadian-infradian cycles. Solar
signatures are found not only by noninvasive cardiology in health and disease, but also in mental
functions, such as the rating of mood and vigor and the estimation of 1 minute around the clock
about 5 times/day over 36 years. The series of mood ratings is characterized by an ~0.56-year (a
trans-half-year). In the series on time estimation, some spectral components are congruent only
with corresponding counterparts in the spectrum of the solar wind's speed, while other spectral
components of the same mental function are congruent only with periods in geomagnetics and still
other spectral components in this human mental function are congruent with both sun and earth,
Figure 8. Fewer components in the para-annual and para-semiannual spectral regions have no
environmental counterpart. The chance of monitoring solar activity biospherically and
prospectively is a challenge in particular in noninvasive cardiology because the same data that
serve for immediate health care can also be used, if they are recorded via a website for medical
investigation and further for transdisciplinary research, as will become apparent from the BIOCOS
contribution to these same proceedings. Archival studies have to be complemented by longitudinal
monitoring of human and other biospheric variables.
Special thanks are expressed to the Phoenix Study Group, composed of volunteering
members of the Twin Cities chapter of the Institute of Electrical and Electronics Engineers
(http://www.phoenix.tc-ieee.org), who are building a website (http://www.sphygmochron.org/) so
that in exchange for the time series from cardiology in everyday practice, we can, with the same
data, monitor solar activity in the light of its important associations with the biosphere and can
apply the existing software for archival studies (86).
1. Halberg F. Physiologic considerations underlying rhythmometry, with special reference to
emotional illness. Symposium on Biological Cycles and Psychiatry. In: Ajuriaguerra J de,
editor. Symposium Bel-Air III. Cycles biologiques et psychiatrie. Geneva: Georg / Paris:
Masson et Cie; 1968. p. 73-126.
2. Halberg F. Laboratory techniques and rhythmometry. In: Mills JN, editor. Biological Aspects
of Circadian Rhythms. London/New York: Plenum Press; 1973. p. 1-26.
3. Berk M, Dodd S, Hallam K, Berk L, Gleeson J, Henry M. Small shifts in diurnal rhythms are
associated with an increase in suicide: the effect of daylight saving. Sleep and Biological
Rhythms 2008; 6: 22-25. doi:10.1111/j.1479-8425.2007.00331.x
4. Cornélissen G, Hillman D, Katinas GS, Rapoport S, Breus TK, Otsuka K, Bakken EE,
Halberg F. Geomagnetics and society interact in weekly and broader multiseptans underlying
health and environmental integrity. Biomed & Pharmacother 2002; 56 (Suppl 2): 319s-326s.
5. Gordon C, Berk M. The effect of geomagnetic storms on suicide. S Afr Psychiatry Rev 2003;
6: 24-27.
57
6. Berk M, Dodd S, Henry M. Do ambient electromagnetic fields affect behaviour? A
demonstration of the relationship between geomagnetic storm activity and suicide.
Bioelectromagnetics 2006; 27: 151-155.
7. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
8. Halberg F, Cornélissen G, Panksepp J, Otsuka K, Johnson D. Chronomics of autism and
suicide. Biomed & Pharmacother 2005; 59 (Suppl 1): S100-S108.
9. Cornélissen G, Halberg F. Chronomics of suicides and the solar wind. Br J Psychiatry 2006;
189: 567-568.
10. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
11. Gonzalez ALC, Gonzalez WD. Periodicities in the interplanetary magnetic field polarity. J
Geophys Res 1987; 92: 4357-4375.
12. Richardson JD, Paularena KI, Belcher JW, Lazarus AJ. Solar wind oscillations with a 1.3year
period. Geophys Res Lett 1994; 21: 1559-1560.
13. Szabo A, Lepping RP, King JH. Magnetic field observations of the 1.3-year solar wind
oscillation. Geophys Res Lett 1995; 22: 1845-1848.
14. Shapiro R. Interpretation of the subsidiary peaks at periods near 27 days in power spectra of
geomagnetic disturbance indices. J Geophys Res 1967; 72: 4945-4949.
15. Fraser-Smith AC. Spectrum of the geomagnetic activity index Ap. J Geophys Res 1972; 77:
4209-4220.
16. Delouis H, Mayaud PN. Spectral analysis of the geomagnetic activity index aa over a 103year
interval. J Geophys Res 1975; 80: 4681-4688.
17. Silverman SM, Shapiro R. Power spectral analysis of auroral occurrence frequency. J
Geophys Res 1983; 88: 6310-6316.
18. Mursula K, Zieger B. The 1.3-year variation in solar wind speed and geomagnetic activity.
Adv Space Res 2000; 25: 1939-1942.
19. Prabhakaran Nayar SR. Periodicities in solar activity and their signature in the terrestrial
environment. ILWS Workshop, Goa, February 19-24, 2006. 9 pp.
20. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, Johnson P,
Gigolashvili M, Breus T, Sonkowsky R, Chibisov SM, Katinas G, Siegelova J, Dusek J,
Singh RB, Berri BL, Schwartzkopff O. Incidence of sudden cardiac death, myocardial
infarction and far- and near-transyears. Biomed & Pharmacother 2005; 59 (Suppl 1): S239-
S261.
21. Chapman S, Bartels J. Geomagnetism. 3rd ed. Oxford: Clarendon Press; 1962. 1049 pp.
22. Grafe A. Einige charakterische Besonderheiten des geomagnetischen
Sonneneruptionseffektes. Geofisica Pura e Applicata 1958; 40: 172-179.
23. Russell CT, McPherron RL. Semiannual variation of geomagnetic activity. J Geophys Res
1973; 78: 92-108.
24. Halberg F, Schwartzkopff O, Cornélissen G, Otsuka K. Life's waves in space-time in and
around us. Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary
Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute
for Theoretical Physics, Kyoto University, October 15-20, 2007. p. 45-47.
58
25. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
26. Wolff CL. Solar irradiance changes caused by g-modes and large-scale convection. Solar
Physics 1984; 93: 1-13.
27. Mayr HG, Wolff CL, Hartle RE. Wave driven nonlinear flow oscillator for the 22 year solar
cycle. Geophys Res Lett 2001; 28, 463.
28. Wolff CL. Rotational sequences of global oscillations inside the sun. Astrophys J 2002; 580,
L181-L184.
29. Wolff CL, Mayr HG. The sun’s reversing flows and heat spike as caused by g-modes.
Astrophys J 2004; 606, L163-L166.
30. Mayr HG, Mengel JG, Wolff CL. Wave-driven equatorial annual oscillation induced and
modulated by the solar cycle. Geophys Res Lett 2005; 32: L20811.
doi:10.1029/2005GL023090. 5 pp.
31. Wolff CL, O'Donovan AE. Coupled groups of g-modes in a sun with a mixed core.
Astrophys J 2007; 661: 568-585.
32. Wolff CL, Hickey JR. Solar irradiance change and special longitudes due to r-modes.
Science 1987; 235: 1631-1633.
33. Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day periodicity in
the occurrence of hard solar flares? Nature 1984; 312: 623-625.
34. Kiplinger AL, Dennis BR, Orwig LE. Detection of a 158-day periodicity in the solar hard Xray
flare rate. Bull Am Astronom Soc 1984; 16: 891.
35. Bogart RS, Bai T. Confirmation of a 152-day periodicity in the occurrence of solar flares
inferred from microwave data. Astrophys J 1985; 299: L51-L55.
36. Bai T, Cliver EW. A 154 day periodicity in the occurrence rate of proton flares. Astrophys J
1990; 363: 299-309.
37. Kile JN, Cliver EW. A search for the 154 day periodicity in the occurrence rate of solar
flares using Ottawa 2.8 GHz burst data, 1955-1990. Astrophys J 1991; 370: 442-448.
38. Carbonell M, Ballester JL. The periodic behaviour of solar activity: the near 155-day
periodicity in sunspot areas. Astron Astrophys 1992; 255: 350-362.
39. Oliver R, Ballester JL. Short-term periodicities in sunspot areas during solar cycle 22. Solar
Physics 1995; 156: 145-155.
40. Ballester JL, Oliver R, Carbonell M. The near 160 day periodicity in the photospheric
magnetic flux. Astrophys J 2002; 566: 505-511.
41. Hamamatsu A, Cornélissen G, Otsuka Ku, Halberg F, Chibisov S (presenter). Linearnonlinear
rhythmometry documents a transyear and a cishalfyear in sudden cardiac death
(ICD 10, code I46.1) in Tokyo. In: Proc., Int. Symp., Problems of ecological and
physiological adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan
2007. Moscow: People's Friendship University of Russia; 2007. p. 542-545.
42. Cornélissen G, Schnaiter D, Halberg F, Mitsutake G, Otsuka K, Fiser B, Siegelova J, Jozsa
R, Olah A, Bakken EE, Chibisov S (presenter). A cis-half-year characterizes the incidence of
sudden cardiac death also in and near Austria. In: Proc., Int. Symp., Problems of ecological
and physiological adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan
2007. Moscow: People's Friendship University of Russia; 2007. p. 545-551.
43. Cornélissen G, Halberg F, Rostagno C, Otsuka K. A chronomic approach to cardiac
arrhythmia and sudden cardiac death. S4-2, Proceedings, 2nd World Congress of
Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 56-59.
59
44. Cornélissen G, Watson D, Mitsutake G, Fiser B, Siegelova J, Dusek J, Vohlidalova L,
Svacinova H, Halberg F. Mapping of circaseptan and circadian changes in mood. Scripta
medica 2005; 78: 89-98.
45. Cornélissen G, Masalov A, Halberg F, Richardson JD, Katinas GS, Sothern RB, Watanabe
Y, Syutkina EV, Wendt HW, Bakken EE, Romanov Y. Multiple resonances among time
structures, chronomes, around and in us. Is an about 1.3-year periodicity in solar wind built
into the human cardiovascular chronome? Human Physiology 2004; 30 (2): 86-92.
46. Tarquini B, Cornélissen G, Perfetto F, Tarquini R, Halberg F. Chronome assessment of
circulating melatonin in humans. In vivo 1997; 11: 473-484.
47. Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. About 5-month
cycle in human circulating melatonin: signature of weather in extraterrestrial space? Poster
presentation, Fourth UN/ESA/NASA/JAXA Workshop on the International Heliophysical
Year 2007 and Basic Space Science: "First Results from the International Heliophysical Year
2007", Sozopol, Bulgaria, June 2-6, 2008.
48. Monteleone P, Esposito P, La Rocca A, Maj M. Does bright light suppress nocturnal
melatonin secretion more in women than men? J Neural Transm [Gen Sect] 1995; 102: 75-
80.
49. Boyce P, Kennaway DJ. Effects of light on melatonin production. Biological Psychiatry
1987; 22: 473-478.
50. Nathan PJ, Burrows GD, Norman TR. The effect of dim light on suppression of nocturnal
melatonin in healthy women and men. J Neural Transm 1997; 104: 643-648.
51. Nathan PJ, Wyndham EL, Burrows GD, Norman TR. The effect of gender on the melatonin
suppression by light: a dose response relationship. J Neural Transm 2000; 107: 271-279.
52. Griefahn B, Brode P, Blaszkewicz M, Remer T. Melatonin productiotn during childhood and
adolescence: a longitudinal study on the excretion of urinary 6-hydroxymelatonin sulfate. J
Pineal Res 2003; 34: 26-31.
53. Fourtillan JB, Brisson AM, Fourtillan M, Ingrand I, Decourt JP, Girault J. Melatonin
secretion occurs at a constant rate in both young and older men and women. Am J Physiol Endocrinol
Metab 2001; 280 (1): E11-E22.
54. Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Bioavailability of
melatonin in humans after daytime administration of D(7) melatonin. Biopharmaceutics &
Drug Disposition 2000; 21: 15-22.
55. Burch JB, Reif JB, Yost MG, Keefe TJ, Pitrat CA. Reduced excretion of a melatonin
metabolite in workers exposed to 60 Hz magnetic fields. Am J Epidemiol 1999; 150: 27-36.
56. Weydahl A, Sothern RB, Cornélissen G, Wetterberg L. Geomagnetic activity influences the
melatonin secretion at latitude 70˚N. Biomed and Pharmacother 2001; 55: 57-62.
57. Otsuka K, Cornélissen G, Weydahl A, Holmeslet B, Hansen TL, Shinagawa M, Kubo Y,
Nishimura Y, Omori K, Yano S, Halberg F. Geomagnetic disturbance associated with
decrease in heart rate variability in a subarctic area. Biomed & Pharmacother 2001; 55
(Suppl 1): 51s-56s.
58. Jozsa R, Halberg F, Cornélissen G, Zeman M, Kazsaki J, Csernus V, Katinas GS, Wendt
HW, Schwartzkopff O, Stebelova K, Dulkova K, Chibisov SM, Engebretson M, Pan W,
Bubenik GA, Nagy G, Herold M, Hardeland R, Hüther G, Pöggeler B, Tarquini R, Perfetto
F, Salti R, Olah A, Csokas N, Delmore P, Otsuka K, Bakken EE, Allen J, Amory-Mazaudier
C. Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts
-- forecasts of geomagnetics. Biomed & Pharmacother 2005; 59 (Suppl 1): S24-S30.
60
59. Wetterberg L, Bratlid T, Knorring Lv, Eberhard G, Yuwiler A. A multinational study of the
relationships between nighttime urinary melatonin production, age, gender, body size, and
latitude. Eur Arch Psychiatr Neurosci 1999; 249: 256-262.
60. Halberg F, Cornélissen G, Sothern RB, Chibisov SM, Wendt HW. Do unseen, very weak
magnetic mechanisms contribute to terrorism in wobbly spectral windows? Proc. 8th
International Congress "Health and education millennium", Moscow, Russia, November 14-
17, 2007, p. 63-66.
61. Cornélissen G, Halberg F, Wendt HW, Sothern RB, Chibisov SM, Kulikov SI, Agarwal RK.
Weak magnetoperiodism rather than socio-photo-thermoperiodism characterizes human
terrorism detection of about 1.3-year aeolian transyear but not precise 1.0-year cycle. Proc.
8th
International Congress "Health and education millennium", Moscow, Russia, November
14-17, 2007, p. 77-80.
62. Grigoryev PYe, Vladimirskii BM. The cosmic weather affects the terrorist activity. Uchenye
zapiski Tavricheskogo Natsionalnogo Universiteta im V.I. Vernadskogo, Series "Biology,
chemistry" 2007; 20 (59) ( 1): 28-46.
63. Cornélissen G, Halberg F, Wendt HW, Nelson RD, Schwartzkopff O, Wang ZR, Otsuka K,
Oinuma S, Revilla M, Katinas GS, Sanchez de la Pena S, Beaty L, Sonkowsky R,
Blagonravov MB, Chibisov SM. Transyears, about 17-month cycles in opinion polls about
US president. Proceedings, 1st
International Workshop, Physiology of adaptation and quality
of life: problems of traditional medicine and innovation, People's Friendship University of
Russia, Moscow, Russia, May 14-16, 2008.
64. Mikulecky M, Florida PL. Daily birth numbers in Davao, Philippines, 1993-2003: Halberg's
transyear stronger than year. Abstract, 26th Seminar, Man in His Terrestrial and Cosmic
Environment, Upice, Czech Republic, May 17-19, 2005.
65. Mikulecky M. Reanalyza natality v jizni brazilii -- opet dominuje Halbergova parasezonalita:
International Conference on the Frontiers of Biomedical Science: Chronobiology, Chengdu,
China, September 24-26, 2006, p. 188-193.
66. Kovac M, Mikulecky M. Time sequence of epileptic attacks from the point of view of
possible lunisolar connections. International Conference on the Frontiers of Biomedical
Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 175-179.
67. Kovac M, Mikulecky M. Secular rhythms and Halberg's paraseasonality in the time
occurrence of cerebral stroke. Bratisl Lek Listy 2005; 106 (2): 423-427.
68. Yamanaka T, Cornélissen G, Kazuma M, Kazuma N, Murakami S, Otsuka K, Siegelova J,
Dusek J, Sosikova M, Halberg F. Further mapping of the natality chronome, in Toda City
(Japan) Maternity Hospital. Scripta medica 2005; 78: 99-106.
69. Cornélissen G, Halberg F, Mikulecky M, Florida P, Faraone P, Yamanaka T, Murakami S,
Otsuka K, Bakken EE. Yearly and perhaps transyearly human natality patterns near the
equator and at higher latitudes. Biomed & Pharmacother 2005; 59 (Suppl 1): S117-S122.
70. Valdés-Galicia JF, Pérez-Enriquez R, Otaola JA. The cosmic-ray 1.68-year variation: a clue
to understand the nature of the solar cycle? Solar Physics 1996; 167: 409-417.
71. Kudela K, Rybak J, Antalova A, Storini M. Time evolution of low-frequency periodicities in
cosmic ray intensity. Solar Physics 2002; 205: 165-175.
72. Cornélissen G, Halberg F, Kudela K, Chibisov SM (presenter). Transdisciplinary transyears
and some of their uncertainties in cosmic rays. In: Proc., Int. Symp., Problems of ecological
and physiological adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan
2007. Moscow: People's Friendship University of Russia; 2007. p. 519-524.
73. Halberg F, Bakken EE, Katinas GS, Cornélissen G, Zaslavskaya RM, Blank MA, Syutkina
EV, Breus TK, Watanabe Y, Masalov A, Chibisov SM. Chronoastrobiology: Vernadsky's
61
future science ? Benefits from spectra of circadians and promise of a new transdisciplinary
spectrum of near-matching cycles in and around us. Opening keynote, Proceedings, III
International Conference, Civilization diseases in the spirit of V.I. Vernadsky, People's
Friendship University of Russia, Moscow, Oct. 10-12, 2005, p. 4-22.
74. Gregori GP. Galaxy – Sun – Earth relations: The origin of the magnetic field and of the
endogenous energy of the Earth, with implications for volcanism, geodynamics and climate
control, and related items of concern for stars, planets, satellites, and other planetary objects.
A discussion in a prologue and two parts. Beiträge zur Geschichte der Geophysik und
Kosmischen Physik, Band 3, Heft 3, 2002, 471 pp. ISNN: 1615 - 2824 – NE: Gregori,
Giovanni P. © Science Ed, Arbeitskreis Geschichte Geophysik / W Schröder, Germany
2002.
75. Sturrock PA, Scargle JD, Walther G, Wheatland MS. Rotational signature and possible rmode
signature in the GALLEX solar neutrino data. Astrophys J 1999; 523: L177-L180.
76. Sturrock PA. Time-series analysis of Super-Kamiokande measurements of the solar neutrino
flux. Astrophys J 2003; 594: 1102-1107.
77. Cowling TG. The non-radial oscillations of polytropic stars. Monthly Notices of the Royal
Astronomical Society 1941; 101: 367-375.
78. Christensen-Dalsgaard J, Bartholemieu G. Theory of solar oscillations. In: Cox AN,
Livingston WC, Mathews MS, eds. Solar Interior and Atmosphere. Tucson: University of
Arizona Press; 1991. p. 401-478.
79. Eff-Darwich A, Korzennik SG, Jiminez-Reyes SJ. Inversion of the internal solar rotation
rate. Astrophys J 2002; 573: 857-863.
80. Sothern RB, Katinas GS, Cornélissen G, Halberg F. A 38-year record, albeit informative, is
not yet enough: womb-to-tomb monitoring is overdue. Appendix 2 of Halberg F, Cornélissen
G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka P, Prikryl P, Chibisov
SM, Holley DC, Wendt HW, Bingham C, Palm SL, Sonkowsky RP , Sothern RB, Pales E,
Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R, Konradov AA,
Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov A V, Faraone P ,
Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T, Pantaleoni GC,
Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki EA, Bathina S,
Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M. Chronoastrobiology: proposal,
nine conferences, heliogeomagnetics, transyears, near-weeks, near-decades, phylogenetic
and ontogenetic memories. Biomed & Pharmacother 2004; 58 (Suppl 1): S179- S186.
81. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clockhour
in long-term investigation is no panacea. Proc., Int. Conf. on the Frontiers of
Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 208-211.
82. Watanabe Y, Cornélissen G, Halberg F, Otsuka K, Ohkawa S-I. Association by signatures
and coherences between the human circulation and helio- and geomagnetic activity. Biomed
& Pharmacother 2001; 55 (Suppl 1): 76s-83s.
83. Watanabe Y, Cornélissen G, Hellbrügge T, Watanabe F, Otsuka K, Schwartzkopff O,
Halberg F. Partial spectral element in the chronome of a human neonatal heart rate at term.
Biomed & Pharmacother 2002; 56 (Suppl 2): 374s-378s.
84. Clark S. The Sun Kings: The Unexpected Tragedy of Richard Carrington and the Tale of
How Modern Astronomy Began. Princeton, NJ: Princeton University Press; 2007. 224 pp.
85. Halberg F, Cornélissen G, Sothern RB, Otsuka K, Revilla M, Siegelova J, Fiser B. Circadian
stage-dependent infradian-modulated changes in a mental function during aging. These
proceedings.
62
86. Halberg F. Challenges from "60 years of translational chronobiology". Uchenyerye zeaniski
Tavricheskogo natsional'iogo Universiteta im V.I. Vernadskogo, Seriya "Biologia, khaimiya"
2007; 20 (19): 107-122, AND Kofler W, ed. Proceedings, International Interdisciplinary
Workshop, Natural Cataclysms and Global Problems of the Modern Civilization, Baku,
Azerbaijan, September 24-27, 2007. Transactions of the International Academy of Science
H&E. Baku/Innsbruck: ICSD/IAS; 2007. p. 165-178.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
63
Reasons for a protocol for radiation treatment aimed at exploiting weekly rhythms
Francine Halberg1
, Germaine Cornélissen2
, Franz Halberg2
, Waldemar Ulmer3
,
Salvador Sanchez de la Peña4
, Jarmila Siegelova5
, Othild Schwartzkopff2
and the broader BIOCOS project
1
Marin Cancer Institute, Greenbrae, and University of California at San Francisco, CA, USA
2
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
3
VARIAN International, Zug, Switzerland
4
Chronomic Res Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City, Mexico
5
Masaryk University, Brno, Czech Republic
Abstract: Circadian timing’s merits have been documented earlier, but the administration of
treatment at optimal clock hours may be difficult to implement in the clinic from a practical
viewpoint, since it may require service outside routine scheduling hours. Scheduling along the scale
of the week, as here proposed, does not depend on irregular treatment hours. Circaseptan
optimization is promising in the experimental laboratory but has not yet been tested systematically
in the radiotherapeutic clinic. Our purpose herein is to advocate a practical protocol.
Aim: To assess any benefit from chronotherapy of lung cancer by using daily radiation doses
varying along the scale of the week. In our time structure (chronome), an about-weekly schedule is
partly built-in (1), while, like many other rhythms, it is also driven by society and the environment
(1, 2), just as circadians are (3).
CRx of Human Oral Cancer
0
20
40
60
80
-8 -4 0 4 8
Treatment Time (Hours from Peak Tumor Temperature)
2yDisease-FreeSurvival(%)
Average
Gain: 200 %
C
Minimum
Gain:
428 %
D
P=0.02 (Peak test)
CRx of Human Oral Cancer
0
20
40
60
80
minimum average maximum conventional
Treatment Time (Hours from Peak Tumor Temperature)
2yDisease-FreeSurvival(%)
Gain:
200 %
Gain:
428 %
Gain:
214 %
D C
Rx as
usual
Figure 1a. Radiotherapy timed at peak tumor temperature
leads to faster tumor regression (not shown) and to more
than doubling of the 2-year disease-free survival rate, as
compared to reference groups treated 4 or 8 hours before
or after the tumor temperature peak. Data from Prof.
emeritus B.D. Gupta and Dr. Akhil Deka. © Halberg.
Figure 1b. Gain from radiotherapy timed at peak tumor
temperature, gauged by the 2-year disease-free survival
rate, is assessed by comparison with the average or
lowest disease-free survival, when treatment is
administered 4 or 8 hours before or after the tumor
temperature peak, or when it is given “as usual” without
consideration of circadian stage. © Halberg.
Circadian background: Disease-free survival was doubled in patients with tumors of the oral cavity
by timing radiotherapy along the scale of the day, when treatment was administered at the circadian
stage of highest tumor temperature, Figure 1a (4, 5). The gain at the best time by reference to the
worst time was 428%; by reference to the average it was 200%. There was a gain of 214% by
comparison with treatment as usual, Figure 1b (4, 5). These findings were empirical, yet supported
by common sense, once it was realized that many tumors and most loads undergo a spectrum of
rhythms.
64
Figure 2. Rhythm determines cost of single load. Hours of changing resistance. As a function of the body's rhythms, a
potentially harmful stimulus, such as a drug given in the same dose at different times to different yet compatible
individuals (top) will have drastically different effects; not even risk is incurred at one time from a stimulus that is deadly
at another time. It is thus common sense to give a potentially harmful drug at the time of highest resistance to it
(bottom). See Figures 3 and 4 for scheduling a series of treatments (10). © Halberg.
Figure 3. Relations of external loads to internal cost in rhythmic systems. The effects of repeated stimuli -- such as a
course of drug or nutriceutical administration -- can be time-dependent; if so, a series of doses given in a time-invariant
way might involve risk or result in death, whereas the same total dosage will be well tolerated when given in a way
varying with due regard for the body's rhythms (10). By the same token, the desired beneficial effect will also be rhythm
stage-dependent, and again dosing will have to be made dependent on timing. © Halberg.
65
Figure 4. Murine tolerance of ara-C on different schedules. Study IV (L1210; inoc. 01.26.1972). Survival time of
leukemic BDF1 mice on different drug administration schedules (top) and timing of doses of ara-C (bottom) in sinusoidal
and reference schedule consisting of 4 courses of 240 mg/kg/24 h each. When the same total dose of ara-C is given,
certain sinusoidal drug administration schedules are definitely better tolerated by the mice than are other sinusoids or a
currently conventional reference treatment of 8 equal doses over a 24-hour span (10). © Halberg.
66
Figure 5. As a follow-up on a circadian rhythm in LD50 (20), a rhythm in therapeutic index was found by 1973 (10) and
awaits use in the clinic, where it already doubled 2-year disease-free survival of patients with perioral cancers using the
tumor temperature as a marker, Figure 1. © Halberg.
67
HARM OR HELP*:
With or without chronobiologic patterning, the same total dose per week
of LENTINAN inhibits or enhances malignant growth, respectively
Figure 6. The same total dose of the same molecule, lentinan, depending on the circadian and circaseptan patterns of its
administration, stimulates vs. inhibits the growth of a subsequently implemented malignancy (left) or shortens or
lengthens survival (right). © Halberg.
Extension of timing to weekly optimization. In the laboratory, the importance of optimizing
circadian and infradian timing (6, 7) was also documented for immunotherapies, Figures 6 and 7.
Opposite effects are thus found, as shown in Figure 6, and a 30% gain in efficacy, above any gain
from optimization according to the daily cycle, is documented in Figure 7 (8), while the
optimization of radiotherapy by circadian and circaseptan timing in the laboratory is shown in
Figure 8.
68
Figure 7. Cyclosporine chronotherapy of pancreas-allo-transplanted rats suggests further gain
in graft function from doses varying from day to day according to a weekly periodicity, beyond
the circadian stage-dependence of equal daily doses. Data of T Liu. © Halberg.
Combined circaseptan and circadian optimization of radiotherapy. Tumor cells of 4 different types
of cancer were shown to grow not uniformly but according to rhythms with periods of 1 day and 1
week, the 1-week cycle being the most prominent (6, 7). Moreover, when radiation was applied at
the time of highest cell division of these daily and weekly cycles, tumor kill by radiation was
statistically significantly more effective than when it was given at the time of lowest cell division,
Figure 8. Moreover, an about-weekly cycle may be amplified in surface temperature measured over
a cancerous vs. a healthy breast (9).
69
Figure 8. Time course of tumor cell growth pooled across all four kinds of tumor cells and both pH values
shown after normalization for weeks 2 and 3 of study to illustrate circaseptan-over-circadian prominence.
Irradiation shortly after the circaseptan-circadian maximum of -ATP is associated with larger tumor cell kill
(lesser survival) than irradiation shortly after the circaseptan-circadian minimum of -ATP (middle). © Halberg.
70
Figure 9. Task 3, illustrated in the left lower box, has been achieved in Figures 1 and 8 for radiation
treatment. © Halberg.
More generally, a properly timed sinusoidal treatment pattern has been superior to an equal-dose
schedule, Figures 4-9 (10). These results from the laboratory, Figures 2-6, and many others all
suggest the possibility of increasing treatment efficacy and bettering outcomes by taking advantage
of weekly cycles of gradually increasing and decreasing doses, as planned in the following protocol.
71
Suggested protocol for consideration or critique by all comers
Aim. To exploit for timed treatment any circaseptan schedules restricted to the five working days do
not require activities during odd hours outside current schedules and hence are more readily
implemented than the circadians.
Patients: Patients with newly diagnosed Stage I-III non-small cell lung cancer are eligible. They are
to be stratified by stage, chemotherapy regimen, age group, and gender.
Outcomes: Before start of treatment and at 3-month intervals after initiation of treatment, maximal
tumor diameter in two dimensions will be determined by CT scan. Tumor regression will be
evaluated by the difference at each follow-up between maximal tumor diameter at that time and
prior to treatment. Other outcome measures will be time to progression and overall survival.
Toxicity will also be assessed during treatment and at each follow-up using the RTOG criteria (a
six-point scale of bladder and bowel symptoms, produced by the Radiation Therapy Oncology
Group).
Treatment: With or without concurrent chemotherapy, radiation therapy will consist of a total dose
of 6000 cGy, to be administered over 6 weeks, 5 days a week (Monday-Friday). A given patient
will be scheduled to always receive radiation therapy at the same time of day. Each daily treatment
time will be recorded for each patient. Treatment will always start on a Monday. Patients on
chemotherapy generally receive 12 mg of dexamethasone as part of their anti-emetic regimen. All
patients in this study will receive the same dose on day 1 of treatment for potential synchronization
of the weekly cycle.
There will be 6 groups.
- Group 1 will receive equal 200cGy doses per day.
- Groups 2-6 will receive the same weekly dose of 1000cGy that will be administered in
different fraction sizes varying between 175 and 220cGy per day, according to a weekly
cycle. The 5 groups will differ in terms of the start dose, as follows:
Week day Group 2 Group 3 Group 4 Group 5 Group 6
Monday 175 193 220 220 193
Tuesday 193 220 220 193 175
Wednesday 220 220 193 175 193
Thursday 220 193 175 193 220
Friday 193 175 193 220 220
Sample size: This observational study will serve to determine uncertainties involved, to serve as a
basis for sample size calculation. With the proposed design, patients can be accrued sequentially, so
that as results accumulate, the required sample size can be determined and progressively refined,
and patients can be recruited until the desired sample size is met. The major criterion will be the
desirability to detect a 50% difference between best and worst outcome with 80% confidence.
Statistical considerations have shown the superiority of the cosinor over the more usual one-way
analysis of variance to achieve this goal (11, 12). Relatively small numbers of subjects evenly
spread over the cycle to be investigated (such as a 24-hour cycle) have already served for
determining the optimal treatment time (13, 14), including radiotherapy of perioral (15) and lung
(16) cancer.
72
Marker rhythmometry: In the case of prior timed radiation treatment, tumor or oral temperature
were used as organismic markers of treatment time (5, 17). Markers should indeed be used, the
sooner the better, in follow-up investigations aimed at the other optimization of benefit from
circaseptan timing of radiotherapy. They are here omitted in order to minimize the therapist’s load
and deviations from the current routine, so as to render the study practical without special support.
Magnetic resonance spectroscopy has already been examined in clinically healthy subjects as a
putative marker for circadian timing based on high-energy phosphate metabolism (18). This was
also the approach taken in the experimental laboratory on cancer cells, yielding statistically
significant differences in tumor cell kill as a function of circadian-circaseptan timing, Figure 8 (6, 7).
Moreover, when there are no specific cancer markers for the kind of tumor to be treated, possibly
even unspecific markers may serve as an index superior to an arbitrarily fixed clock hour or day of
the week (19). One option being considered in this protocol is the possibility to synchronize the
circaseptan component by the administration of a fixed dose of steroids, already given to patients
undergoing complementary chemotherapy.
Conclusion: Chronotherapy started with the demonstration of a circadian rhythm in the response to
whole-body X-ray irradiation (20). The importance of circaseptans soon was also seen (21). As
compared to the cost of instrumentation for radiotherapy, timing is very cheap, and its benefits in
the laboratory are duplicated for the case of circadian timing in the clinic. Circaseptans can also be
considered for optimization in the clinic on the basis of evidence obtained in the laboratory. Marker
rhythms remain to be sought for all aims in Figure 9, in keeping with common sense, Figures 2 and
3, and laboratory evidence, Figures 4-8, so that the gains made in the clinic, Figure 1, can be
augmented by infradians.
References
1. Halberg F, Engeli M, Hamburger C, Hillman D. Spectral resolution of low-frequency, smallamplitude
rhythms in excreted 17-ketosteroid; probable androgen induced circaseptan
desychronization. Acta endocrinol (Kbh) 1965; 50 (Suppl 103): 5-54.
2. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
3. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
4. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc.
30th Ann. Cong. Rad., January 1977, Post-Graduate Institute of Medical Education and
Research, Chandigarh, India, 8 pp.
5. Halberg Francine, Halberg J, Halberg E, Halberg Franz. Chronobiology, radiobiology and
steps toward the timing of cancer radiotherapy. In: Goldson AL, volume editor. Cancer
Growth and Progression, vol. 9, ch. 19, Kaiser H, series editor. Dordrecht: Kluwer Academic
Publ.; 1989. p. 227-253.
6. Ulmer W, Cornélissen G, Revilla M, Siegelova J, Dusek J, Halberg F. Circadian and
circaseptan dependence of the beta-ATP peak of four different cancer cell cultures:
implications for chronoradiotherapy. Scripta medica (Brno) 2001; 74: 87-92.
73
7. Cornélissen G, Ulmer W, Halberg F. Basic research on cancer cell cultures for circadiancircaseptan
optimization of radiotherapy. PS-001, Proceedings, 2nd World Congress of
Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 62.
8. Liu T, Cavallini M, Halberg F, Cornélissen G, Field J, Sutherland DER. More on the need for
circadian, circaseptan and circannual optimization of cyclosporine therapy. Experientia 1986;
42: 20-22.
9. Simpson HW, Pauson AW, Wilson DW. The chronobra – the ‘electrocardiogram’ of the
breast? Proc. 2nd Ann. IEEE Symp. on Computer-Based Medical Systems, Minneapolis, June
26-27, 1989, Computer Society Press, Washington DC, pp. 214-225.
10. Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE,
Runge W, Spalding JF, Lee JK, Good RA. Toward a chronotherapy of neoplasia: Tolerance of
treatment depends upon host rhythms. Experientia (Basel) 1973; 29: 909-934.
11. Bingham C, Cornélissen G, Halberg F. Power of "Phase 0" chronobiologic trials at different
signal-to-noise ratios and sample sizes. Chronobiologia 1993; 20: 179-190.
12. Halberg F, Bingham C, Cornélissen G. Clinical trials: the larger the better? Chronobiologia
1993; 20: 193-212.
13. Günther R, Herold M, Halberg E, Halberg F. Circadian placebo and ACTH effects on urinary
cortisol in arthritics. Peptides 1980; 1: 387-390.
14. Cornélissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J, International Wombto-Tomb
Chronome Study Group: Prophylactic aspirin treatment: the merits of timing. JAMA
1991; 266: 3128-3129.
15. Halberg F, Cornélissen G, Wang ZR, Wan C, Ulmer W, Katinas G, Singh Ranjana, Singh RK,
Singh Rajesh, Gupta BD, Singh RB, Kumar A, Kanabrocki E, Sothern RB, Rao G, Bhatt
MLBD, Srivastava M, Rai G, Singh S, Pati AK, Nath P, Halberg Francine, Halberg J,
Schwartzkopff O, Bakken E, Shastri VK. Chronomics: circadian and circaseptan timing of
radiotherapy, drugs, calories, perhaps nutriceuticals and beyond. J Exp Therapeutics Oncol
2003; 3: 223-260.
16. Wang ZR, Wan CM, Lei Y, Cornélissen G, Halberg F. Phase-zero trial of clinical
chronoradiotherapy of lung cancer. Chronobiologia 1994; 21: 155-157.
17. Gupta BD, Cornélissen G, Halberg F, Verma G. Oral and cervical temperature as marker
variables for chronoradiotherapy of patients with cervical cancer. Progress in Clinical and
Biological Research 1987; 227B: 349-356.
18. Halberg E, Jardetzky N, Halberg F, Soong LB, Halberg F, Wu J, Zhou S, Jardetzky O.
Magnetic resonance spectroscopy and ambulatory cardiovascular monitoring noninvasively
gauge timing of phosphate metabolism and circulation. Chronobiologia 1989; 16: 1-8.
19. Halberg E, Long HJ III, Cornélissen G, Blank MA, Elg S, Touitou Y, Bakken E, Delmore P,
Haus E, Sackett-Lundeen L, Prem K, Halberg F. Toward a chronotherapy of ovarian cancer
with taxol: Part II: Test pilot study on CA125. Chronobiologia 1992; 19: 17-42.
20. Halberg F. Temporal coordination of physiologic function. Cold Spr Harb Symp quant Biol
1960; 25: 289-310. Discussion on LD50, p. 310.
21. Ulmer W, Cornélissen G, Halberg F. Physical chemistry and the biologic week in the
perspective of chrono-oncology. In vivo 1995; 9: 363-374.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
74
Brückner-Egeson-Lockyer (BEL) climate cycle in original Brückner’s, Lockyer’s and
follow-up data
Franz Halberg1
, Germaine Cornélissen1
, Jerzy Czaplicki2
, S.R. Prabhakaran Nayar3
,
Jarmila Siegelova4
1
Halberg Chronobiology Center, Univ. of Minnesota, Minneapolis, MN, USA
2
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
3
Department of Physics, Kerala Univ., Kariavattom, Trivandrum, India
4
Masaryk Univ., Brno, Czech Republic
Cycles of 30 to 40 years are dubbed BEL, after the initials of Eduard Brückner (1), Charles
Egeson (2) and W.J.S. Lockyer (3) and his father Norman Lockyer (4), who discovered (1-3) or
discussed (4) about (~) 33-35-year cycles, the former two in terrestrial climate, the latter two
aligning periodic changes in solar cycle length with climate, an association subsequently reported
again without reference to an ~30-year cyclicity or its discoverers (5-7). The BEL findings,
immediately (8) and later again (9, 10) questioned by some, confirmed by others (11), sensational
a century ago (12), with notable exceptions (13, 14) forgotten, are here inferentially statistically
validated as nonstationary (to the point of intermittency) and as transdisciplinary, extending from
meteorology to societal affairs. Elsewhere in these proceedings, we report the BEL in a consumer
price index over centuries, in over 2.5 millennia of international battles assembled by Raymond H.
Wheeler, and military-political affairs presented rightly by Alexander Leonidovich Chizhevsky as
setting the course of history. Elsewhere also, we report on the BEL in human heart rate, in a
mental function, the estimation of 1 minute, and in the interplanetary magnetic field, findings
suggesting a possible origin in heliogeomagnetics (15). The biosphere mirrors space weather, also
in the circulation of blood. Solar variability may be monitored via several of its biospheric
associations, notably as a dividend from individualized self-assessed preventive cardiologic health
care.
Background
By contrast to the rapid development of an inferential statistical circadian physiology in the
last 60 years (16-20), based on the relatively easy replicability of a 24-hour profile, infradians --
spectral components with a period, , longer than 28 hours -- are less extensively explored with
uncertainties such as CIs (95% confidence intervals) of their parameters (15, 21-32). The longer
the period of a cycle, the more time it takes to assess it, the fewer will be the numbers of
documented cycles available for analysis, the greater will be the uncertainties of any prospective
quantifications; and accordingly the broader have to be the tentative limits set for the range of a
given cyclicity. Despite the great duration requirements for prospective approaches to infradians,
immediate benefit may well be anticipated from focusing retrospectively (as well as prospectively)
on infradians in archives and in already-accumulated, decades-long psychophysiological
monitoring records, e.g., within the aims of a project on The BIOsphere and the COSmos, BIOCOS
(22), which advocates eventually lifelong monitoring across generations.
With advice from Roederer (33), solar-terrestrial associations in the biosphere were
classified as photic, when relating to electromagnetic radiation in the visible domain, whereas
nonphotics were related to corpuscular emissions from the sun or from beyond and more broadly
to heliogeomagnetics, ultraviolet flux, gravitation etc. Nonphotics such as transyears -- neartransyears
(1.00 year < [ - CI] < [ + CI] < 1.20 years) and far-transyears (1.2 years [ - CI] <
[ + CI] < 1.9 years) (30) -- were broadly classified as spectral regions; components described in
physics by adjectives such as "quasiperiodic", "quasipersistent" (34) or "mid-term", among other
names, often drift in frequency, bifurcate, rejoin, and wax and wane in amplitude to the point of
becoming transiently undetectable, be it because they are obscured by noise or they actually
disappear from a given spectral line or band to reappear, e.g., to be re-excited later. The
nonstationary behavior, particularly characteristic of the solar wind's speed (15, 23), has been
75
described as aeolian (after Aeolus, mythical ruler of the winds), in keeping with a consensus
meeting of physicists and engineers with physicians and other biologists (35).
The transdisciplinary validation of aeolian biospheric behavior by corresponding cycles'
length in physics and vice versa, was added as a desirable possibility to the definition. Aeolian
transyears in some but not in other geographic locations characterize human natality (24, 25 vs.
36, 37), morbidity (27-29) and mortality from myocardial infarction (26), sudden cardiac death
(26, 28, 38), suicide (30, 31) and violence (32, 39, 40). The further documentation, prospectively
of 500-year cycles, not only in the concomitant emergence on different continents that did not
communicate with each other of leading physicians, poets and historians (41, 42; cf. 15), but also
in climate will take more than a few generations. Different cultures may prospectively reveal,
along the scale of millions of years, myriadennian cycles already mapped on the ocean floor (43,
44).
Circatranstridecadals
Transtridecadal, aeolian cycles longer than (beyond = trans) 30 and shorter than 40 years,
such as the BEL, are defined as having a CI of its overlapping the 30-40-year range, even when
the point estimate of lies outside that range. These broad limits are proposed in view of the great
variability and hence of the great extent of uncertainty associated with ~35-year cycles that have to
be assessed often on the basis of data hardly covering more than a single cycle, notably in
prospective biospheric studies. We dubbed this ~35-year cycle the Brückner-Egeson-Lockyer,
briefly BEL. Brückner documented it most extensively (1); Egeson's publication preceded
Brückner's by a few months and covered a shorter span less densely (2); he had the audacity to
refer to "sunspot causality" in the title and the scholarship to quote Lord (Francis) Bacon (1561-
1626): "They say it is observed in the Low Countries [...] that every five and thirty years the same
kind and suit of years and weathers comes about again; as great frosts, great wet, great droughts,
warm winters, summers with little heat, and the like; and they call it the Prime" (LVIII. Of
Vicissitude of Things, in Essays, Civil and Moral; 1597).
W.J.S. Lockyer's contribution was an ~35-year period in the changing length of the sunspot
cycle, which he promptly related to climate (3), as did his father Sir Norman Lockyer, discoverer
of helium and founder of the journal Nature, in a historical perspective written for the journal
Science (4). To cite W.J.S. Lockyer verbatim: "There is an alternate increase and decrease in the
length of a sunspot period reckoning from minimum to minimum. ... The total spotted area
included between any two consecutive minima varies regularly. The cycle of this variation is about
thirty-five years. ... The climate variations indicated by Professor Brückner are generally in
accordance with the thirty-five-year period" (3). That the length of the solar cycle relates to
environmental temperature was subsequently repeatedly reported (5-7), including a historical
review (6), albeit without any citation of the Lockyers or of an ~35-year cycle in climate and in
"the frequency of aurorae and magnetic storms" (3), for which a scholarly review by Samuel M.
Silverman provided power spectral corroboration (45).
Procedures and scope. We here analyze Brückner's original summarizing chart, Figure 1
(1), and W.J.S. Lockyer's data in the light of information accumulated in the interim, Figure 2. The
latter shows all Zürich relative sunspot (Wolf) numbers that became available in the interim
bracketing those considered by the original investigators indicated by horizontal arrows. The
variability of the solar cycle's length is shown in Figure 3 by two methods, one based on official
cycle lengths, the other by chronomic serial sections, both computed from a longer series of Zürich
numbers than Brückner and Lockyer had at their disposal. In Figure 4, we present results as global
spectral windows computed from data taken off Brückner's chart as point estimates of the s with
CIs given in the middle, as well as by chronomic serial sections, left and right, the latter to see how
the data vary as a function of time. For the latter purpose, in serial sections, we use intervals, each
covering about 3 cycles (105 years).
76
Figure 1. Brückner's chart summarizing his secular ~33.3-year variation (1) neither shows a regular cycle to
the unaided eye, nor was it convincing in a mathematical analysis to Arthur Schuster (9), the opinionleading
analyst of his time, who introduced periodograms, for seeking hidden periods.
Figure 2. Displays of the durations of the ascending (Rise to Max), descending (Fall to min), and entire
cycle length of consecutive solar activity cycles as reflected by sunspots between 1610.8 and 2000.3.
Variability in overall solar cycle length is shown with its uncertainty. Variability in stages shows that the
recently longer descending vs. the ascending stage of the solar cycle did not consistently prevail 200 or
more years ago. The more limited spans of serial data available to Brückner, Egeson and the Lockyers are
highlighted with double-headed horizontal arrows. © Halberg.
77
About 35-year cycles in climate are examined as part of a broad, partly novel spectrum of
transdisciplinary periods. With geographic site- and time-dependence, nonphotic components not
only coexist with photic ones such as the seasons, but can even replace the yearly component.
Thus we arrive at biospheric associations with physical solar-terrestrial indices, steps toward
breaking down disciplinary barriers, as suggested by Gregori (46) and Roederer (47). Biospheric
studies then become tools of the physicist as well as vice versa.
The dangers of extrapolating from data limited to a few cycles, if not from hardly more than
a single cycle, are noted at the outset. Thereby we also emphasize the urgent need for monitoring
the many aspects of the biosphere and of aligning the results thus obtained with transdisciplinary
ones. Lifelong physiological familial monitoring over generations should be investigated with
much longer continuous systematic as-one-goes analyzed archival surveillance. This endeavor
could match and enlarge the scope of the ongoing physical geomagnetic, solar and cosmic
surveillance started by Humboldt with Gauss's (48) and Sabine's (49) magnetic "crusade", and
extended by manned and in particular by unmanned satellites (50) in astrophysics complemented
by telescope-based observations of solar magnetism.
The BEL constitutes critical control information for the foreseeable future and beyond, for
those concerned with global warming and other problems of our civilization in health and disease.
Methods for a transdisciplinary chronomic (time-structural) analysis (51-55) beyond those leading
to the figures here presented seem desirable for an inferential statistical scrutiny not only of the
forgotten BEL in the Figure 1 data originally interpreted only by Brückner's ingenious eyeballing
but also for exploring the BEL's origins (56) and its signatures in the biosphere (57).
Results. Figure 4 quantifies the irregular cycles, i.e., the nonstationarity (sometimes
intermittency) of Brückner's variables in Figure 1’s time plots. Figures 2 and 3 show the variability
in solar cycle length with the uncertainties added in a tabulation on top of Figure 3, which with
Table 1 shows the CI of the amplitudes of each , including one of ~38 years, rather close to
Lockyer's ~35-year variation. Table 2 summarizes some of the spectral components found in the
time series taken off Brückner's chart. One glance suffices to show that a transtridecadal was the
only statistically significant component in rainfall in the window examined and that a BEL was not
found in the sunspot data considered by Brückner, shown with a horizontal double-headed arrow
in Figure 2. The column entitled "PR" (percent rhythm, i.e., coefficient of determination, namely
the percentage of the total variance contributed by a given spectral component) was biggest for a
BEL not only in rainfall but also for environmental temperature, cold winters and ice-free rivers,
but not for the wine harvest. For the latter variable, the CIs of the A slightly overlapped zero, as
they did for the A of ice-free rivers. When the time course of the same variables is analyzed in
separate chronomic serial sections of the span documented, Figure 4, sporadic intervals each of
105 years show statistical significance, indicated by dots bracketing the plotted acrophases, , for
each of the variables and in the case of rainfall and the frequency of cold winters, statistical
significance for a BEL prevailed in the majority of the intervals analyzed.
In the top row of Figure 4 on the left, the presence of dots indicates a nearly consistent
statistical significance in environmental temperature. For several other variables, the intermittent
presence of dots bracketing the acrophase indicates intermittent statistical significance. With the
trial and interval used for analysis, BEL is statistically significant only part of the time in 4
variables other than the almost consistent periodicity in only one time series on the top left of
Figure 4. The right section of Figure 4 again summarizes each series of Brückner's chart by a
chronomic serial section with the fit of the precise period best fitting a given series, shown in the
middle of Figure 4. This approach allows validation of the period indicated on the right of each
row of at least some intervals of all time series, except for Zürich sunspot numbers in the bottom
row of the chronomic serial sections of Figure 4.
78
Table1:Durationscharacterizingthe~11-yearcycleinZürich(Wolf)numbers(WN)analyzedfrom1600tothepresentin
2008*
Endpoint
Period**
(BestFit)(y)
P-value
(H0:A=0)
M(y)A(y)(˚)
Nonlinearperiod(y)***
[95%CI]
A[95%CI][1-parameterCI]
RisetoMax44.440.0514.760.81-157˚43.15[40.33,45.98]0.91[-0.14,1.96][0.26,1.57]
FalltoMin26.670.0146.300.88-315˚26.80[25.71,27.88]0.88[-0.05,1.82][0.30,1.47]
WNcyclelength38.100.03711.060.93-246˚38.05[35.57,40.54]0.93[-0.22,2.09][0.22,1.65]
*M:MESOR(midline-estimatingstatisticofrhythm),arhythm-adjustedmean
A:Amplitude(halftheextentofpredictablechangewithinacycle)
:Acrophase(timeofoverallhighvaluesrecurringineachcycle),expressedin(negative)degrees,with360˚equatedtotrialperiod:
tRef(0˚)=1600.
CI:Confidenceinterval
**Linearinfrequencyanalysis;fundamentalperiod=400years(y);harmonicincrement=0.5(18harmonics).
***Nonlinearresultsqualifiedbythechoiceoftrialperiod,selectedastheperiodofthelinearly-determinedspectralpeak;whenthe
anticipatedperiodof35yearsisusedastrialperiod,resultsarenotstatisticallysignificantandfailtoconvergetospectralpeaks
detectedlinearly.Itseemsimportanttoalwaysconsiderboththeanticipatedpeak(hereof35years,basedonW.J.S.Lockyer'sreport,
andthereafteranypeaksthatarenotanticipated,andhenceresultsaretentative).TheCIsoftheamplitudeyieldedbytheconservative
approachoverlapzero,albeitonlyslightly(firstsetofCIs),whilethoseofa1-parameterapproach(inbold)rejectthezero-amplitude
(nocycle)assumption.
79
Figure 3. Variations of sunspot cycle length in Zürich relative sunspot (Wolf) numbers in a broader
perspective than was available to Brückner, the Lockyers and Egeson. From a table listing dates of
solar minimum and maximum since the minimum of 1610.8 until the estimated maximum of 2000.3,
durations of consecutive solar cycle lengths were derived, as were durations from minimum to
maximum ("Rise to Max") and from maximum to minimum ("Fall to min"), all assigned to the date of
minimum (start of cycle). The data spanning about 400 years were analyzed by least squares spectra,
in the frequency range of one cycle in 400 years to one cycle in about 22.2 years (18 harmonics, with
a half harmonic increment). Components that accounted singly for most of the variation had periods of
44.4 (Rise to Max), 26.7 (Fall to min), and 38.1 (entire cycle length) years. When using as initial value
the individual best-fitting periods found linearly, the conservative CIs for the amplitude overlapped
zero, while the 1-parameter CIs did not (Table 1, and top of the graph). Period estimates and their CIs
were 43.15 [40.33, 45.98], 26.80 [25.71, 27.88], and 38.05 [35.57, 40.54] years for Rise to Max, Fall to
min, and cycle length, respectively, with corresponding amplitudes (and 1-parameter CIs) of 0.91
[0.26, 1.57], 0.88 [0.30, 1.47], and 0.93 [0.22, 1.65] years. © Halberg.
80
CHRONOMIC SERIAL SECTIONS OF BRÜCKNER's CHART (1565-1885)
AT FIXED 35-YEAR PERIOD (left) AND
AT NONLINEARLY ASSESSED BEST-FITTING PERIOD (right)
Figure 4. To study any time-varying behavior, Brückner's original series were each analyzed as a whole by
the extended linear-nonlinear cosinor, and results are shown in the middle of this figure as periods with their
CIs (95% confidence intervals) in parentheses. The global periods are bracketed by chronomic serial
sections, carried out with intervals of 105-year length displaced with increments of 5 years for the fit of a
period of precisely 35 years on the left side of this graph, whereas on the right, the serial sections are
repeated with the period best-fitting a given series, differing slightly among the time series (shown in the
middle section of the graph). Statistical significance is indicated by bracketing dots above and below the
acrophase. Dots are consistently seen only for environmental temperature in the top rows on the left and
right and for the frequency of cold winters in the penultimate row on the right. For rainfall, statistical
significance is seen for over half of the available data span in the third row on the left and right, while a
P<0.05 from the zero-amplitude test is more limited in rows 2, 4 and 5. A BEL cycle component in the
spectrum of Zürich relative sunspot (Wolf) numbers during the spans here analyzed (bottom row) was not
detected. This chronomic serial section, while showing the sometimes aeolian intermittent nature of BEL,
validates and qualifies Brückner's intuition and accounts for Schuster's caution. The cycle is aeolian,
including intermittency. © Halberg.
81
Irregular nonstationary behavior in the variables analyzed is characteristic of aeolian
behavior; what is critical, the behavior is amenable not only to inferential statistical analyses but
also to transdisciplinary validation, e.g., by the detection of beat and other periods found in solar
dynamics as signatures in biospheric variables and vice versa for physical ones. The
transdisciplinary covariation becomes informative when, upon removal and replacement of a
spectral component in a physical variable (done by the cosmos), there is corresponding behavior in
the biospheric variable (38, 58, 59). The evidence for a rhythm between the biosphere and the solar
wind's speed becomes convincing when an amplification of the biospheric component by the
presence of an environmental counterpart is accompanied by the damping of the biospheric
component in the absence of the environmental counterpart (38, 58, 59).
The solar wind is certainly a major driver in the biosphere, revealing a BEL cycle in its speed
and in proton density among other counterparts in the interplanetary magnetic field (56) and in the
biosphere (57). As compared with the ~10.5-year Schwabe cycle in sunspots, we are dealing with
much more irregular BEL cycles of smaller amplitudes, but not necessarily lacking importance, as
noted elsewhere (14, 58, 59). Moreover, the power spectrum of a nearly 500-year series of 45,000
auroral observations analyzed by Samuel M. Silverman (45) globally in his Figure 5, based on
monthly averages from 1500 to 1942, a sharp peak at ~33.3 years, as a follow-up on results from
1001-1900 (60, 61). Brückner deserves credit for including in his database the time of harvest in
vineyards (1) along with that of cold winters. These variables allowed him in his climate research
to backtrack to the year 1020. Analyzed globally, the no-35-year cycle assumption yields P=0.065.
As to behavior in time in a chronomic serial section in Figure 4, only a few intervals are associated
with a P<0.05, as apparent from dots bracketing the acrophase. But borderline significance
globally and significance in some intervals of a predicted transtridecadal cycle is noteworthy and
complements the thorough scholarship of Nico Stehr (14).
Brückner realized that the cycle he discovered has wide implications (62): in his monograph,
he even presented statistics of an infectious disease, typhus (14; cf. 1). His legacy, in our climateconscious
era, is the systematic collection of long time series to check the far-reaching conclusions
already drawn by Brückner in 1890 and by the Lockyers soon thereafter. On October 11, 1912,
Brückner lectured at Columbia University in New York, suggesting that human migration to the
USA and westward in the USA depended on his wet/dry cycles (12, 63). He also focused on
rainfall. It is telling that in a picture he is shown with an umbrella. Rainfall and cloud cover remain
important variables, being related to our cosmos (63, 64). More generally, nonphotic cycles coexist
with and can override and replace seasonal effects, thus opening a broad chapter of
biometeorology in space. We need to continue to map nonphotics systematically, with point-andinterval
estimates of parameters, globally and as a function of time, as done for BEL in Figure 4
and Table 2.
Figure 5. Power spectrum of monthly
auroral occurrence for New England
for the interval 1800-1948. Lag = 1200,
truncated at 10; power at 11.1 = 32.2.
Reproduced by permission of Samuel
M. Silverman (45).
82
In the 21st
century, Maravilla et al. (65) report on a "possible peak at around 30 years" in a
time series of (solar) polar coronal hole evolution. A spectrogram of this time series, with
frequency on the ordinate and time on the abscissa displaying peaks as contours, validates this
spectral component only for a relatively small section of that time series, not globally in our hands,
where the global peak's point estimate is at ~29.14 years.
In a 2006 publication in turn, we read: "The wavelet decomposition analysis also [among
other cycles] exhibits the presence of a 33-year variation in all the solar terrestrial parameters with
a minimum amplitude centered around 1997" (13). The much broader-than-circadian mapping of
nonphotic as well as photic components in the spectral element of time structures is an overdue
complement to Alexander von Humboldt's legacy, nearly 150 years after his death, and to the
legacies of Raymond Holder Wheeler (66) and Alexander Leonidovich Chizhevsky (67).
Table 2. Extended cosinor analyses of Brückner's charted data (in Figure 2)*
Linear analyses Nonlinear analyses (trial period = 35 years)
Variable Period (y) PR P Period (95% CI) Amplitude (95% CI)
Rainfall 33.9 57.5 <0.001 33.63 (29.87, 37.40)** 3.99 (1.31, 6.68)
85.5 11.6 0.179
36.9 39.5 <0.001Temperature
25.0 38.0 0.001
36.82 (32.64, 41.00)** 1.54 (0.33, 2.75)
67.7 11.8 0.020
36.1 8.4 0.066Wine Harvest
25.4 10.3 0.035
36.27 (33.28, 39.26)** 1.09 (-.37, 2.56)
95.6 10.5 0.109
58.0 15.3 0.036Cold Winters
40.6 31.0 <0.001
40.63 (37.37, 43.88)** 1.60 (0.36, 2.84)
54.2 22.9 0.016
36.1 21.7 0.020Ice-Free Rivers
24.3 21.2 0.024
35.81 (31.43, 40.20)** 2.64 (-.31, 5.59)
81.2 59.3 <0.001
Sunspots
25.4 8.0 NS
Not statistically significant‡¶
*The point-and-interval estimates for environmental temperature and rainfall prompt admiration for
Brückner's intuition and success in eyeballing. Four point estimates of the period of 36.82, 33.63, 36.27 and
35.81 and three interval estimates of the amplitude are in keeping with his proposition of s(a)ecular
variation in the sense of a variation corresponding to one human generation of 33.3 years. Note for wine
harvest and ice-free rivers that the 95% confidence intervals given in () of the amplitude slightly overlap
zero; those suggestive estimates remain inconclusive.
‡In denser monthly data starting in January 1749 (rather than 1735 in Brückner's chart) and ending in 1885
(as in Brückner's chart), the frequencies of one cycle in 33-35 years correspond to a trough. In a longer
span, ending in July 2003, there is at most a tiny peak accounting for no more than 0.3% of the total
variance.
¶The nearest peaklet detected in Wolf numbers with a period of 25.75 years has a confidence interval of
(22.14, 29.36 years).
83
It is to the credit of the Lockyers in turn to have shown on relatively limited data, Figure 2,
not only a periodicity of ~35 years in the length of the solar cycle, but also of having associated
this periodicity with climate, referring to the agreement of their results with Brückner's findings.
A. Wolfer in 1902 concluded "... from examination of the relative numbers and epochs from 1750
[to his time] that no regular periodicity exists and that 'the continued existence of a 35-year cycle
is not yet demonstrated". Clough in 1905 was more positive (11). So are we, based on more than
another century's evidence that validate W.J.S. Lockyer's contribution in 1901, Table 1 and Figure
3 (3).
By 1991, a number of physiological and pathological cycles were each validated in
inferential statistical terms as biospheric signatures of solar frequencies (21). They were charted in
70 pages of figures, some of them complex, complementing an introduction to chronobiology (68).
Further accumulating data will require complementary maps of chronomics, i.e., cycles around as
well as in us and of their time course in the face of additions and subtractions (58, 59).
Discussion
The aligned mapping of time structure in and around us and the study of similarities and
differences in their temporal behavior must go on not only for the sake of a better understanding of
solar dynamics. It can start as a cost-effective dividend from a preventive noninvasive cardiology
aiming to nip major severe debilitating vascular diseases in the bud. The same long-term
monitoring that ushers in a new health care also extends modern technology to the recognition that
cycles constitute life as it evolved and still depends on the cycles of our environment (59).
Chronomics, by extending focus to infradians, provides critical information for any research in
time, as already documented for aging, that in different circadian stages shows interactions of
photic and nonphotic cycles, to the extent that time passes faster at 60 as compared to 25 years of
age at one circadian stage (09:00-12:00), while the opposite is found at another stage in the
evening. Moreover, the change with age at certain circadian stages is modulated by a BEL, as
documented elsewhere in these Proceedings. Reference standards for BEL must accordingly be
mapped at various circadian stages, since evidence is on hand to show that the detection of a halfyearly
cycle in human blood pressure is possible in the evening but not in the morning (69). Maps
of infradians may place all research in time, organic and inorganic, on a more solid basis. A
website for both analyses of data for health care delivery and use of the same information for
transdisciplinary research in chronomics is a step in the direction of systematic mapping.
Legislation to support test pilots for lifetime physiologic monitoring in the family across
generations, begun thus far only by two pairs of father and son (69-72), constitutes another
important step; it does not, however, replace longitudinal mapping from womb to tomb.
Conclusion
Figure 3 and Table 1 validate, in inferential statistical lines, William J.S. Lockyer's report of
an ~35-year period in solar cycle length, in the light of data accumulated from before and after
those he examined. As to terrestrial variables, Eduard Brückner's scholarship also withstands
inferential scrutiny in Figure 4, Wolfer's admonition and Schuster's and Kostin's concerns
notwithstanding. Credit is also to be given (according to Norman Lockyer and to Rudolf Wolf) to
Giovanni Battista Riccioli, who associated sunspots with weather on earth apparently soon after
sunspots were discovered by Galileo, Scheinert and others. Figure 6 takes artistic license by
depicting a meeting of individuals who in real life lived generations apart. It is apparently the only
pictorial depiction of Riccioli, who in turn was preceded by Polybius (73) in relating climate to
human affairs, including aggression, an important topic then and now.
84
Figure 6. Giovanni Battista Riccioli (1598-1671) is credited by
Norman Lockyer (4) and Rudolf Wolf (74) with an early association
of sunspots with weather on earth. Since no authentic images of
Riccioli are known to exist, we include a fanciful artistic depiction of
Riccioli with Tycho Brahe (1546-1601). "[This photo was taken] in a
conference in Prague celebrating the 400th anniversary of the death
of Tycho Brahe. It is a small detail of a larger ceiling mural in one of
the rooms in the Clementinum, the old Jesuit college in downtown
Prague, just off the Charles Bridge. ... The building today houses
the Czech national library. ... [T]he likeness to Tycho Brahe's other
known images is quite good ... Considering that Riccioli was only 3
at most when Tycho died, the 'conversation' depicted must be
emblematic rather than historical." (Jole R. Shackelford, Adjunct
Assistant Professor, History of Medicine, University of Minnesota,
personal communication, 30 April 2008)
85
1. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
2. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
3. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
4. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
5. Friis-Christensen E, Lassen K. Length of the solar cycle: an indicator of solar activity closely
associated with climate. Science 1991; 254: 698-700.
6. Lassen K, Friis-Christensen E. Variability of the solar cycle length during the past five
centuries and the apparent association with terrestrial climate. J Atmos Solar-Terr Phys 1995;
57: 835-845.
7. Kelly PM, Wigley TML. Solar cycle length, greenhouse forcing and global climate. Nature
1992; 360: 329-331.
8. Wolfer A. Revision of Wolf's sun-spot relative-numbers. Monthly Weather Review 1902; 30:
171-176.
9. Schuster A. On Newcomb's method of investigating periodicities and its application to
Brückner's weather cycle. Proc Roy Soc Lond A 1914; 90: 349-355.
10. Kostin SI. Is the Brikner (Brueckner) cycle real? Directorate of Scientific Information
Services Ottawa (Ontario), May 1965. 4 pp.
http://stinet.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0615768
11. Clough HW. Synchronous variations in solar and terrestrial phenomena. Astrophysical J
1905; 22: 42-75.
12. Rain Affects Emigration. New York Times, October 12, 1912. http://query.nytimes.com
/mem/archive-free/pdf?res=9C05E1DC133CE633A25751C2A9669D946396D6CF
13. Prabhakaran Nayar SR. Periodicities in solar activity and their signature in the terrestrial
environment. ILWS Workshop 2006, Goa, February 19-24, 2006. 9 pp.
14. Stehr N, von Storch H, eds (Stehr B, Gamlin G, trans). Eduard Brückner: the sources and
consequences of climate change and climate variability in historical times.
Dordrecht/Boston: Kluwer Academic Publishers; 2000. 338 p.
15. Halberg F, Cornélissen G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka
P, Prikryl P, Chibisov SM, Holley DC, Wendt RW, Bingham C, Palm SL, Sonkowsky RP,
Sothern RB, Pales E, Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R,
Konradov AA, Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov
AV, Faraone P, Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T,
Pantaleoni GC, Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki
EA, Bathina S, Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M.
Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks,
near-decades, phylogenetic and ontogenetic memories. Biomed & Pharmacother 2004; 58
(Suppl 1): S150-S187.
16. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
17. Reinberg A, Smolensky MH. Biological rhythms and medicine. Cellular, metabolic,
physiopathologic, and pharmacologic aspects. New York: Springer; 1983. 305 pp.
18. Touitou Y, Haus E (Eds.) Biological Rhythms in Clinical and Laboratory Medicine. Berlin:
Springer-Verlag; 1992. 730 pp.
86
19. Refinetti R. Circadian Physiology. 2nd ed. Boca Raton, Florida: CRC Press; 2006. 700 pp.
20. Koukkari WL, Sothern RB. Introducing Biological Rhythms: A primer on the temporal
organization of life, with implications for health, society, reproduction and the natural
environment. New York: Springer; 2006. 655 pp.
21. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P,
Bakken E, International Womb-to-Tomb Chronome Initiative Group: Chronobiology in
space. Keynote, 37th Ann. Mtg. Japan Soc. for Aerospace and Environmental Medicine,
Nagoya, Japan, November 8-9, 1991. University of Minnesota/Medtronic Chronobiology
Seminar Series, #1, December 1991, 21 pp. of text, 70 figures.
22. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A,
Gorgo Y, Zhao ZY, Weydahl A, Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV,
Perfetto F, Tarquini R, Singh RB, Rhees B, Lofstrom D, Lofstrom P, Johnson PWC,
Schwartzkopff O, International BIOCOS Study Group. Cross-spectrally coherent ~10.5- and
21-year biological and physical cycles, magnetic storms and myocardial infarctions.
Neuroendocrinol Lett 2000; 21: 233-258.
23. Halberg F, Bakken EE, Katinas GS, Cornélissen G, Zaslavskaya RM, Blank MA, Syutkina
EV, Breus TK, Watanabe Y, Masalov A, Chibisov SM. Chronoastrobiology: Vernadsky's
future science ? Benefits from spectra of circadians and promise of a new transdisciplinary
spectrum of near-matching cycles in and around us. Opening keynote, Proceedings, III
International Conference, Civilization diseases in the spirit of V.I. Vernadsky, People's
Friendship University of Russia, Moscow, Oct. 10-12, 2005, p. 4-22.
24. Mikulecky M, Florida PL. Daily birth numbers in Davao, Philippines, 1993-2003: Halberg's
transyear stronger than year. Abstract, 26th Seminar, Man in His Terrestrial and Cosmic
Environment, Upice, Czech Republic, May 17-19, 2005.
25. Mikulecky M. Reanalyza natality v jizni Brazilii -- opet dominuje Halbergova
parasezonalita: International Conference on the Frontiers of Biomedical Science:
Chronobiology, Chengdu, China, September 24-26, 2006, p. 188-193.
26. Cornélissen G, Halberg F, Breus T, Syutkina EV, Baevsky R, Weydahl A, Watanabe Y,
Otsuka K, Siegelova J, Fiser B, Bakken EE. Non-photic solar associations of heart rate
variability and myocardial infarction. J Atmos Solar-Terr Phys 2002; 64: 707-720.
27. Kovac M, Mikulecky M. Secular rhythms and Halberg's paraseasonality in the time
occurrence of cerebral stroke. Bratisl Lek Listy 2005; 106 (2): 423-427.
28. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, Johnson P,
Gigolashvili M, Breus T, Sonkowsky R, Chibisov SM, Katinas G, Siegelova J, Dusek J,
Singh RB, Berri BL, Schwartzkopff O. Incidence of sudden cardiac death, myocardial
infarction and far- and near-transyears. Biomed & Pharmacother 2005; 59 (Suppl 1): S239-
S261.
29. Kovac M, Mikulecky M. Time sequence of epileptic attacks from the point of view of
possible lunisolar connections. International Conference on the Frontiers of Biomedical
Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 175-179.
30. Halberg F, Cornélissen G, Panksepp J, Otsuka K, Johnson D. Chronomics of autism and
suicide. Biomed & Pharmacother 2005; 59 (Suppl 1): S100-S108.
31. Cornélissen G, Halberg F. Chronomics of suicides and the solar wind. Br J Psychiatry 2006;
189: 567-568.
32. Halberg F, Cornélissen G, Sothern RB, Chibisov SM, Wendt HW. Do unseen, very weak
magnetic mechanisms contribute to terrorism in wobbly spectral windows? Proc. 8th
International Congress "Health and education millennium", Moscow, Russia, November 14-
17, 2007, p. 63-66.
87
33. Roederer JG. Are magnetic storms hazardous to your health? Eos, Transactions, American
Geophysical Union 1995; 76: 441, 444-445.
34. Bartels J. Statistical studies of quasi-periodic variables: with illustrative examples from
geophysics. Washington DC: Carnegie Institution of Washington; 1959. (Reprints of three
papers from Terrestrial Magnetism and Atmospheric Electricity: Terrestrial magnetic activity
and its relations to solar phenomena. Terr Mag Atmosph Electr 1932; 37: 1-52; Statistical
methods for research on diurnal variations, Terr Mag Atmosph Electr 1932; 37: 291-302;
Random fluctuations, persistence, and quasi-persistence in geophysical and cosmical
periodicities. Terr Mag Atmosph Electr 1935; 40: 1-60.)
35. Chibisov SM (summarized by). Resolution concerning chronobiology and chronomics. III
International Conference, Civilization diseases in the spirit of V.I. Vernadsky, People's
Friendship University of Russia, Moscow, Oct. 10-12, 2005, p. 23-25.
36. Yamanaka T, Cornélissen G, Kazuma M, Kazuma N, Murakami S, Otsuka K, Siegelova J,
Dusek J, Sosikova M, Halberg F. Further mapping of the natality chronome, in Toda City
(Japan) Maternity Hospital. Scripta medica 2005; 78: 99-106.
37. Cornélissen G, Halberg F, Mikulecky M, Florida P, Faraone P, Yamanaka T, Murakami S,
Otsuka K, Bakken EE. Yearly and perhaps transyearly human natality patterns near the
equator and at higher latitudes. Biomed & Pharmacother 2005; 59 (Suppl 1): S117-S122.
38. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
39. Cornélissen G, Halberg F, Wendt HW, Sothern RB, Chibisov SM, Kulikov SI, Agarwal RK.
Weak magnetoperiodism rather than socio-photo-thermoperiodism characterizes human
terrorism detection of about 1.3-year aeolian transyear but not precise 1.0-year cycle. Proc.
8th
International Congress "Health and education millennium", Moscow, Russia, November
14-17, 2007, p. 77-80.
40. Grigoryev PYe, Vladimirskii BM. The cosmic weather affects the terrorist activity. Uchenye
zapiski Tavricheskogo Natsionalnogo Universiteta im V.I. Vernadskogo, Series "Biology,
chemistry" 2007; 20 (59) ( 1): 28-46.
41. Mikulecky M. Solar activity, revolutions and cultural prime in the history of mankind.
Neuroendocrinol Lett 2007; 28: 749-756.
42. Pales E, Mikulecky M. Periodic emergence of great physicians in the history of ancient
Greece, India and China. Abstr., 23rd Semin., Man in his Terrestrial and Cosmic
Environment, Upice, Czech Republic, May 21–23, 2002.
43. Rohde RA, Muller RA. Cycles in fossil diversity. Nature 2005 (March 10); 434: 208-209.
44. Cornélissen G, Bakken EE, Sonkowsky RP, Halberg F. A 38-million-year cycle among
myriadennians in the diversity of oceanic genera. Abstract, III International Conference,
Civilization diseases in the spirit of V.I. Vernadsky, People's Friendship University of
Russia, Moscow, Oct. 10-12, 2005, p. 47-49.
45. Silverman SM. Secular variation of the aurora for the past 500 years. Rev Geophys 1992; 30
(4): 333-351.
46. Gregori GP. Galaxy – Sun – Earth relations: The origin of the magnetic field and of the
endogenous energy of the Earth, with implications for volcanism, geodynamics and climate
control, and related items of concern for stars, planets, satellites, and other planetary objects.
88
A discussion in a prologue and two parts. Beiträge zur Geschichte der Geophysik und
Kosmischen Physik, Band 3, Heft 3, 2002, 471 pp. ISNN: 1615 - 2824 – NE: Gregori,
Giovanni P. © Science Edition, Arbeitskreis Geschichte Geophysik / W. Schröder, Germany
2002.
47. Roederer JG. Tearing down disciplinary barriers. Eos, Transactions, American Geophysical
Union 1985; 66: 681, 684-685.
48. Biermann K-R (Ed.) Briefwechsel zwischen Alexander von Humboldt und Carl Friedrich
Gauß: Zum 200. Geburtstag von C.F. Gauß im Auftrage des Gauß-Komitees bei der
Akademie der Wissenschaften der DDR. Berlin: Akademie-Verlag; 1977. 202 pp. + plates.
49. Clark S. The Sun Kings: The Unexpected Tragedy of Richard Carrington and the Tale of
How Modern Astronomy Began. Princeton, NJ: Princeton University Press; 2007. 224 pp.
50. Foerstner A. James Van Allen: The First Eight Billion Miles. Iowa City: University of Iowa
Press; 2007. 322 pp.
51. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
52. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
53. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
54. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
55. Czaplicki J, Cornélissen G, Halberg F. GOSA, a simulated annealing-based program for
global optimization of nonlinear problems, also reveals transyears. J Applied Biomedicine
2006; 4: 87-93. http://www.zsf.jcu.cz/vyzkum/jab/4_2/czaplicki.pdf
56. Brückner-Egeson-Lockyer cycle in heliogeomagnetics. These proceedings.
57. Selective infradian, notably multidecadal solar-physiologic congruences. These proceedings.
58. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
59. Halberg F, Schwartzkopff O, Cornélissen G, Otsuka K. Life's waves in space-time in and
around us. Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary
Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute
for Theoretical Physics, Kyoto University, October 15-20, 2007. p. 45-47.
60. Charvatova-Jabukcova I, Strestik J, Krivsky L. The periodicity of aurorae in the years 1001-
1900. Stud Geophys Geor 1988; 32: 70-77.
61. Fritz H. (Reed WW, trans). The periods of solar and terrestrial phenomena. Monthly Weather
Review 1928; 56: 401-407. Originally published as Die Perioden solarer und terrestrischer
Erscheinungen in Vierteljahrschrift der Naturforschenden Gesellschaft in Zurich, Heft 1,
1890.
62. Brückner E. The settlement of the United States as controlled by climate and climatic
oscillations. In: Memorial Volume of the Transcontinental Excursion of 1912 of the
American Geographical Society of New York. New York: American Geographical Society;
1915. p. 125-139.
63. Abbot CG. Solar variation and weather, a summary of the evidence, completely illustrated
and documented. Washington DC: Smithsonian Miscellaneous Collections 146, No. 3 (Publ.
4545); 1963. 67 pp. + 4 plates.
89
64. Svensmark H, Friis-Christensen E. Variation of cosmic ray flux and global cloud coverage --
a missing link in solar-climate relationships. J Atmospheric Solar-Terrestrial Physics 1997;
59: 1225-1232.
65. Maravilla D, Lara A, Valdés Galicia JF, Mendoza B. An analysis of polar coronal hole
evolution: relations to other solar phenomena and heliospheric consequences. Solar Physics
2001; 203: 27-38.
66. Wheeler RH. The effect of climate on human behavior in history. Transactions Kansas Acad
Sci 1943; 46: 33-51.
67. Chizhevsky AL. Astronomy, psychology and history. Moscow: M.A. Institute; 1921. 78 pp.
68. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology
Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580;
http://www.msi.umn.edu/~halberg/)
69. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clockhour
in long-term investigation is no panacea. Proceedings, International Conference on the
Frontiers of Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006,
p. 208-211.
70. Sothern RB, Halberg F. Longitudinal human multifrequency structure of blood pressure selfmeasured
for over 2 decades. Proc. 2nd Ann. IEEE Symp. on Computer-Based Medical
Systems, Minneapolis, June 26-27, 1989. Washington DC: Computer Society Press; 1989. p.
288-294.
71. Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T,
Schwartzkopff O, Bakken E, Halberg F. Methodology: partial moving spectra of postnatal
heart rate chronome. Neuroendocrinol Lett 2003; 24 (Suppl 1): 139-144.
72. Watanabe Y, Cornélissen G, Halberg F. Thousands of blood pressure and heart rate
measurements at fixed clock hours may mislead. Neuroendocrinol Lett 2003; 24: 339-340.
73. Polybius (Paton WR trans). Histories. 6 vol. Loeb Classical Library. Cambridge, Mass.:
Harvard University Press; 1923.
74. Wolf R. Geschichte der Astronomie. Münich: Druck und Verlag von M. Oldenbourg; 1877.
815 pp.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
90
Should 7-day/24-hour chronobiologically interpreted blood pressure monitoring replace single
measurements before cataract surgery?
Germaine Cornélissen1
, Franz Halberg1
, Stephen C. Kaufman1
, Salvador Sanchez de la Peña2
,
Kuniaki Otsuka3
, Jarmila Siegelova, Bohumil Fiser and the broader BIOCOS group
1
University of Minnesota, Minneapolis, Minnesota, USA
2
Chronomic Res. Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City, Mexico
3
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
Abstract. In an 89-year-old man (FH), who monitored his blood pressure (BP) and heart rate
(HR) around-the-clock at half-hour intervals for decades (with interruptions) and continued to do so
before, during and after cataract surgery, we seek any alterations in the time structure of BP and/or
HR in relation to this intervention (even though FH recognized no anxiety himself). First, we look at
BP and HR within the individualized range of the subject at the given time by a sequential test, and
second by reference to broader standards derived from clinically healthy peers of the same gender
and corresponding age. The sequential test applied to detect any abnormalities used an
individualized reference standard and found changes hidden in the normal range of peers, while data
remained within that range. In the week following successful mid-week surgery, the circadian
amplitude of diastolic BP increased above peer limits, a reason for caution in the interpretation of
the results during the week of intervention as possibly related to subconscious anxiety about the
surgery. If they were so related at all, these abnormalities were exceeded by the pleasure (in
retrospect "tension") associated with preparations of materials for publication at a conference,
including this report. Apart from testing for physical or emotional loads (stress), we advocate, for
any and all estimations of health more generally, a chronobiologically interpreted ambulatory
automatic 7-day/24-hour BP and HR monitoring (C-ABPM) as soon as an appointment for a
preoperative or any other health check is made, including cataract surgery.
Background. Concern about BP variability was emphasized in a doctoral thesis in 1880 (1; cf.
2), by Theodore C. Janeway (3) in 1904, by Frederic C. Bartter, head of the Hypertension-Endocrine
Branch of the National Institutes of Health (NIH) in the 1970s (4), and subsequently by others (5).
In 2008, we have tools to assess this variability (6), which has not yet been accounted for by official
guidelines (7). Chronobiologic evidence in Table 1 (8) and Figures 1 and 2 (6, 8-10) has led to
vascular variability disorders, VVDs. Several coexisting VVDs constitute vascular variability
syndromes, VVSs, which cannot be detected without C-ABPM, Figure 2.
Opinion leaders already discourage in their recommendations (11) -- albeit not (yet) in official
guidelines (7) -- reliance upon office BP measurements, as is now practiced for any health check.
Consensus meetings (10) recommend a chronobiologically interpreted 7-day/24-hour profile
obtained by automatic ambulatory BP monitoring (C-ABPM), which can detect prehypertension (8,
9), prediabetes (12, 13) and elevations of the circadian amplitude and MESOR of BP associated
with minimal change retinopathy (14), another reason for monitoring BP in ophthalmology.
Outcomes in a 7-year follow-up could be predicted from 9 days of half-hourly around-theclock
ambulatory automatic monitoring, but not from 2-, 3- or 4-day profiles (15). The same study
showed that the response to surgery detected an increase in BP and HR in the morning and a
decrease in the afternoon (15; figure on lower inside cover of 10). Conceivably, a "white-coat
hypertension" in the morning will be a "white-coat hypotension" in the afternoon. Terms such as
"white-coat effect" or "masked hypertension", originating from justified concern to account for
variability, prompt much investigation (16-38) to account for plain false positive and false negative
diagnoses due to variability, but are no substitute for C-ABPM 7/24 for ruling out abnormality (8, 9,
91
12, 13) and much longer C-ABPM to evaluate VVDs and VVSs (Figures 1 and 2), that carry a risk
larger than a high BP, and/or to study the development of high BP, also one of the VVDs.
Table 1. Outcomes of chronobiological screens of blood pressure and heart rate*
N of
patients
N at follow-up Sampling N measurements:
Total (outcomes)
Finding
10 10 (up to 5y) 5/day daily Up to 9,125 (only
partially analyzed)
Among P. Scarpelli's patients, the 4 who died with malignant
hypertension had a larger circadian BP amplitude than the 6 who
were still alive (SBP: t=1.84; P=0.103; DBP: t=2.99; P=0.017)
63 21 after 28y ~every 4h
for 2 days
756 (252) 9 of 10 subjects without CHAT are alive while 7 of 11 subjects with
CHAT are dead 28 years later (chi-square=6.390; P<0.01)
56 56
Concomitant
LVMI
every 15min
for 24h
5,376 (5,376) Classification by Y. Kumagai of patients by LVMI (<100; 100-130;
>130 g/m2) reveals elevation of circadian amplitude at LVMI in 100-
130 range whereas MESOR elevation occurs only at LVMI >130.
221 221
(time of
delivery)
every 1h/48h
in each trimester
of pregnancy
(336 profiles)
16,128 (16,128) In addition to an 8 mmHg difference in mean value between women
who will or will not develop complications (gestational hypertension,
preeclampsia) already observed during the first trimester of
pregnancy, the occurrence of complications is also associated with
BP profiles characterized by an elevated circadian BP amplitude. In
particular, one case (JK) of CHAT where warning was not heeded,
was followed 8 weeks later by severe pre-eclampsia, premature
delivery and 26 months of hospitalization of offspring at a cost of
about $1 million
297 297 after 6y every 15min
for 48h
57,024 (57,024) CHAT or a reduced circadian standard deviation of heart rate, or an
excessive pulse pressure (>60 mm Hg) are large risk factors (larger
than hypertension) for cerebral ischemic events, nephropathy and
coronary artery disease, even when the blood pressure is within
acceptable limits.
2039 2039
Concomitant
LVMI
Hourly averages
for 24h
48,936 (48,936) LVMI is increased in patients with CHAT, a reduced circadian
standard deviation of heart rate, or an elevated pulse pressure. The
relation between LVMI and the circadian endpoints is nonlinear.
23 12 after 7y every 15min
for 9 days
19,872 (10,368) 10 of 20 patients with no consistent BP abnormality are alive and
well; 2 of 3 patients with consistent BP abnormality reported an
adverse vascular event (P=0.015 by Fisher's Exact Test).
80 80 Response
to treatment
administered
2 h before
daily BP peak
vs. control
group treated
3 times a day
every 4h for 24h
before and on
treatment
960 (960) With smaller doses of medications, BP was lowered by R.
Zaslavskaya to a larger extent and treatment was accompanied by
fewer complications.
Treatment: propranolol, clonidine, or alpha-methyldopa (P<0.05 for
each effect)
18 18 (12 weeks) every 30min
( 24h) on 3
regimens
2592 ( 2592) Treating CHAT may prevent adverse vascular events: As compared
to placebo, nifedipine (1 mg b.i.d. at 08 & 20) increases and
benidipine (4 mg/day at 08) decreases the circadian amplitude of
blood pressure. The resulting increase vs. decrease in the incidence
of CHAT on nifedipine vs. benidipine may account for the
corresponding difference between the number of stroke events of 7.6
vs. 3.5 and the total number of cardiovascular events of 20.4 vs. 8.8
per 1,000 person-years.
Totals:
2,807 2,754 160,769 (>141,636)
*SBP and DBP: Systolic and Diastolic blood pressure; HR: heart rate; CHAT: Circadian Hyper-AmplitudeTension,
a condition defined by a circadian amplitude exceeding the upper 95% prediction limit of acceptability
(for healthy peers matched by gender and age). CHAT is a VVD, as is, among others, an excessive pulse pressure
(PP), a deficient (below-threshold) HR variability (DHRV), an odd timing of the circadian BP but not of the HR
rhythm (BP ecphasia), and a reliably diagnosed high BP, MESOR-hypertension or MH. LVMI: left ventricular
mass index. By comparison with some classical studies, the number of measurements in chronobiological work
completed thus far is likely to be larger, and confounding by inter-subject variability smaller.
92
Figure 1. Illustrative results supporting the need for continued surveillance, and for a chronomic analysis of blood pressure series.
I: Nocturnal hypertension: data stacked from 11 days of around-the-clock monitoring. Office spotchecks cannot detect nocturnal
pathology. II A: Among risk factors, an excessive circadian blood pressure (BP) amplitude (A) raises the risk of ischemic stroke
most. II B: Among risk factors, an excessive circadian blood pressure (BP) amplitude (A) raises the risk of nephropathy most. II C:
An excessive circadian BP A is a risk factor for ischemic stroke independent from the 24-hour mean (MESOR). III A: Individualized
assessment (by CUSUM) of a patient’s initial response and subsequent failure to respond to autogenic training (AT) (EO, F, 59 y).
III B: Individualized BP chronotherapy. Lower circadian double A (2A) and MESOR (M) after switching treatment time from 08:30
(left) to 04:30 (right)*. III C – Control chart assesses individualized anti-MESOR-hypertensive chronotherapy.
Chronomics detects nocturnal escape from hypotensive treatment taken in the morning (I above); a circadian overswing, CHAT; a
risk of stroke and nephropathy, greater than hypertension (IIA-B), even in MESOR-normotension (IIC) and monitors transient and/or
lasting success of treatment (IIIA-C). Merits are:
· Detection of abnormality during the night when the dose of medication taken in the morning may no longer be effective in certain
patients, facts not seen during office visits in the afternoon but revealed as consistent abnormality by around-the-clock monitoring;
· Detection of abnormal circadian pattern of blood pressure (CHAT, “overswinging”) associated with a risk of cerebral ischemia and
nephropathy larger than other risks (including “hypertension”) assessed concomitantly (IIA and B);
· Finding that CHAT carries a very high risk even among MESOR-normotensives who do not need anti-hypertensive drugs (IIC);
· Availability of statistical procedures such as a self-starting cumulative sum (CUSUM) applicable to the individual patient to
determine whether an intervention such as autogenic training is effective and if so for how long it remains effective (IIIA);
· N-of-1 designs for the optimization of treatment timing: the same dose of the same medication can further lower the same
subject's blood pressure MESOR and circadian amplitude when the timing of daily administration is changed (IIIB and C), as
ascertained by as-one-goes (sequential) testing and parameter tests, procedures applicable to the given individual. © Halberg.
93
Figure 2. Based on C-ABPM 7/24, a decreased heart rate variability (DHRV), gauged by the standard deviation of HR, in relation to
a threshold, preferably eventually assessed by reference to data from clinically healthy gender- and age-matched peers, a
circadian hyper-amplitude-tension (CHAT) and an elevated pulse pressure (EPP) (the difference between systolic [S] and diastolic
[D] blood pressure [BP], i.e., between the heart's contraction or relaxation, or the extent of change in pressure during a cardiac
cycle) are separate vascular variability disorders (VVDs) that may coexist to form vascular variability syndromes (VVSs), along
with other risk conditions such as an abnormal circadian timing of BP but not of HR, not shown, and of course with or without an
abnormal, e.g., elevated BP average (MESOR), i.e., MESOR-hypertension. Vascular disease risk is elevated in the presence of
any one of these VVDs and is elevated further when more than a single VVD or other risk factor is present, suggesting that these
abnormalities in variability of BP and HR are mostly independent and additive. Abnormalities in the variability of BP and HR,
impossible to find in a conventional office visit (the latter aiming at the fiction of a "true" blood pressure), can raise cardiovascular
disease risk (gauged by the occurrence of a morbid event like a stroke in the next six years) from 4% to 100%. By comparison to
subjects with acceptable BP and HR variability, the relative cardiovascular disease risk associated with a DHRV, an EPP and/or
CHAT is greatly and statistically significantly increased. These VVDs and VVSs, silent to the person involved and to the care
provider, notably the risk of CHAT, can usually be reversed by chronobiologic self-monitoring and thus self-help, also with a nonpharmacologic
approach in the absence of MESOR-hypertension. © Halberg.
Methods. FH, an 89-year-old man planning to have cataract surgery on his right eye, was
informed that his use of Flomax® (tamsulosin hydrochloride), an -1 blocker for benign prostatic
hypertrophy, may cause a condition known as intraoperative floppy iris syndrome (IFIS). IFIS
results in prolapse of a billowing, floppy iris, causing progressive intraoperative miosis which
increases the risk of intraoperative complications. Because of these increased surgical risks, the
package insert for Flomax states that "If you are contemplating cataract surgery, make certain to
advise your eye surgeon that you have taken Flomax".
On the day of surgery, FH was brought into the preoperative holding area, where a retrobulbar
anesthetic was administered. The anesthetic consisted of a 50% mixture of 2% lidocaine and 50%
mixture of 0.75% bupivicaine. After approximately 15 minutes, FH was transported to the operating
room. He was given O2 by nasal cannula while his BP, HR, respiratory rate and blood oxygenation
94
were monitored by anesthesia personnel. FH was prepped and draped in a sterile fashion, after
which the surgery commenced. The iris demonstrated poor dilation, which was likely to be
secondary to the use of Flomax. A Malyugin ring was placed to expand the pupil and stabilize the
iris. The remainder of the cataract surgery progressed in a standard fashion. Upon completion, FH's
operated eye was patched closed and he was taken to the recovery room.
FH had monitored his BP around-the-clock at half-hourly intervals for decades (with
interruptions) with a TM-2421 monitor from A&D (Tokyo, Japan). He provided data for analyses
by cosine fitting (top) and by stacking (bottom), summarized in a sphygmochron (39) in Figures 3
and 4. Cosinors were prepared on a daily basis (not shown) to examine characteristics of BP and HR
variability on the day of surgery and during the days and weeks preceding and following the
operation. Comparisons were made by parameter tests (40; cf. 39) and sequential testing (cusums)
(41).
Results. The sphygmochron in Figure 3 summarizes the chronobiologically interpreted
monitoring profile for the week bracketing surgery. On top, the upper half of parametric analyses
yields measures of predictable extent of change, or double amplitude, 2A, and of timing of change,
or acrophase, , as well as a midline-estimating statistic of rhythm, or MESOR, M, that are listed
with reference ranges of acceptable values from clinically healthy peers matched by gender and age.
The HR-M is below an age- and gender-matched peer-threshold HR-M; the timing of the circadian
HR rhythm is odd, but these alterations were noted for the subject during the preceding years.
Figure 4, another sphygmochron, summarizes results for the subsequent week. A diastolic BP
overswing, CHAT, short for circadian hyper-amplitude-tension, is then diagnosed. A finding in the
week of surgery of an elevation of the circadian DBP-2A, which was then still in the acceptable
range, is exaggerated rather than damped in the week following successful uncomplicated surgery.
Figures 5a and 5b show the original data in the week bracketing the day of surgery and the
following week, while the data of the day of surgery are seen in Figure 6, with dots representing
measurements during the procedure and bracketing it by minutes rather than hours. Figures 7-9
show stacked data with a large circadian BP swing in the week bracketing surgery (left) and in the
following week (right) after successful recovery. Figure 10 reveals that the sequential individualized
test by cumulative sums led to a breakout from the decision interval for 3 of the 7 endpoints
monitored, namely SBP-M and DBP-M and DBP-A, as indicated by an asterix on the abscissa. The
sphygmochron in Figure 4 shows that this circadian amplitude alteration was more pronounced in
the week following successful surgery.
Discussion. Chronobiologically interpreted ambulatory, automatic BP and HR monitoring has
been suggested as a test of the emotional and physical load impinging upon an individual (42-45). In
FH, unknown to him, changes in BP MESORs and in his diastolic but as yet not in the systolic
circadian amplitude were detected in the week bracketing surgery. There were no detectable
changes in HR or pulse pressure by cusum (41). The finding of an effect of the load (unconscious
worry about the operation, if any), within the physiologic range of clinically healthy gender- and
age-matched peers, is remarkable if one's attention is restricted to the week bracketing surgery, but
is minor if compared to the greater alterations associated with the task of preparing this paper and a
number of more complex reports for publication in a forthcoming conference volume.
95
Name:--------------------- Patient #: FHal389
Age: 89 Sex: M
To:
Patient Peer Group Patient Peer Group Patient Peer Group
Value Reference Value Reference Value Reference
Limits Limits Limits
Range Range Range
Range Range Range
Range Range Range
(hr:min) (hr:min) (hr:min)
(mmHg x hour) (mmHg x hour) (mmHg x hour)
(mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units)
Individualized bounded indices: (STD = Standard)(Min = Minimum)(Max = Maximum)(HBI = Hyperbanic Index)
INTERVENTION NEEDED MORE MONITORING NEEDED
No Annually
Yes Drug Non-Drug As soon as possible
Other specify_________________________
Prepared By_________________________________________ Date____/____/________
1) Unusually long standing or lying down during waking: unusual activity, such as exercise, emotional
loads, or schedule changes, e.g. shiftwork; etc.; 2) Salt, calories, kind and amount, other, etc.
Copyright, Halberg Chronobiology Center, University of Minnesota, Mayo Hospital, Rooms 715,
733-5 (7th floor), Minneapolis Campus, Del Code 8609, 420 Deleware Street SE,
Minneapolis, MN 55455, USA. Fax 612-624-9989.
For questions, call F. Halberg or G. Cornelissen at 612-624-6976.
SPHYGMOCHRON-TM
Monitoring Profile over Time;
Computer Comparison with Peer Group Limits
Blood Pressure (BP) and Related Cardiovascular Summary.
(DOUBLE AMPLITUDE)
TIMING OF OVERALL
Monitoring From:
Comments:
CHRONOBIOLOGIC CHARACTERISTICS
ADJUSTED 24-h MEAN
8/2/2008 16:30
HIGH VALUES
(ACROPHASE) (hr:min)
SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg)
28.09 3.41-34.00 23.34 0.00-27.55
(MESOR)
PREDICTABLE CHANGE
HEART RATE (bpm)
137.9 109.3-141.6 83.2 69.6-86.8 60.6 65.9-87.9
3.70 0.00-33.40
14:38 8:30-18:27 14:41 8:54-16.58 23:47 9:39-18:57
DURING 24 HOURS
HBI*
10-YEAR CUMULATIVE
PERCENT TIME
OF ELEVATION
TIMING OF
EXCESS 20:55 20:04 0:00
EXTENT OF EXCESS
79 11 0EXCESS
8/9/2008 11:32
22 3 0
STD (MIN; MAX)* STD (MIN; MAX)* STD (MIN; MAX)*
7.8% 7.4% 0.0%
Figure 3. Sphygmochron of the data during the week bracketing the operation. Abnormality such as that for HR was present during
prior years and does not seem pertinent to cataract surgery. Other abnormality in Figure 10 needs a personalized reference
standard provided by cusums for FH on the basis of his accumulating data. © Halberg.
96
Name:--------------------- Patient #: FHal390
Age: 89 Sex: M
To:
Patient Peer Group Patient Peer Group Patient Peer Group
Value Reference Value Reference Value Reference
Limits Limits Limits
Range Range Range
Range Range Range
Range Range Range
(hr:min) (hr:min) (hr:min)
(mmHg x hour) (mmHg x hour) (mmHg x hour)
(mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units)
Individualized bounded indices: (STD = Standard)(Min = Minimum)(Max = Maximum)(HBI = Hyperbanic Index)
INTERVENTION NEEDED MORE MONITORING NEEDED
No Annually
Yes Drug Non-Drug As soon as possible
Other specify_________________________
Prepared By_________________________________________ Date____/____/________
1) Unusually long standing or lying down during waking: unusual activity, such as exercise, emotional
loads, or schedule changes, e.g. shiftwork; etc.; 2) Salt, calories, kind and amount, other, etc.
Copyright, Halberg Chronobiology Center, University of Minnesota, Mayo Hospital, Rooms 715,
733-5 (7th floor), Minneapolis Campus, Del Code 8609, 420 Deleware Street SE,
Minneapolis, MN 55455, USA. Fax 612-624-9989.
For questions, call F. Halberg or G. Cornelissen at 612-624-6976.
SPHYGMOCHRON-TM
Monitoring Profile over Time;
Computer Comparison with Peer Group Limits
Blood Pressure (BP) and Related Cardiovascular Summary.
(DOUBLE AMPLITUDE)
TIMING OF OVERALL
Monitoring From:
Comments:
CHRONOBIOLOGIC CHARACTERISTICS
ADJUSTED 24-h MEAN
8/9/2008 13:00
HIGH VALUES
(ACROPHASE) (hr:min)
SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg)
27.84 3.41-34.00 27.95 0.00-27.55
(MESOR)
PREDICTABLE CHANGE
HEART RATE (bpm)
135.1 109.3-141.6 82.5 69.6-86.8 61.1 65.9-87.9
2.83 0.00-33.40
14:54 8:30-18:27 15:12 8:54-16.58 20:43 9:39-18:57
DURING 24 HOURS
HBI*
10-YEAR CUMULATIVE
PERCENT TIME
OF ELEVATION
TIMING OF
EXCESS 21:10 20:52 0:00
EXTENT OF EXCESS
60 22 0EXCESS
8/16/2008 15:00
16 6 0
STD (MIN; MAX)* STD (MIN; MAX)* STD (MIN; MAX)*
9.9% 7.4% 0.0%
Figure 4. Sphygmochron revealing (in bold) a diastolic circadian overswing, called circadian hyper-amplitude-tension, CHAT,
associated, when persistent, with a risk of severe disease greater than a high blood pressure, but reversible in FH by relaxation or
drugs (found on the basis of years of prior monitoring to be transient and amenable to treatment). The appearance of CHAT in the
week following surgery, rather than in that of the intervention, prompts one to compare the lesser association with surgery of the
breakout from the decision interval of the sequential test of the circadian DBP amplitude in Figure 10 with the appearance in Figure
4 of CHAT, the latter perhaps as a response to the pleasure of completing scientific papers. © Halberg.
97
Figure 5a. Data bracketing cataract surgery on August 6, 2008, scheduled for 1:30 pm. The unaided eye sees an elevation of SBP
and DBP on 2 days before surgery, but also sees elevations after surgery. Sequential tests in Figure 10 are more objective. ©
Halberg.
Figure 5b. Data from the week following that of mid-week surgery. © Halberg.
98
Figure 6. Original C-ABPM data of FH connected by lines on the day of monitoring with data of FH from the institute where surgery
was performed, added as dots. © Halberg.
Systolic Blood Pressure
Bracketing Surgery Following Week
90
100
110
120
130
140
150
160
170
180
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
SBP(mmHg)
SBP
SBP-lo
SBP-hi
90
100
110
120
130
140
150
160
170
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
SBP(mmHg)
SBP
SBP-lo
SBP-hi
Figure 7. Systolic blood pressure plexogram of FH: data during the week bracketing surgery (left) and the following week (right),
stacked along an idealized day at half-hour intervals, framed by time-varying reference limits from clinically healthy peers matched
by gender and age. © Halberg.
99
Diastolic Blood Pressure
Bracketing Surgery Following Week
50
60
70
80
90
100
110
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
DBP(mmHg)
DBP
DBP-lo
DBP-hi
50
60
70
80
90
100
110
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
DBP(mmHg)
DBP
DBP-lo
DBP-hi
Figure 8. Diastolic blood pressure plexogram of data of FH during the week bracketing surgery (left) and the following week (right),
stacked along an idealized day at half-hour intervals, framed by time-varying reference limits from clinically healthy peers matched
by gender and age. © Halberg.
Heart Rate
Bracketing Surgery Following Week
Figure 9. Heart rate plexogram of data of FH during week bracketing surgery (left) and the following week (right), stacked along an
idealized day at half-hour intervals, framed by time-varying reference limits from peers matched by gender and age. © Halberg.
100
Date SBP-M DBP-M HR-M PP SBP-2A DBP-2A HR-2A
19-Jul-08 112.1 67.7 62.1 44.4 21.40 5.23 7.64
20-Jul-08 119.3 70.1 60.2 49.2 20.51 17.21 10.89
21-Jul-08 129.7 73.6 64.2 56.1 33.12 8.35 3.97
22-Jul-08 115.8 69.4 65.7 46.4 13.90 11.56 27.55
23-Jul-08 125.7 72.4 60.9 53.3 6.27 11.03 5.66
24-Jul-08 122.2 69.5 61.4 52.7 27.76 20.07 6.51
2-Aug-08 125.8 77.6 58.5 48.2 11.05 12.23 2.15
3-Aug-08 131.0 79.3 63.4 51.7 11.99 20.93 9.60
4-Aug-08 143.6 84.9 64.1 58.7 37.29 24.73 18.20
5-Aug-08 137.4 86.3 56.2 51.1 36.62 30.04 5.49
6-Aug-08 145.6 82.5 57.5 63.1 23.79 15.08 6.46
7-Aug-08 135.3 84.1 61.0 51.2 32.80 33.27 9.01
8-Aug-08 143.5 87.0 63.9 56.5 40.83 33.04 7.82
100
110
120
130
140
150
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
SBP-M(mmHg)
60
65
70
75
80
85
90
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
DBP-M(mmHg)
*
0
5
10
15
20
25
30
35
40
45
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
SBP-2A(mmHg)
0
5
10
15
20
25
30
35
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
DBP-2A(mmHg)
*
*
50
55
60
65
70
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
HR-M(beats/min)
40
45
50
55
60
65
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
PP(mmHg)
0
5
10
15
20
25
30
16-Jul-08 21-Jul-08 26-Jul-08 31-Jul-08 5-Aug-08 10-Aug-08
Time (calendar date)
HR-2A(beats/min)
Figure 10. Cumulative sums serve for sequential testing. Asterix on abscissa of rows 1 and 2 (left) and row 2 (right) indicates
detection of deviation from norm. © Halberg.
The elderly man here monitored (FH) is professionally active, usually 7 days a week,
including the morning before surgery, scheduled for 13:30, and the hours after surgery and the
continuance of his endeavors involving reading. Thus, his eyesight is important to him, but he was
unaware of any anxiety and pursued his activities routinely. Hence the detection by cusum of an
increase in the circadian DBP-A and of the SBP-M and DBP-M is noteworthy in the absence of
conscious concern about the operation. These changes for a relatively brief span are almost certainly
a physiologic response. But in other subjects, a CHAT of longer duration can be a useful warning
even when the cardiologist's stress test is non-contributory, Figure 11 (46-48). Monitoring of BP for
the week prior to surgery may be part of preoperative screening, yet the restriction of the monitoring
101
span to a week of recording holds only until automatic, unobtrusive and affordable devices become
available.
Figure 11. Excessive circadian BP-A is a more sensitive warning (flag) than a conventional “stress test”*. A myocardial infarction
(MI) in April 1996, after an ignored chronobiologic warning of a fulminant CHAT, was necessary to convince a 35-year-old man
(BR) of the need for C-ABPM. Four months before the MI, BR reluctantly agreed to be monitored for 7 days, but stopped after 1 day
(of a weekend; Profile 1: 12/02/1995); 18 days later, he returned for another 7 days, but monitored only for 2 added days (midweek;
Profile 2: 12/20-21/1995) 4 months before a myocardial infarction (MI) in April 1996:
Endpoint (units)* SBP (mmHg) DBP (mmHg) HR (beats/min)
Profiles 1 2 1 2 1 2
MESOR 130.3 144.0** 81.0 86.5* 70.6 82.4***
2A (amplitude) 40.5 57.5* 20.0 45.8*** 27.1 29.2
(hr:min) 15:39 15:06 16:34 14:52 15:25 15:33
PTE (%) 17 54.8 8.5 15.8 0 9.2
tEx (hr:min) 14:49 14:59 22:56 16:23 - 15:57
Index (HBI or TCI) 29 230 7 92 0 15
PTE: percent time elevation (of BP or HR above time-specified reference limit computed on upper 95% prediction limit); tEx: timing
of excess; index: extent of excess measured as area under the curve delineated by time-specified upper reference limit; for BP;
HBI: hyperbaric index in mmHg x h during 24h; for HR; TCI: tachycardic index, in beats/min x h during 24h. Values in bold are
outside chronodesmic (time-varying and time-specified) reference limits. P: *0.05; **<0.01; ***<0.001. In BR's first profile, only the
SBP-2A was deviant; 18 days later, the SBP-MESOR and both the SBP-2A and DBP-2A and HBIs were deviant.
102
We routinely advocate a 1-week BP and HR profile at the outset, since there are cases where MESOR-hypertension was
observed for up to 5 initial days of monitoring but not for a year thereafter, and since there can be large day-to-day differences in
MESOR and 2A when monitoring is limited to 24 hours (in addition to any weekend vs. weekday difference, as part of multiseptan
variation). With these qualifications, in BR, a circadian hyper-amplitude-tension, CHAT, with MESOR-normotension may have
alternated with or preceded (as in the Okamoto rat and in human studies) the MESOR elevation of the second profile (see
tabulation above), then associated with an elevated HBI of SBP and DBP. The recommended continued monitoring after the first
profile and the urged immediate treatment after the second profile were not acted upon. The subject went to a care provider, who
ordered a stress test which was acceptable. He started long-term monitoring 4 months later, after having had an MI.
BR and others could be isolated cases, but not 297 patients followed prospectively for 6 years, established first on a
population basis in the hands of Kuniaki Otsuka (47, 48), the high relative vascular disease risk of CHAT, which can be fleeting or
gradual as well as fulminant. With a proxy outcome, the left ventricular mass index, the risk of CHAT involving the heart, as well as
the brain, kidney and eye, has been extended to a much larger number of patients, Table 1.
An increase of the human BP-2A can precede adverse vascular events at the time when as yet there is no change in other
parametric or non-parametric chronobiologic or conventional indices for a deviant BP. Methods here used allow us to extend
inferential statistical considerations from groups to the given patient. Preferably with more user-friendly instrumentation, yet with
education in chronobiology irrespective of the kind of available tools, the monitoring of BP in time and its chronobiologic
interpretation should prompt action for timely vascular disease prevention. © Halberg.
C-ABPM should constitute part of a preoperative screening routine and should further serve in
research for a post-operative follow-up, so that the effects in spans bracketing the operation can be
compared with those of other loads. Thus, an emotional load is detected by chronobiologically
interpreted changes in the circadian amplitude of DBP and of changes in BP-MESORs coincident
with cataract-related (or any other) surgery, yet their effect compares unfavorably with that of other
loads. In FH, other presumably benetensive tasks (44), such as the (to him) pleasure of writing in
preparation for a meeting abroad, involve more drastic changes than cataract surgery that exceeded
the individualized limits set on the basis of his data prior to surgery but neither did the response
exceed the limits of clinically healthy gender- and age-matched peers, nor did it equal changes
associated with routine tasks.
Conclusion. The wear and tear of everyday life can be assessed by C-ABPM and is best
interpreted on the basis of long-term monitoring of BP and HR. Objective findings that are
statistically significant, made, e.g., in the context of cataract surgery, may then be identified as
physiological transients and as minor by comparison to changes associated with other routine tasks.
1. Zadek I. Die Messung des Blutdrucks am Menschen mittelst des Basch'chen Apparates.
Berlin, med. F., Diss., 25. Nov 1880. Berlin: Schumacher; 1880. 48 p.
2. Zadek I. Die Messung des Blutdrucks am Menschen mittelst des Basch'chen Apparates. Z klin
Med 1881; 2: 509-551.
3. Janeway TC. The clinical study of blood pressure. New York: D. Appleton & Co.; 1904. 300
pp.
4. Bartter FC. Periodicity and medicine. In: Scheving LE, Halberg F, Pauly JE, eds.
Chronobiology. Tokyo: Igaku Shoin Ltd.; 1974. p. 6-13.
5. Scarpelli PT, Gallo M, Chiari G. Chronobiology of blood pressure. J Nephrol 2000; 13: 197-
204.
6. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla
M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G,
Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P,
Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress:
season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and
site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38.
http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
103
7. World Health Organization, International Society of Hypertension Writing Group. 2003 World
Health Organization (WHO)/International Society of Hypertension (ISH) statement on
management of hypertension. J Hypertens 2003; 21: 1983-1992.
8. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual and
proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64.
9. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
10. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group:
Resolution from a meeting of the International Society for Research on Civilization Diseases
and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995:
Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18
figures. http://www.msi.umn.edu/~halberg/
11. Pickering TG. Masked hypertension and white-coat hypertension. In: Proc., 59th Annual
Meeting, Japan Society of Neurovegetative Research, Tokyo, Nov. 1-3, 2006. p. 32.
12. Sanchez de la Pena S, Gonzalez C, Cornélissen G, Halberg F. Blood pressure (BP), heart rate
(HR) and non-insulin-dependent diabetes mellitus (NIDDM) chronobiology. Int J Cardiol
2004; 97 (Suppl 2): S14.
13. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633.
doi:10:1038/jhh.2008.32.
14. Cugini P, Cruciani F, Turri M, Regine F, Gherardi F, Petrangeli CM, Gabrieli CB. 'Minimalchange
hypertensive retinopathy' and 'arterial pre-hypertension', illustrated via ambulatory
blood-pressure monitoring in putatively normotensive subjects. International Ophthalmology
1999; 22(3): 145-149.
15. Schaffer E, Cornélissen G, Rhodus N, Halhuber M, Watanabe Y, Halberg F. Outcomes of
chronobiologically normotensive dental patients: a 7-year follow-up. JADA 2001; 132: 891-
899.
16. Matsui Y, Eguchi K, Ishikawa J, Hoshide S, Shimada K, Kario K. Subclinical arterial damage
in untreated masked hypertensive subjects detected by home blood pressure measurement. Am
J Hypertension 2007; 20: 385-391.
17. Hoshide S, Ishikawa J, Eguchi K, Ojima T, Shimada K, Kario K. Masked nocturnal
hypertension and target organ damage in hypertensives with well-controlled self-measured
home blood pressure. Hypertension Research - Clinical and Experimental 2007; 30: 143-149.
18. Obara T, Ohkubo T, Asayama K, Metoki H, Imai Y. Definition of masked hypertension. J
Hypertension 2007; 25: 1511-1512.
19. Pickering TG, Eguchi K, Kario K. Masked hypertension: a review. Hypertension Research Clinical
and Experimental 2007; 30: 479-488.
20. Eguchi K, Ishikawa J, Hoshide S, Pickering TG, Shimada K, Kario K. Masked hypertension in
diabetes mellitus: a potential risk. J Clin Hypertension 2007; 9: 601-607.
21. Grassi G, Seravalle G, Trevano FQ, Dell'oro R, Bolla G, Cuspidi C, Arenare F, Mancia G.
Neurogenic abnormalities in masked hypertension. Hypertension 2007; 50: 537-542.
22. Verberk WJ, Thien T, de Leeuw PW. Masked hypertension: a review of the literature. Blood
Pressure Monitoring 2007; 12: 267-273.
23. Marchesi C, Maresca AM, Solbiati F, Franzetti I, Laurita E, Nicolini E, Gianni M, Guasti L,
Marnini P, Venco A, Grandi AM. Masked hypertension in type 2 diabetes mellitus.
Relationship with left-ventricular structure and function. Am J Hypertension 2007; 20 (10):
1079-1084.
104
24. Fagard RH, Cornélissen VA. Incidence of cardiovascular events in white-coat, masked and
sustained hypertension versus true normotension: a meta-analysis. J Hypertension 2007; 25:
2193-2198.
25. Kawabe H, Saito I. Reproducibility of masked hypertension determined from morning and
evening home blood pressure measurements over a 6-month period. Hypertension Research --
Clinical and Experimental 2007; 30: 845-851.
26. Wang GL, Li Y, Staessen JA, Lu L, Wang JG. Anthropometric and lifestyle factors associated
with white-coat, masked and sustained hypertension in a Chinese population. J Hypertension
2007; 25: 2398-2405.
27. Verberk WJ, Thien T, Kroon AA, Lenders JW, van Montfrans GA, Smit AJ, de Leeuw PW.
Prevalence and persistence of masked hypertension in treated hypertensive patients. Am J
Hypertens 2007; 20: 1258-1265.
28. Pierdomenico SD. The Odyssey of Masked Hypertension in the HOMERUS Trial. Am J
Hypertension 2007; 20: 1266-1267.
29. Mahmud A, Jatoi M, Chee YR, Feely J. History of gestational hypertension is associated with
the metabolic syndrome and masked hypertension but not arterial stiffness in women with
essential hypertension. J Clin Hypertens 2008; 10: 21-26.
30. Verdecchia P, Angeli F, Gattobigio R, Borgione C, Castellani C, Sardone M, Reboldi G. The
clinical significance of white-coat and masked hypertension. Blood Pressure Monitoring 2007;
12: 387-389.
31. Papadopoulos DP, Makris TK. Masked hypertension definition, impact, outcomes: a critical
review. J Clin Hypertens 2007; 9: 956-963.
32. Hwang ES, Choi KJ, Kang DH, Nam GB, Jang JS, Jeong YH, Lee CH, Lee JY, Park HK, Park
CH. Prevalence, predictive factor, and clinical significance of white-coat hypertension and
masked hypertension in Korean hypertensive patients. Kor J Int Med 2007; 22: 256-262.
33. Yamasue K, Hayashi T, Ohshige K, Tochikubo O, Souma T. Masked hypertension in elderly
managerial employees and retirees. Clin Exp Hypertens 2008; 30: 203-211.
34. Obara T, Ohkubo T, Asayama K, Kikuya M, Metoki H, Inoue R, Komai R, Murai K,
Hashimoto J, Totsune K, Imai Y, J-Home Study Group. Prevalence of masked hypertension in
subjects treated with antihypertensive drugs as assessed by morning versus evening home
blood pressure measurements: the J-HOME study. Clin Exp Hypertens 2008; 30: 277-287.
35. Kawano Y, Horio T, Matayoshi T, Kamide K. Masked hypertension: subtypes and target
organ damage. Clin Exp Hypertens 2008; 30: 289-296.
36. Kotsis V, Stabouli S, Toumanidis S, Papamichael C, Lekakis J, Germanidis G, Hatzitolios A,
Rizos Z, Sion M, Zakopoulos N. Target organ damage in "white coat hypertension" and
"masked hypertension". Am J Hypertens 2008; 21: 393-399.
37. Pickering TG. The natural history of hypertension: prehypertension or masked hypertension? J
Clin Hypertens 2007; 9: 807-810.
38. Mallion JM, Ormezzano O, Barone-Rochette G, Neuder Y, Salvat M, Baguet JP. Masked
hypertension: myth or reality? Presse médicale 2008; 37 (6 Pt. 2): 1034-1037.
39. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber M,
Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Peña S,
Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N, Borer K,
Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7-day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical Instrumentation &
Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
40. Bingham C, Arbogast B, Cornélissen Guillaume G, Lee JK, Halberg F. Inferential statistical
methods for estimating and comparing cosinor parameters. Chronobiologia 1982; 9: 397-439.
105
41. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of
antihypertensive response by self-starting cumulative sums. J Medical Engineering &
Technology 1997; 21: 111-120.
42. Cornélissen G, Halberg F, Wall D, Siegelova J, Zaslavskaya RM. How long to screen: ice
hockey game and transient circadian hyperamplitudetension, CHAT. Scripta medica (Brno)
1997; 70: 189-198.
43. Halberg F, Cornélissen G, Otsuka K, Katinas GS, Schwartzkopff O, Halpin C, Mikulecky M,
Revilla M, Siegelova J, Homolka P, Dusek J, Fiser B, Singh RB. Chronomics* (*the study of
time structures, chronomes) detects altered vascular variabilities constituting risks greater than
hypertension: with an illustrative case report. In: Mitro P, Pella D, Rybar R, Valocik G (Eds.)
Proceedings, 2nd Congress on Cardiovascular Diseases, Kosice, Slovakia, 25-27 April 2002.
Bologna: Monduzzi Editore; 2002. p. 223-258.
44. Halberg F, Cornélissen G, Spector NH, Sonkowsky RP, Otsuka K, Baciu I, Hriscu M,
Schwartzkopff O, Bakken EE. Stress/strain/life revisited. Quantification by blood pressure
chronomics: benetensive, transtensive or maletensive chrono-vasculo-neuro-immunomodulation.
Biomed & Pharmacother 2003; 57 (Suppl 1): 136s-163s.
45. Maschke C, Harder J, Cornélissen G, Hecht K, Otsuka K, Halberg F. Chronoecoepidemiology
of "strain": infradian chronomics of urinary cortisol and catecholamines during nightly
exposure to noise. Biomed & Pharmacother 2003; 57 (Suppl 1): 126s-135s.
46. Cornélissen G, Halberg F, Gubin D, Carandente F, Halberg J, Zaslavskaya R, Syutkin V,
Kumagai Y, Watanabe Y, Otsuka K. Carpe diem mensuratem: Fulminant CHAT, its
recognition a chronobiologic path to preventing a myocardial infarction? Abstract, 4°
Convegno Nazionale, Società Italiana di Cronobiologia, Gubbio (Perugia), Italy, June 1-2,
1996. p. 35-36.
47. Otsuka K, Cornélissen G, Halberg F. Predictive value of blood pressure dipping and swinging
with regard to vascular disease risk. Clinical Drug Investigation 1996; 11: 20-31.
48. Otsuka K, Cornélissen G, Halberg F, Oehlert G. Excessive circadian amplitude of blood
pressure increases risk of ischemic stroke and nephropathy. J Medical Engineering &
Technology 1997; 21: 23-30.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
106
Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics
Germaine Cornélissen1
, S.R. Prabhakaran Nayar2
, Jerzy Czaplicki3
,
Jarmila Siegelova4
, Blanca Mendoza5
, Franz Halberg1
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Department of Physics, Kerala University, Kariavattom, Trivandrum, India
3
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
4
Masaryk University, Brno, Czech Republic
5
Instituto de Geofisica UNAM, Mexico City, Mexico
Aim. In the foreseeable future, noninvasive cardiology may be based on dense if not
continuous monitoring of variables such as beat-to-beat heart rate and related endpoints from the
ECG. The ECG is already combined with blood pressure measurements around the clock in an
automatic instrument for ambulatory use. Eventually, other variables such as the EEG will also be
recorded automatically, ambulatorily, unobtrusively and affordably. Such monitoring has been
started on a few "test pilots", but not yet from womb to tomb. Monitoring in schools could
examine the merits of prehabilitation, i.e., of diagnosing and treating pre-hypertension (1, 2), prediabetes
(3, 4) and other vascular variability disorders (VVDs), and if several VVDs coexist, the
resulting vascular variability syndromes (VVSs). Thereby, incapacitation by morbid events such as
strokes and the great cost of rehabilitation will be reduced by self-surveillance cost-free, for
prehabilitation (5-7). With such records, it will become possible, as a dividend, to consider and
analyze some of the already-known psychophysiological signatures of the cycles of the habitat
near and far, including those of solar interplanetary and galactic as well as terrestrial variability (5,
8-19).
Background. Not only cycles with a period that fits, in length, within the lifetime of an
individual organism, but also those with a longer period, detected on a population basis, are
pertinent in an epidemiological context. Cycles with a period occupying decades and much longer
ones, some exceeding by far several individuals' lifespan have already been found in populations
as in nature (9, 10; cf. 19). A tridecadal cycle was described by Charles Egeson, who wrote in
1889 that "we hear Lord Bacon say: '... every five and thirty years the same kind and suit of years
and weathers come about again; as great frosts, great wet, great droughts, warm winters, summers
with little heat and the like, and they call it the Prime'" (20). Shortly after Egeson, Eduard
Brückner documented, more extensively albeit macroscopically, a 33-35-year variation (21),
which was elaborated in relation to the length of the sunspot cycle by W.J.S. Lockyer (22), with
comment in a historical context in the journal Science by his father Sir Norman Lockyer (23),
discoverer of helium and founder of the journal Nature (24; cf. 25). Transtridecadals have been
reported as a possible 35.6-year period by Dolores Maravilla et al. (26) in polar coronal holes,
where this period is found in a spectrogram only transiently in the early 1990s, Figure 1. They are
also cited by S.R. Prabhakaran Nayar (27) as a 33-year variation, the latter with an indication of a
high degree of generality in solar-terrestrial associations.
Materials and methods. Against this background, a database consisting of 40 series (OMNI2;
ftp://nssdcftp.gsfc.nasa.gov/spacecraft_data/omni/) was analyzed chronomically by the extended
cosinor (28-30), to start with globally, as whole series.
Results. By the criterion of a positive lower limit of the CI (95% confidence interval) of the
amplitude (i.e., by the rejection of the zero-33-year amplitude assumption), five of the OMNI2
series qualify as BEL, Table 1 (one of these variables, Na/Np, the alpha/proton ratio, is noted only
in this table's footnote).
107
Table 1: Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics*
Variable Period (years) [95% CI] Amplitude (%M)** [95% CI]
Interplanetary magnetic field
Proton Temperature 34.28 [26.99, 41.57] 13.62 [6.56, 20.68]
Sigma (Bx) 31.87 [24.70, 39.04] 6.81 [3.41, 10.71]
Plasma Speed 33.04 [20.10, 45.97] 2.47 [0.10, 4.83]
Planetary geomagnetic index
Kp 32.65 [28.27, 37.03] 12.74 [8.58, 16.86]
*Monthly means from 1963 to 2003 (41 years), analyzed by the extended cosinor with nonlinear
least squares, using 33.0 years as a trial period. By the criterion of a CI of the period overlapping
the 30-40-year range and, if so, of a positive lower limit of the CI of the amplitude, 5 time series in
the OMNI2 database qualify as compatible with a BEL cycle. Na/Np (alpha/proton ratio:
http://nssdcftp.gsfc.nasa.gov/spacecraft_data/omni/omni2.text) also has a period of 36.84 years
[29.97, 43.72]; 22 other variables converge to periods shorter than 30 years or longer than 40
years; 3 others do not reach statistical significance, and the remaining 10 do not converge, i.e., do
not allow a period estimate with the trial period used. Zürich (Wolf) sunspot numbers for the span
from 1745 to 2003 yield a period of 29.068 (27.92, 30.22) years.
**%M: percentage of MESOR
Figure 1. Spectrogram of coronal holes with calendar date on the abscissa and period in years on
the ordinate reveal prominent, slightly longer than 10-year Schwabe cycles, other drifting
components and a component around 29.14 years that for only a relatively short span, near the
beginning of the last quarter of the display, shows a peak crossed by the upper horizontal line
drawn at 35.6 years. © Halberg.
108
Note, at a 32-year trial period on the ordinate, a consistent spectral component in the
geomagnetic index Ap (top) and an intermittent one in Zürich relative sunspot numbers
(bottom)
Wavelet spectrum of geomagnetic disturbance
Wavelet spectrum of relative sunspot numbers, WN
Figure 2: Top: Wavelet spectrum of the planetary geomagnetic index Ap, displaying the time
course of this variable. Compared to other oscillations with a relatively short period, the semiannual
oscillation of the Ap index is very strong and is seen as a band present during most of the
time, in keeping with results on the antipodal index aa in Figure 3. The strength of oscillations
corresponding to about 1, 1.3, 3.3 and 5.5 years varies with time. The band in the 9- to 11-year
range is very strong during the spans from 1934 to 1972 and from 1980 to 1996. Although the 33year
BEL-period is also strong, it is embedded in the cone of influence outside the paraboloidal
curve.
Bottom: Wavelet spectrum of Zürich (Wolf) numbers showing a prominent about 11-year
Schwabe cycle during 1850 to 2000, with maximal amplitude during 1944-1998, interrupted within
the cone of resolution only during a minimum in that circadecadal cycle. The wavelet spectrum of
Zürich numbers differs from the wavelet spectrum of Ap (top), also in keeping with the results of
the extended cosinor. Solar effects may bring about the about 33-year variation by solar wind
speed rather than by phenomena mediated by the number of sunspots. A transtridecadal period
BEL cycle is intermittent in the wavelet spectrum of Zürich sunspot numbers.
109
Figure 3. The merits of studying variation in time with the overall data summary, as done in Figure
2, are here implemented by a separate aligned gliding spectral window (left) and a global spectral
window of the antipodal geomagnetic disturbance index aa. © Halberg.
Chronomics are thus in keeping with the assumption that a BEL cycle may originate in the
interplanetary magnetic field (IMF), notably since it was not detected as a constant component
with coronal holes, Figure 1. The solar wind may act directly and/or by displacing galactic cosmic
rays and/or via terrestrial magnetism, as suggested by the finding of a BEL cycle in a planetary
geomagnetic index, Kp, Table 1. The consequences of BEL may pertain to other aspects of the
environment, such as temperature, in which a concomitant 35-year variation was consistently
documented (31). While the periodicity of a "Brikner" or Brückner cycle was questioned (32, 33),
the results in Table 1 are presented to add evidence concerning its degree of generality, with
estimates of the uncertainty involved and a hint at a mechanism underlying the BEL's origins (as
noted specifically in the solar wind that may act upon the biosphere directly and/or by the effect of
displacing galactic cosmic rays and/or by affecting terrestrial magnetic disturbances).
Discussion. A presentation complementary to that in Table 1 is shown in a wavelet spectrum
provided in Figure 2 for the geomagnetic activity index Ap (top), and for Zürich (Wolf) relative
sunspot numbers (bottom). This wavelet approach has the advantage of resolving the time course
of a spectral component, which more often than not varies by drifting and bifurcating in frequency
and in amplitude by waxing and waning to the point of disappearing and reappearing, be it because
the signal is lost or because it is too weak to emerge from the noise. In this figure, the power
corresponding to each period indicates a strong time-dependence, including intermittency. The
110
thick contours plotted in this figure enclose regions of greater than 95% confidence for a red noise
process. Also important is the cone of the influence region, delineated by a paraboloidal curve,
where edge effects arising from truncation of the time series can be important. Hence the region
external to this curve is considered with this qualification. In Figure 2 (top), a strong contour
corresponding roughly to a 32-year variation is readily apparent, and is continuous, whereas
Figure 2 (bottom) showing the wavelet spectrum of Zürich (Wolf's) relative sunspot numbers
along a much longer abscissa (1840-2003) than that for Ap (1932-2003), the component
corresponding to 32 years is clearly intermittent. This result can be aligned with extended cosinor
analyses which did find the BEL cycle in a 40-year series during a relatively recent span, but did
not detect an about 33-year variation in the Zürich numbers available to and interpreted by
Brückner as not pertinent, or in a much longer series of Zürich numbers.
Thus, an about 33-year variation in sunspots is intermittent by cosinor and by a wavelet
spectrum (Figure 2, bottom), but an exception is the span from 1967 to 2007, when it is
demonstrable by cosinor with one of the models used, as a descriptor of the waveform and in that
case, it had the smallest amplitude, Table 2. By contrast, during the same 40-year span, the
circatridecadal component of heart rate of a clinically healthy man (RBS) had the largest
amplitude in the infradian spectral region in the domain of years and decades. The related weak
counterpart in Zürich (Wolf's) numbers to a relatively more prominent biospheric tridecadal
component can perhaps be interpreted as indicating that a BEL cycle is genetically coded.
Heliogeophysical cycles (in the solar wind and/or other aspects of the IMF, Table 1, or the length
of the sunspot cycle) may have exhibited a transtridecadal cycle for billions of years. This renders
it likely that the tridecadal component in human heart rate is coded in genes, and a remove-andreplace
approach (8, 34, 35) can help clarify this problem.
Figure 4. Similar cycle lengths characterize solar wind speed and geomagnetism, yet the lengths
of the ascending versus the descending stages differ in the same Schwabe cycle. Partial results
from wavelet decomposition using Daubechies wavelets.
111
Table 2: Periods and their uncertainties in Zürich (Wolf) numbers¶
Variable (units) MESOR (units)* Period (y) [CI] Amplitude [CI] Acrophase (°) [CI]*
Congruence
s
ENVIRONMENT
32.82 [23.40, 42.16]** 13.91 [9.45, 18.37] -218 [-199, -238] S1
10.56 [10.34, 10.78] 65.08 [59.28; 70.89] -217 [-213, -221] S2
Schwabe value, S
(Wolf numbers [WN],
count)
72.74 [69.96, 75.83]
8.02 [7.52, 8.52] 16.83 [11.34, 22.32] -83 [-68, -98]
¶ Components fitted concomitantly: CIs (95% confidence intervals) in [ ].
*MESOR = midline-estimating statistic of rhythm; 1 cycle = 360°.
**This component, validated by two separate programs as descriptor of the waveform in the
particular 3-component model used, was not detected with statistical significance when the
shorter-than-10-year component was omitted, or when Zürich numbers over spans longer than the
one considered herein were similarly analyzed.
Since Figure 2 (top) shows an about 33-year variation in geomagnetic activity, documented
in Table 1 only globally, without depicting its time course, it strengthens an inquiry into the origin
of the BEL cycle in space weather. Table 1 reveals a congruent period for solar wind speed (SWS)
and Kp, suggesting, as wavelet analyses do (27) that the solar wind and/or the broader
interplanetary magnetic field and/or galactic cosmic rays, may all be considered as possibly
underlying the BEL cycle, which all methods used validate as a transdisciplinary entity. In
Brückner's original data, it is an aeolian, nonstationary entity (31).
Figure 4 bears upon another aspect of the extent of agreement between solar wind speed
(SWS) and geomagnetics gauged by Ap (27). The daily average values of solar wind speed and the
Ap index during the span from 1964-2003 were subjected to wavelet decomposition using
Daubechies wavelet ('db3' from the wavelet tool kit of MATLAB for 12 levels of successive
approximations and details). The circatranstridecadal periods seem to be the same, but an
asymmetry suggests that the effect in SWS persists in Ap while the strength of SWS starts
declining. The coefficients obtained on reconstruction, plotted against time to identify various
oscillations present (not shown) include a circatranstridecadal cycle demonstrated for SWS and
geomagnetics (Ap), Figure 4. The two variables have a common time domain insofar as the cycles'
length is very similar. SWS, however, has a faster (shorter) ascending stage and a slower (longer)
descending stage while the opposite holds true for Ap, Figure 4.
Figure 3 is of methodological interest, showing for a limited spectral window the merit of
complementing a global summary of periods with CIs (right) with a gliding least-squares
spectrum, an approach applicable to non-equidistant data, with the qualification that long gaps
could create artifacts. Figure 1 shows a spectrogram of (equidistant) data on coronal holes for
which a 35.6-year period had been reported but could not be confirmed by cosinor. It is readily
apparent that a peak in that spectral region occurs only during the beginning of the last fourth of
the graph and is short-lived, and that the main periods in this variable are in the region of trial
periods shorter than 30 years and are not likely to account for a BEL cycle. Of historic interest,
however, is a 33-year peak reported by Samuel M. Silverman (36) and by Clough (37) who in
1933 wrote about the BEL cycle in the frequency of aurorae, Nile floods, Arizona pine growth
and wheat prices.
112
It will be desirable in the future to fit multiple cosine models to the now longer time series
that have accumulated since Egeson's, Brückner's and the Lockyers' time, e.g., on rainfall and
temperature and accordingly, to stack data for the cycle lengths found as plexograms for an
analysis of variance, and to compare waveforms in this way and/or by Daubechies wavelets
(Figure 4). Brückner's terrestrial variables and other biospheric data may or may not reveal an
asymmetry of their stages, but if they did so, their resembling the SWS pattern may suggest that
the effect of the SWS is direct or vice versa, if the pattern had a slow ascending and a faster
descending stage, terrestrial magnetic disturbance may be the proximate cause of other
environmental (temperature, rainfall) or biospheric (human heart rate) BEL cycles. Any pattern of
geomagnetics should be best gauged by the longer (than Ap) antipodal aa series to explore any
direct effect of terrestrial magnetism, tasks for the future. In the interim, it can be noted that by the
criterion of congruence, some components in biospheric variables have overlapping or overlying
CIs of their periods corresponding to those of geomagnetics; others are congruent with periods of
the solar wind, and fewer biospheric periods are congruent with both helio- and geomagnetics.
Beyond the criterion of congruence, a remove-and-replace approach (8, 34, 35) to the time
courses of possibly interacting variables is highly desirable and awaits implementation, the sun
willing, since this entity does the removal and replacement or at least the addition and subtraction,
i.e., the waxing and waning of amplitudes.
Brückner preceded Chizhevsky in recognizing the broad impact of cosmos-related climate
change. Chizhevsky in turn assembled, among many others, data on "universal human militarypolitical
activity" from 1748 until 1922 (38). Our meta-analysis by an extended cosinor of data
from Chizhevsky's graph, taken off a curve (at guesstimates of the intervals used), yields mostly an
anticipated number of previously reported components in solar variability. The major component
in the decadal/multidecadal range is a Schwabe cycle of about 10.1 years accounting for about
13.2% of the total variance. The corresponding percentage rhythm (PR) contributed by a
Gleissberg cycle of about 77.3 years is 9.1%. There is also a global cycle contribution with a
period of about 17.7 years, with a PR of 8.2% and an unaccounted-for neighboring spectral peak at
about 14.4 years with a PR of 7.2%. The Hale cycle component of about 22.5 years accounts for
5.4% of the variance. A further period of about 30.74 (95% CI: 27.53, 33.95) years with a PR of
5.1% provides another hint of the broad (here including military and political) importance of the
BEL cycle, among other related consequences of weather in extraterrestrial space in human affairs,
in violence (39-42) and in war as well as peace, beyond "any change from wet and cold to dry and
warm climates", that according to Brückner determined immigration from Europe to the USA and
the westward migration within the USA (43). The topic of secular periods of solar activity and
synchronous variation in terrestrial phenomena, reviewed by H.W. Clough in 1933 (37), can also
be extended to include the biosphere. It is hardly surprising to find that the BEL cycle is a
prominent component, second only to the Schwabe cycle in the spectrum of the aurora (36).
Conclusion. The BEL transtridecadal cycle characterizes the proton temperature and the
speed of the solar wind, among other aspects of heliogeomagnetics. The interplanetary magnetic
field may contribute one of the aeolian nonstationary origins of terrestrial BEL cycles, to be
aligned with the many other nonphotic as well as photic cyclic aspects of the variable sun, in
whose atmosphere we reside (44), and its broader cosmos.
113
1. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
2. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual
and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64.
3. Sanchez de la Pena S, Gonzalez C, Cornélissen G, Halberg F. Blood pressure (BP), heart rate
(HR) and non-insulin-dependent diabetes mellitus (NIDDM) chronobiology. Int J Cardiol
2004; 97 (Suppl 2): S14.
4. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633.
doi:10:1038/jnh.2008.32.
5. Cornélissen G, Halberg F, Schwartzkopff O, Delmore P, Katinas G, Hunter D, Tarquini B,
Tarquini R, Perfetto F, Watanabe Y, Otsuka K. Chronomes, time structures, for
chronobioengineering for "a full life". Biomed Instrum Technol 1999; 33: 152-187.
6. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber
M, Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la
Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N,
Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7day/24-hour
chronobiologic blood pressure and heart rate screening: Part I. Biomedical
Instrumentation & Technology 2002; 36: 89-122.
7. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber
M, Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la
Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N,
Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7day/24-hour
chronobiologic blood pressure and heart rate screening: Part II. Biomedical
Instrumentation & Technology 2002; 36: 183-197.
8. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
9. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A,
Gorgo Y, Zhao ZY, Weydahl A, Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV,
Perfetto F, Tarquini R, Singh RB, Rhees B, Lofstrom D, Lofstrom P, Johnson PWC,
Schwartzkopff O, International BIOCOS Study Group. Cross-spectrally coherent ~10.5- and
21-year biological and physical cycles, magnetic storms and myocardial infarctions.
Neuroendocrinol Lett 2000; 21: 233-258.
10. Halberg F, Cornélissen G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka
P, Prikryl P, Chibisov SM, Holley DC, Wendt RW, Bingham C, Palm SL, Sonkowsky RP,
Sothern RB, Pales E, Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R,
Konradov AA, Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov
AV, Faraone P, Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T,
Pantaleoni GC, Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki
EA, Bathina S, Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M.
Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks,
114
near-decades, phylogenetic and ontogenetic memories. Biomed & Pharmacother 2004; 58
(Suppl 1): S150-S187.
11. Mikulecky M (Ed.) The Moon and Living Matter. Kosice, Slovakia, September 23-25, 1993.
Bratislava: Slovak Medical Society; 1993. 97 pp.
12. Mikulecky M (Ed.) Sun, Moon and Living Matter. Bratislava, Slovakia, June 28-July 1,
1994. Bratislava: Slovak Medical Society; 1994. 159 pp.
13. Mikulecky M (Ed.) Chronobiology & Its Roots in the Cosmos. High Tatras, Slovakia,
September 2-6, 1997. Bratislava: Slovak Medical Society; 1997. 287 pp.
14. Otsuka K (Ed.) Proceedings, 1st International Symposium Workshop on Circadian Rhythms
and Clinical Chronotherapy, 11 Nov 2000, Tokyo, Japan. Biomed & Pharmacother 2001; 55
(Suppl 1): 7s-190s.
15. Otsuka K (Ed.) Proceedings, 2nd International Symposium Workshop on Circadian Rhythms
and Clinical Chronotherapy, 17 Nov 2001, Tokyo, Japan. Biomed & Pharmacother 2002; 56
(Suppl 2): 231s-382s.
16. Otsuka K (Ed.) Proceedings, 3rd International Symposium Workshop on Circadian Rhythms
and Clinical Chronotherapy, 9 Nov 2002, Tokyo, Japan. Biomed & Pharmacother 2003; 57
(Suppl 1): 1s-198s.
17. Otsuka K (Ed.) Proceedings, 4th International Symposium Workshop on Circadian Rhythms
and Clinical Chronotherapy, 8 Nov 2003, Tokyo, Japan. Biomed & Pharmacother 2004; 58
(Suppl 1): S1-S188.
18. Otsuka K (Ed.) Proceedings, 5th International Symposium Workshop on Circadian Rhythms
and Clinical Chronotherapy, 6 Nov 2004, Tokyo, Japan. Biomed & Pharmacother 2005; 59
(Suppl 1): S1-S261.
19. Mikulecky M. Solar activity, revolutions and cultural prime in the history of mankind.
Neuroendocrinology Lett 2007; 28 (6): 749-756.
20. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
21. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
22. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
23. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
24. Lockyer N. The Sun's Place in Nature. London: Macmillan; 1897. 360 pp.
25. Clark S. The Sun Kings: The Unexpected Tragedy of Richard Carrington and the Tale of
How Modern Astronomy Began. Princeton, NJ: Princeton University Press; 2007. 224 pp.
26. Maravilla D, Lara A, Valdés Galicia JF, Mendoza B. An analysis of polar coronal hole
evolution: relations to other solar phenomena and heliospheric consequences. Solar Physics
2001; 203: 27-38.
27. Prabhakaran Nayar SR. Periodicities in solar activity and their signature in the terrestrial
environment. ILWS Workshop 2006, Goa, February 19-24, 2006. 9 pp.
28. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
29. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
30. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
31. Brückner-Egeson-Lockyer (BEL) climate cycle in original BEL and societal data. These
proceedings.
115
32. Schuster A. On Newcomb's method of investigating periodicities and its application to
Brückner's weather cycle. Proc Roy Soc Lond A 1914; 90: 349-355.
33. Kostin SI. Is the Brikner (Brückner) cycle real? Directorate of Scientific Information
Services Ottawa (Ontario), May 1965. 4 pp.
http://stinet.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0615768
34. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
35. Halberg F, Schwartzkopff O, Cornélissen G, Otsuka K. Life's waves in space-time in and
around us. Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary
Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute
for Theoretical Physics, Kyoto University, October 15-20, 2007. p. 45-47.
36. Silverman SM. Secular variation of the aurora for the past 500 years. Rev Geophys 1992; 30
(4): 333-351.
37. Clough HW. The 11-year sun-spot period, secular periods of solar activity, and synchronous
variations in terrestrial phenomena. Monthly Weather Review 1933; 60: 99-108.
38. Chizhevsky AL. Astronomy, psychology and history. Moscow: M.A. Institute; 1921. 78 pp.
39. Halberg F, Cornélissen G, Sothern RB, Chibisov SM, Wendt HW. Do unseen, very weak
magnetic mechanisms contribute to terrorism in wobbly spectral windows? Proc. 8th
International Congress "Health and education millennium", Moscow, Russia, November 14-
17, 2007, p. 63-66.
40. Cornélissen G, Halberg F, Wendt HW, Sothern RB, Chibisov SM, Kulikov SI, Agarwal RK.
Weak magnetoperiodism rather than socio-photo-thermoperiodism characterizes human
terrorism detection of about 1.3-year aeolian transyear but not precise 1.0-year cycle. Proc.
8th
International Congress "Health and education millennium", Moscow, Russia, November
14-17, 2007, p. 77-80.
41. Grigoryev PYe, Vladimirskii BM. The cosmic weather affects the terrorist activity. Uchenye
zapiski Tavricheskogo Natsionalnogo Universiteta im V.I. Vernadskogo, Series "Biology,
chemistry" 2007; 20 (59) ( 1): 28-46.
42. Wendt HW. Interplanetary magnetic field (IMF) polarity, collective emotions and entropy
changes of random event generators. Bulletin of the People's Friendship University of
Russia, Proceedings, 8th International Congress "Health and education millennium",
Moscow, Russia, November 14-17, 2007, pp. 81-84.
43. Rain Affects Emigration. New York Times, October 12, 1912. http://query.nytimes.com
/mem/archive-free/pdf?res=9C05E1DC133CE633A25751C2A9669D946396D6CF
44. Kamide Y. We reside in the sun's atmosphere. Biomed & Pharmacother 2005; 59 (Suppl 1):
S1-S4.
Acknowledgments: The authors are grateful to KW Ogilvie (NASA GSFC), AJ Lazarus (MIT) and
MR Aellig (MIT) for access to the Omniweb data.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
116
BODY MASS INDEX (BMI), PULSE PRESSURE (PP) AND PREMETABOLIC
SYNDROME
Germaine Cornélissen1
, Jarmila Siegelova2
, Jerome Abramson3
, Balasasikumar Sundaram4
,
Jack Mandel3
, Dan Holley4
, Franz Halberg1
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
2
Masaryk University, Brno, Czech Republic
3
Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
4
San Jose State University, San Jose, California, USA
Aim. To complement the detection of pre-hypertension (1, 2) and pre-diabetes (3, 4) with
chronobiologically interpreted ambulatory blood pressure (BP) and heart rate (HR) monitoring by
focus with the same approach upon obesity.
Background. On 140 clinically healthy adults, Abramson et al. (5) reported a positive
association of markers of inflammation and BP variability. In a slightly extended subject
population, the MESOR of HR and the pulse pressure (PP) were found to be positively associated
with C-reactive protein (CRP) (6). Vascular variability disorders (VVDs) (7), such as CHAT
(Circadian Hyper-Amplitude-Tension, a condition characterized by an excessive circadian BP
variation), were also detected in this population of clinically healthy subjects (6).
Method. The data from Abramson et al. (5, 6) are reanalyzed herein with another smaller
sample of clinically healthy immigrants from Silicon Valley (8) to examine any relation to BMI of
PP and markers of inflammation.
Results. Figure 1 shows an association of PP with BMI (r=0.418, P <0.001) which holds
separately for subjects with BMIs below and above 30 kg/m2
, as seen in Figure 2. A similar
relation is found for men and for women in the USA, but only for women in 7-day records from
the Czech Republic. Figures 3 and 4 show some association with BMI of CRP (r=0.431, P <0.001)
and tumor necrosis factor (r=0.164, P<0.042). Figure 5 is in keeping with the assumption that
inflammation, gauged by CRP, relates to PP (r=0.296, P < 0.001). We had earlier found in young
117
healthy individuals that an increased BMI is associated with a lower double amplitude of systolic
and diastolic blood pressure (8).
Discussion. All of the correlation coefficients reported herein are below 0.5, and there are
discrepancies in that a gender difference seen in less unreliable 7-day records from the Czech
Republic is not reproduced in the less reliable 24-hour profiles from the USA. That profiles for 2,
3 and 4 days scan fail when longer series separate severe or early outcomes from health has been
reported earlier (4, 9).
The US sample allowed a check on ethnic differences that were not found in the limited
available sample. The gender difference found in Europeans in Europe, but not in "white"
Americans, remains a puzzle. The data suffice, however, to suggest that prospective studies are
warranted to investigate, notably in schools, any associations of VVDs, such as an elevated PP,
with other aspects of physiology and pathology, notably obesity (10), so as to institute timely
preventive treatment.
Supported by grant MSM 0021622402
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH).
REFERENCES
1. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual
and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64
2. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
3. Sanchez de la Pena S, Gonzalez C, Cornélissen G, Halberg F. Blood pressure (BP), heart rate
(HR) and non-insulin-dependent diabetes mellitus (NIDDM) chronobiology. Int J Cardiol
2004; 97 (Suppl 2): S14.
4. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633
doi:10.1038/jhh.2008.32.
118
5. Abramson JL, Lewis C, Murrah NV, Anderson GT, Vaccarino V. Relation of C-reactive
protein and tumor necrosis factor-alpha to ambulatory blood pressure variability in healthy
adults. Am J Cardiol 2006; 98: 649-652. doi:10.1016/j.amjcard.2006.03.045.
6. Abramson J, Cornélissen G, Mandel J, Halberg F. Blood pressure overswinging, CHAT,
found by 24-hour monitoring, needs validation by follow-up. Proceedings, International
Conference on the Frontiers of Biomedical Science: Chronobiology, Chengdu, China,
September 24-26, 2006, p. 43-45.
7. Halberg F, Cornélissen F, Schwartzkopff O, Blagonravov ML, Chibisov SM, Otsuka K,
Siegelova J, Beaty L, Nolley E, Sanchez de la Peña S, Zaslavskaya R, Radysh IV. Vascular
variability disorders (VVDs) and syndromes (VVSs): MESOR-hypertension, CHAT and
other. Proceedings, 1st International Workshop, Physiology of adaptation and quality of life:
problems of traditional medicine and innovation, People's Friendship University of Russia,
Moscow, Russia, May 14-16, 2008. p. 401-403.
8. Sundaram B, Hanumansetty R, Cornélissen G, Otsuka K, Katinas G, Siegelova J, Homolka
P, Sanchez de la Peña S, Borer K, Schaffer E, Holley DC, Halberg F. Blood pressure and
pulse dynamics quantify everyday life's emotions -- if excessive by circadian overswinging,
CHAT. Am J Hypertens 2004; 17 (5 Part 2): 57a-58a.
9. Schaffer E, Cornélissen G, Rhodus N, Halhuber M, Watanabe Y, Halberg F. Outcomes of
chronobiologically normotensive dental patients: a 7-year follow-up. JADA 2001; 132: 891-
899.
10. Després JP. Cardiovascular disease under the influence of excess visceral fat. Critical
Pathways in Cardiology 2007; 6: 51-59.
119
25
30
35
40
45
50
55
60
65
15 20 25 30 35 40 45
BMI (kg/m
2
)
PP(mmHg)
r=0.418, P<0.001
All subjects
Figure 1
120
25
30
35
40
45
50
55
60
65
15 20 25 30 35 40 45
BMI (kg/m2
)
PP(mmHg)
r=0.283, P=0.069
Key:
Open circles: BMI<30
Filled circles: BMI>30
r=0.348, P<0.001
Figure 2
121
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
15 20 25 30 35 40 45
BMI (kg/m
2
)
Log10(CRP)
r=0.431, P<0.001
All subjects
Figure 3
122
-1.0
-0.5
0.0
0.5
1.0
1.5
15 20 25 30 35 40 45
BMI (kg/m
2
)
Log10(TNF-)
r=0.164, P=0.042
All subjects
Figure 4
123
0.0
1.0
2.0
3.0
4.0
5.0
25 30 35 40 45 50 55 60 65
PP (mmHg)
Log10(CRP)
All subjects
r=0.295, P<0.001
Figure 5
124
Auroral aeolian periodicity during 1545-1724, including the Maunder minimum
Germaine Cornélissen1
, Franz Halberg1
, Miguel Revilla2
, Jarmila Siegelova3
,
Othild Schwartzkopff1
, Jerzy Czaplicki4
, Salvador Sanchez de la Peña5
, Wilfried Schröder6
and the BIOCOS group
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Dept Applied Mathematics and Computation, Univ of Valladolid, Valladolid, Spain
3
Masaryk University, Brno, Czech Republic
4
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
5
Chronomic Res. Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City, Mexico
6
Geophysikalische Station, Bremen-Rönnebeck, Germany
Abstract. Myocardial infarctions increase in frequency in association with a magnetic storm
(1-3), as does the aurora. Geomagnetic disturbances are accompanied by a decrease in heart rate
variability (4-6). We here assess cyclicity, with its uncertainties when possible, in the incidence of
aurorae in the 16th
, 17th
and earliest 18th
centuries (1545-1724) in central Europe, with focus upon
the Maunder minimum (from 1645 to 1715). During the second, but not the first half of this span,
95% confidence limits could be and were computed for each parameter separately, albeit not
conservatively, for a persisting circadecadal component, using the 1-parameter approach of
Marquardt's nonlinear algorithm (7).
Background. The yearly incidence of aurorae during the span 1545-1724 compiled by
Wilfried Schröder and Hans-Jürgen Treder (8) was analyzed by linear-nonlinear rhythmometry
with the extended cosinor (9-11; cf. 7). A global least-squares spectrum reveals several peaks,
among which one corresponding to about 11.4 years is not the most prominent. Of similar or larger
prominence are other peaks corresponding to periods of about 139-150, 72, 47, 29, and 23.4 years,
the latter close to a peak of about 22 years previously reported by Usoskin, Mursula and Kovaltsov
for sunspot activity (12-14), and of about 18.8, 12.7, 8.3, and 7.4 years, as well as to periods
shorter than 6 years, beyond our scope herein.
Methods. The question investigated is whether any relative prominence of an about 11-year
cycle, as reflected in observations of the northern lights, as an (only approximate) proxy for
sunspots, was present during the Maunder minimum (from 1645 to 1715) and, if so, whether any
of its characteristics were altered (8, 15, 16). Least squares spectra were computed from 35-year
intervals (corresponding roughly to the Brückner-Egeson-Lockyer cycle) pergressively moved by
increments of 5 years throughout the time series, the first interval spanning the years 1545-1579
and the last one spanning the years 1690-1724 (30 intervals, among which 8 occurred during the
Maunder minimum and 14 did not even partially cover the Maunder minimum). The trial periods
varied between 35 and 3.5 years, in harmonic progression with a harmonic increment of 0.2.
For each interval, results at a trial period of 10.5 years (anticipated best fitting period for
Zürich numbers (also called Wolf numbers, after Rudolf Wolf; available only after 1700) were
considered, namely the percentage rhythm (PR, i.e., the proportion of variance accounted for by
the fitted 10.5-year cosine model), the MESOR (M, midline estimating statistic of rhythm),
amplitude (A, half the extent of predictable change within one cycle), and relative amplitude
(expressed as % of MESOR). The period of the component accounting for the highest variance
among the trial periods in the least-squares spectra was determined for each interval, together with
its PR.
125
Using a trial period of 11 years, nonlinear analyses also determined the best-fitting period
with a measure of its uncertainty and that of its corresponding A, using Marquardt's algorithm (7).
95% confidence intervals were determined as 1-parameter limits and as conservative limits
(estimated jointly for all parameters).
Results. Results from both approaches are summarized in Table 1. The different endpoints from
linear rhythmometry were compared by Student t-test between intervals prior to (outside) or during
the Maunder minimum. Results need to be qualified by the fact that intervals were overlapping,
thereby failing to respect the assumption of independence.
Table 1: Circadecadal point estimates of auroral cycles' incidence before and during the Maunder
minimum*, with uncertainties**
Interval
Start End Period,
(years)
1-parameter**
(95% CI of )
Amplitude,
A (N/y)
(Conservative**
95% CI of A)
(1-parameter**
95% CI of A)
1545 1579 9.92 (8.09, 11.75) 1.72 (-0.40, 3.84) (0.41, 3.03)
1550 1584 9.18 (7.89, 10.46) 2.54 (0.06, 5.01) (1.00, 4.07)
1555 1589 9.36 (8.23, 10.49) 2.42 (0.19, 4.65) (1.04, 3.81)
1560 1594 8.28 (7.13, 9.44) 2.14 (0.13, 4.16) (0.89, 3.40)
1565 1599 9.54 (8.47, 10.61) 2.70 (0.62, 4.79) (1.41, 4.00)
1570 1604 10.79 (8.23, 13.36) 2.05 (-0.30, 4.39) (0.59, 3.50)
1575 1609 11.07 (8.76, 13.38) 2.03 (0.06, 4.00) (0.80, 3.26)
1580 1614 11.57 (9.59, 13.55) 2.23 (0.14, 4.32) (0.93, 3.53)
1585 1619 14.85 (11.15, 18.56) 1.39 (-0.18, 2.96) (0.42, 2.36)
1590 1624 10.66 (8.01, 13.31) 1.26 (-0.63, 3.15) (0.09, 2.43)
1595 1629 11.22 (8.03, 14.41) 1.31 NS
1600 1634 12.34 (6.79, 17.89) 1.01 NS
1605 1639 9.06 (5.51, 12.60) 0.83 NS
1610 1644 11.02 (0.62, 21.42) 0.50 NS
1615 1649 9.50 (4.81, 14.20) 0.75 NS
1620 1654 NS
1625 1659 12.00 (6.16, 17.85) 0.81 NS
1630 1664 11.02 (5.40, 16.65) 0.67 NS
1635 1669 12.11 (7.95, 16.27) 0.64 NS
1640 1674 17.22 (7.85, 26.59) 0.59 NS
1645 1679 7.40 (5.51, 9.29) 0.51 NS
1650 1684 9.15 (7.02, 11.27) 0.63 NS
1655 1689 10.24 (5.95, 14.53) 0.45 NS
1660 1694 10.66 (6.89, 14.44) 0.57 NS
1665 1699 9.91 (5.10, 14.72) 0.38 NS
1670 1704 12.71 (9.18, 16.24) 0.77 (-0.44, 1.99) (0.02, 1.53)
1675 1709 11.95 (8.42, 15.49) 1.42 (-0.85, 3.69) (0.00, 2.83)
1680 1714 12.04 (8.51, 15.56) 1.65 (-0.87, 4.17) (0.08, 3.21)
1685 1719 11.35 (9.11, 13.60) 2.99 (-0.59, 6.57) (0.77, 5.21)
1690 1724 13.10 (9.30, 16.91) 2.72 NS
*Trial period: 11 years; Interval: 35 years; Increment: 5 years; NS: not statistically significant. Note that the
last three spans during the Maunder minimum allow assessment of the uncertainty of the period estimate by
a 95% confidence interval of the amplitude which does not overlap zero (last 3 columns).
**One-parameter and conservative limits were computed according to Marquardt’s algorithm (7).
126
Whether intervals only partially covering the Maunder minimum are included or excluded in
the comparison, Student-t tests show that, as expected, the Maunder minimum is associated with a
smaller PR at a trial period of 10.5 years, and that both the MESOR and amplitude are smaller,
Table 2. Of interest, however, is the observation that there is no statistically significant difference
in the relative amplitude (underlined), Table 2. Moreover, among the trial periods in the leastsquares
spectra, the period of the component contributing most to the overall variance is shorter
during the Maunder minimum, Table 2. This is best seen for the frequency (1/period), which
follows a uniform distribution, whereas that of the period is long-tailed, Table 2. The difference in
PR at the best-fitting period between intervals prior to or during the Maunder minimum is much
smaller than that at the fixed 10.5-year period. Whereas the difference remains statistically
significant when intervals partially covering the Maunder minimum are excluded, it is not
statistically significant when all intervals are included, Table 2. Best-fitting periods corresponding
to the longest or shortest trial periods were excluded, as they indicated that a maximum could not
be reached within the window investigated.
Table 2: Comparison of results from linear rhythmometry outside and during the span from
1645-1715, the Maunder minimum*
Intervals compared
All intervals
(20 vs. 8)
Interval overlapping 1645-1715 excluded
(14 vs. 8)
Means Student t P Means Student t P
Endpoint Outside During Outside During
At trial period of 10.5 years
PR 11.5 5.3 1.767 0.088 15.1 5.3 2.857 0.010
M 3.37 1.93 6.495 <0.001 3.57 1.93 9.378 <0.001
A 1.17 0.58 2.150 0.040 1.37 0.58 3.284 0.004
A/M(%) 34.3 29.4 0.563 0.578 37.9 29.4 1.250 0.226
At trial period accounting for largest variance in least-squares spectra
Period (years) 13.6 6.51 2.046 0.051 15.2 6.51 2.571 0.018
Frequency (1/period) 0.112 0.198 -2.958 0.007 0.088 0.198 -4.495 <0.001
PR 27.7 23.6 1.487 0.149 30.6 23.6 2.964 0.008
*PR: Percentage Rhythm (proportion of variance accounted for by fitted model; %); M: MESOR (midlineestimating
statistic of rhythm; rhythm-adjusted mean); A: Amplitude: measure of half of extent of
predictable change within one cycle; M and A expressed as N of aurorae/year.
Discussion and Conclusion. By the criterion of Marquardt's 1-parameter 95% confidence
interval, the persistence of cycles during the second half of the Maunder minimum is documented
with the uncertainties involved, whereas only point estimates of the amplitude could be computed
during the first half of the Maunder minimum (cf. also 15). The results in Table 1, insofar as they
lend themselves as a proxy, must be viewed in the light of observation on sunspot activity
reporting that the change in the Maunder minimum was abrupt (12-14). Abruptness is indeed
suggested by our failure to compute a 95% confidence interval for the period around the start of
the Maunder minimum (1620-1654 interval). The loss of statistical significance for a Schwabe
cycle, gauged by the overlap of zero by the 95% confidence interval for the amplitude, however,
starts with the 1595-1629 interval, preceding the Maunder minimum. The aurorae, just like
geomagnetic fluctuations, may not necessarily be the best proxy for sunspot activity, but may be a
sensitive proxy. Other approaches based on sunspots are pertinent (12-14) and their report of an
abrupt change in the Maunder minimum is here confirmed, notwithstanding the prior loss of
statistical significance here reported before 1645, actually during a span including the Thirty Years
127
War, which devastated central Europe and thus did not allow for many observations. It would be
interesting to scrutinize any records of cardiovascular and other disease during vs. before and after
the Maunder minimum as another proxy for solar effects in the biosphere (17, 18).
1. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P, Bakken E,
International Womb-to-Tomb Chronome Initiative Group: Chronobiology in space. Keynote, 37th
Ann. Mtg. Japan Soc. for Aerospace and Environmental Medicine, Nagoya, Japan, Nov 8-9, 1991.
Univ of Minnesota/Medtronic Chronobiology Seminar Series, #1, Dec 1991, 21p. of text, 70 figures.
2. Villoresi G, Breus TK, Iucci N, Dorman LI, Rapoport SI. The influence of geophysical and social
effects on the incidences of clinically important pathologies (Moscow 1979-1981). Physica Medica
1994; 10: 79-91.
3. Roederer JG. Are magnetic storms hazardous to your health? Eos, Transactions, American
Geophysical Union 1995; 76: 441, 444-445.
4. Cornélissen G, Halberg F, Schwartzkopff O, Delmore P, Katinas G, Hunter D, Tarquini B, Tarquini
R, Perfetto F, Watanabe Y, Otsuka K. Chronomes, time structures, for chronobioengineering for "a
full life". Biomed Instrum Technol 1999; 33: 152-187.
5. Otsuka K, Cornélissen G, Weydahl A, Holmeslet B, Hansen TL, Shinagawa M, Kubo Y, Nishimura
Y, Omori K, Yano S, Halberg F. Geomagnetic disturbance associated with decrease in heart rate
variability in a subarctic area. Biomed & Pharmacother 2001; 55 (Suppl 1): 51s-56s.
6. Cornélissen G, Halberg F, Breus T, Syutkina EV, Baevsky R, Weydahl A, Watanabe Y, Otsuka K,
Siegelova J, Fiser B, Bakken EE. Non-photic solar associations of heart rate variability and
myocardial infarction. J Atmos Solar-Terr Phys 2002; 64: 707-720.
7. Marquardt DW. An algorithm for least-squares estimation of nonlinear parameters. J Soc Indust Appl
Math 1963; 11: 431-441.
8. Schröder W, Treder H-J. Note on the estimating the Sun's radiation output during the Maunder
Minimum and the problem of solar variability. Acta Geod Geophys Hung 2001; 36: 257-259.
Reprinted in Schröder W (Ed.). Case studies on the Spörer, Maunder and Dalton minima. (Beiträge
zur Geschichte der Geophysik und Kosmischen Physik, Band VI, Heft 4 [2005].)
Rönnebeck/Potsdam: AKGGP, Science Edition; 2005. p. 123-125.
9. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
10. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T, editors. Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
11. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Research 2007; 38 (4): 275-325. http://dx.doi.org/10.1080/09291010600903692
12. Usoskin IG, Mursula K, Kovaltsov GA. Cyclic behavior of sunspot activity during the Maunder
minimum. Astron Astrophys 2000; 354: L33-L36.
13. Usoskin IG, Mursula K, Kovaltsov GA. Heliospheric modulation of cosmic rays and solar activity
during the Maunder minimum. J Geophys Res 2001; 106: 16039-16046.
14. Kovaltsov GA, Usoskin IG, Mursula K. An upper limit on sunspot activity during the Maunder
minimum. Solar Physics 2004; 224: 95-101.
15. Eddy JA. The Maunder Minimum. Science 1976; 192: 1189-1202.
16. Schröder W (Ed.) Case studies on the Spörer, Maunder and Dalton minima. Beitrage zur Geschichte
der Geophysik und Kosmischen Physik, Band VI, Heft 4, 2005. 190 pp.
17. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F. BrücknerEgeson-Lockyer
(BEL) cycle in heliogeomagnetics. These proceedings.
18. Halberg F, Cornélissen G, Schwartzkopff O, Bakken EE. Cycles in the biosphere in the service of
solar-terrestrial physics? In: Schroeder W (Ed.) Case studies in physics and geophysics. Bremen:
Wilfried Schroeder/Science Edition, 2006, p. 39-87. [Beiträge zur Geophysik und Kosmischen
Physik/Journal for the History of Geophysics and Cosmical Physics, Special issue, 2006/2. ISSN
1615-2824]
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM 0021622402
128
On Gaps and Interpolation Methods to Avoid Errors in Period Estimation with
Conventional Time Series Analysis
Jerzy Czaplicki1
, Jarmila Siegelova, Bohumil Fiser, Germaine Cornélissen2
and Franz Halberg2
1
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
2
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA, Masaryk
University, Brno, Czech Republic
Abstract
While methods for time series analysis have been developed to deal with missing values in
equidistant time series and/or in altogether non-equidistant data, commonly available software
usually assumes data to be sampled at equal intervals. In the presence of gaps, data are
sometimes compressed to eliminate the gaps without adjusting the time scale. This procedure
leads to errors in period estimates and alterations of the actual frequency/time structure in
spectrograms. An obvious example consisting of a 7-day record of systolic blood pressure was
simulated. Gaps of 6 hours on 6 instances randomly distributed over the 7 days were introduced
and the resulting data analyzed in various ways. Several methods of interpolation are considered
to fill gaps, so that programs applicable only to equidistant data can be used. Results from a
linear prediction by singular value decomposition (LP-SVD) are presented, showing how in the
selected case, it can restore the actual time structure in conventional spectrograms. These results
are compared with those of least squares spectra and chronobiological serial sections that are
readily applicable to non-equidistant data.
Introduction
Spectrograms depict the time-frequency dependence of analyzed signals. Under usual
conditions, the locations of peaks correspond to frequencies present in the signal at given
instants in time. Unfortunately, input signals often present deficiencies, mostly associated with a
transitory absence of measurements (such as interruptions of self-measurements during sleep).
These gaps sometimes appear frequently for short time spans, or they can last for longer spans
on fewer occasions, for instance in association with instrument failure. When gaps are ignored
by compressing the data, the actual frequency/time structure is altered, leading to erroneous
period estimates. Some peaks shift in the frequency domain, some may be lost and others may
be spuriously generated. This leads to important errors in period estimations.
Accordingly, an analysis of data with gaps is far from straightforward. Least squares spectra can
bridge a few missing values, but as the gaps widen, there comes a point when artifacts
predominate because of insufficient information. As long as critical information is not lost,
interpolation methods may also be used to fill the gaps, thus allowing the data to be analyzed by
a large selection of conventionally available methods of time series analysis. In general,
discontinuous data produce spectra with parasitic oscillations of the sin(x)/x type, whose
amplitudes may be important enough to render any analysis useless. On the other hand, simple
interpolation schemes may fail to represent the characteristics of the signal. Instead, we have
opted for a variant of a linear prediction approach.
129
Interpolation methods
A number of methods permit the estimation of missing parts of a signal. Their common
characteristic is the analysis of the available signal to extract a set of coefficients, which best
describe the mutual interdependence of the measured points (in the least-squared sense). These
so-called auto-regressive techniques lead to several common algorithms, depending mostly on
the definition of the target error function, which is to be minimized. First, we have tried the
auto-correlation method [1]. It has the advantage of producing stable solutions, but makes an
assumption that the signal is zero outside the analyzed interval, and may produce important
undesirable end-point effects. Another formulation of this approach is the auto-covariance
method [2, 3], which works on signals extending beyond the analyzed intervals, but whose
solutions are not guaranteed to be stable. Indeed, in some cases our solutions were unacceptable,
because of large deviations of the predicted points from the general trends of the analyzed
signals. Another approach is the Burg’s algorithm [2, 4], which appeared in the context of
maximum entropy methods. It is stable and takes into account both forward and backward
prediction, but is known for introducing bias in frequency estimation and for splitting peaks into
several components, particularly for higher-order estimations. Thus far, the best results have
been obtained with the LP-SVD (linear prediction by singular value decomposition) method [5].
This technique is robust and worked well in all cases for which we have conducted tests.
In order to obtain a set of predicted points as close as possible to the signal from which they are
derived, we have adopted the following procedure. For each gap in the input data we analyze
two sets of points: the one directly preceding it and that which follows the gap. For the first set
we apply the LP-SVD method to calculate a forward prediction, covering the gap. Next, we
calculate the backward prediction for the second set of points. Ideally, they should produce two
identical sets of predictions. In practice, however, this is not the case. It is due to noise inherent
in the data, as well as to the finite length of the two data sets from which predictions are
obtained. Then, we combine the two predicted sets of points, by computing a weighted average,
based on the assumption that the further we stray from the end of valid data (i.e. to the right
from the end of the first data set and to the left from the beginning of the second data set), the
lower the probability that the prediction is correct. The end result is substituted back to the
original time series, and it is this full signal which is further transformed into a spectrogram.
Illustrative example
An example of the application of this approach is given in Figures 1-6. While the selected
illustrative example may appear obvious to some, it was purposely chosen to unmistakably show
that data compression, occasionally misused by some investigators, is not an option when the
time structure of a phenomenon needs to be assessed. Fig. 1 (top left) shows the original data, a
synthetic signal with noise, consisting of 168 points, representing a signal with a period of 24
hours, sampled once an hour for seven consecutive days. The simulated signal has a mean value
of 120 mmHg, a circadian amplitude of 20 mmHg and an acrophase of -270° (18:00). Noise
consists of uniformly distributed random numbers in the range of -5 to +5 mmHg. Data were
removed over 6 intervals, each covering 6 hours. Fig. 1 (middle left) shows the series with gaps.
Fig. 1 (bottom left) shows the series resulting from considering all available data as being
continuous, as if there were no gaps, an approach that is tempting but intuitively unreasonable.
Fig. 1 (right) illustrates the corresponding least squares spectra. A spectral peak at 24 hours is
readily apparent for the original series (top right). Very similar results are obtained for the series
with gaps, the only difference being a slightly higher noise level that in some cases could be
misinterpreted as small peaks (middle right). A clear shift in frequency occurs, however, when
gaps are ignored and data are considered to be continuous (bottom right), validating the
130
prediction from intuition. Indeed, instead of having 7 peaks in 168 hours, corresponding to a
period of 168/7 = 24 hours, the compressed series consists of 7 peaks in 168 – 6x6 = 132 hours,
corresponding to a period of 132/7 = 18.9 hours.
Fig. 2 is obtained by fitting a 24-hour cosine curve by least squares to data in a 24-hour interval
displaced throughout the time series by 1 hour. This procedure is known as a chronobiologic (or
chronomic) serial section based on the least squares fit of cosine function(s) [6-8]. The data from
Fig. 1 are shown again in the top row. In the second row, the lower curve represents the MESOR
(midline estimating statistic of rhythm, a rhythm-adjusted mean value), and the distance between
the two curves corresponds to the 24-hour amplitude of the signal, plotted at the midpoint of the
24-hour interval considered for analysis. The 24-hour acrophase (phase of the maximum) is
plotted in the third row. The P-value from the zero-amplitude (no-rhythm) test is shown in the
fourth row and the number of data per interval is plotted in the fifth row. It can be seen that for
the original data series (left), the number of data is constant, that the MESOR, 24-hour
amplitude and acrophase assume similar values throughout the time series, and that the circadian
rhythm is invariably statistically significant. In the presence of gaps (middle), the number of
data per interval changes as a function of time, but affects only slightly the estimates of the
MESOR and 24-hour amplitude and acrophase, statistical significance being invariably reached
as well. But when the data are compressed by ignoring the gaps (right), large variations in the
MESOR and 24-hour amplitude are observed as a function of time, and the 24-hour acrophase is
steadily drifting to earlier and earlier times, in keeping with the shift to a higher frequency (or
shorter period), as seen in the least squares spectrum (Fig. 1, bottom right).
Fig.3 shows the spectrogram of the original data without gaps. Basically, spectrograms are
Fourier transforms of a product of original data and a window function, which moves in time.
The window length is adjustable and affects the time and frequency resolutions. Herein, the
frequency resolution was maximized by setting the window length to the number of data N (N/2
at both ends of the time series). In the LP-SVD algorithm, 1/3 of the number of points used to
predict data was used as number of coefficients.
In Fig. 3, the dashed black horizontal line marks the 24-hour “target” period. Fig. 4 shows the
same spectrogram, obtained on data with 6 gaps, eliminated by compressing the remaining data
points. One can see a large shift in frequency, appearing now at 19.25 hours. An attempt to
obtain a spectrogram from a fragment of data, consisting of continuously sampled points, for a
short time between gaps, leads to Fig. 5. The significant width of the frequency profile is due to
the very small number of available points. Fig. 6 shows the spectrogram of data, where gaps
were replaced with points, obtained from predictions, as described above. As can be seen, we
have recovered the correct period of 24 hours. Results in Fig. 6 do not relate to the original data
but to a series that has been modified to fill the gaps by the LP-SVD algorithm. Hence, it does
not reflect the greater uncertainty of the location of the spectral peak by spreading out of the
contours at times when original data are missing, a task for future work. The satisfactory result
in Fig. 6 does not guarantee that the method will work in all cases. We are working on
modifications, aimed at improving this approach by introducing different statistical weights due
to differences in lengths of the data segments used in forward/backward predictions.
Discussion
The LP-SVD algorithm is not the only approach available to fill gaps. An alternative approach
suggested by Professor Christopher Bingham consists of computing a spectrum from an
autoregressive operator computed from an autocorrelation function computed from the nonmissing
data, yielding a very sharp peak near a frequency of 1/24 hours with an order of the
131
autoregressive operator of 15. With missing data, however, the autocorrelation function is often
not positive definite, in which case there is a somewhat artificial limit on the order of the
autoregression. Such a least squares approach may not be far removed in spirit from the LPSVD
algorithm, which attempts to filter out some of the noise in the predictors in the
autoregression, so as to come closer to the autoregressive relationship that the underlying mean
function is assumed to have.
Self-measurements may be missed during sleep and instrument failure may be responsible for
gaps, for instance in physiological data collected by ambulatory monitors or in physical data
recorded by satellites. It seems important to include, as blanks, in each analysis of a given time
series also analyses of a set of (say 100) noise series generated to simulate the characteristics of
the actual data in terms of sampling and noise, which may be colored rather than white. Just as
in the development of laboratory techniques, there invariably were blanks and standards, the
same precautions should apply in chronobiology and chronomics. Standards could consist of
comparing results from several approaches on complete reference time series analyzed as such
or after removing data to match the sampling of the actual time series under study, to see
whether the time structure is at all altered by the presence of gaps, and, if so, to what extent.
Spectrograms provide a global view of the time-frequency dependencies in analyzed signals.
Since our attention herein was focused on periods, the subsequent optimizations concern the
frequency resolution, at the expense of the time dimension. Consequently, exact time instants at
which frequencies change are blurred. For this reason, it is beneficial to compare the results
obtained from spectrograms with those coming from several different approaches, such as
chronomic serial sections and gliding or global least square spectra. The combination of results
from several sources can only be beneficial for the understanding of the studied phenomena.
It should also be stressed that whatever the method used to fill gaps, the assumption is made that
data that would have been collected during gaps carry no new information. If this is not the case,
results will be misleading, as will those obtained with methods based on least squares. Extreme
caution is thus to be used whenever gaps are not reasonably few and far apart.
Conclusion
The best validation of a periodicity detected in a time series that has a transdisciplinary
counterpart record is to compare their time/frequency behavior, e.g., by spectrograms and by
chronomic serial sections that provide for a specific spectral component uncertainties for each
parameter (MESOR, amplitude, and acrophase). Notably when dealing with wobbly signals with
characteristics such as period, amplitude and/or phase that change as a function of time, it is then
possible to assess by a remove-and-replace approach [9, 10] whether the changes in the time
series of interest coincide with or are congruent with those of the counterpart series, serving as
reference.
References:
1. M.H. Hayes, “Statistical Digital Signal Processing and Modeling”, J. Wiley & Sons, Inc.,
New York, 1996.
2. S. Kay, “Modern Spectral Estimation”, Prentice Hall, 1988.
3. P. Stoica and R. Moses, “Introduction to Spectral Analysis”, Prentice Hall, 1997.
4. S. Orfanidis, “Optimum Signal Processing”, 2nd
ed., Macmillan, 1988.
132
5. W.H. Press, S.A. Teukolsky, W.T. Vetterling and B.P. Flannery, “Numerical Recipes in
Fortran”, 2nd
ed., Cambridge University Press, 1992.
6. Halberg F, Engeli M, Hamburger C, Hillman D. Spectral resolution of low-frequency, smallamplitude
rhythms in excreted 17-ketosteroid; probable androgen induced circaseptan
desychronization. Acta endocrinol (Kbh) 1965; 50 (Suppl 103): 5-54.
7. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
8. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (eds.) Encyclopedia of
Biostatistics, 2nd
ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
9. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
10. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
Acknowledgements: The kind and critical comments of Professor Christopher Bingham are
gratefully incorporated in this note within the confines of the authors’
competence.
Support : GM-13981 (FH), University of Minnesota Supercomputing Institute, MSM
0021622402.
133
Legends to figures
Figure 1. Test series here illustrated for noninvasive cardiology by systolic blood pressure (left):
original equidistant data (top), with six 6-hour gaps randomly distributed (middle), and after
elimination of gaps by compression (bottom). Corresponding least squares spectra (right) are
characterized by a 24-hour spectral peak as long as the original time scale is preserved, in the
absence (top) or presence (middle) of gaps, but with a peak spuriously shifted toward a
shorter period of about 18.7 hours (bottom). In this obvious illustrative example, the
erroneous period estimate can be derived intuitively from the chronogram showing 7 cycles
in 168 – 6x6 = 132 hours, corresponding to a period of 132/7 = 18.9 hours, close to the
spectral peak when only integer harmonics are assessed.
Figure 2. Chronobiologic-chronomic serial sections of the original data without gaps (left), with
gaps (middle), and after compression of the gaps (right). The spuriously shorter period
detected in the latter case is evidenced by the downward drift of the 24-hour acrophase to
earlier and earlier times. The acrophase (phase of the maximum of the 24-hour cosine fitted
by least squares to data in a 24-hour interval displaced by 1 hour throughout the time series)
is expressed in (negative) degrees, with 360° 24 hours, and 0° set to 00:00).
Figure 3. Spectrogram of original data (no gaps). The horizontal dashed black line at 24 hours
represents the “target” period of the simulated signal. The outer contours correspond to the
bandwidth of the detected component, with narrower and narrower contours associated with
the increasing strength of the signal best detected in the middle of the time series, when the
short-term Fourier transform is using all data available for analysis. Results closer to the start
or the end of the data series only use partial data, a fact also accounting for the larger
bandwidth as compared to that at the middle of the time series.
Figure 4. Spectrogram of data with gaps that have been compressed. A shift in frequency is
clearly observed, the signal’s period estimate being well shorter than the “target” of 24 hours,
represented by the horizontal dashed line.
Figure 5. Spectrogram of partial data (second fragment covering the span from the 15th
to the
34th
hour). Whereas the estimated period is close to the target of 24 hours, the frequency
resolution is much poorer, as evidenced by the much broader bandwidth, in keeping with the
much shorter length of the series used for analysis (only 20 hours).
Figure 6. Spectrogram of data with gaps filled by means of a linear prediction by singular value
decomposition (LP-SVD) algorithm. In the case examined, the signal is sufficiently well
restored to allow the detection of a 24-hour signal similar to that found in the original data
without gaps (see Fig. 3). Results do not convey the loss of information in relation to missing
values that should then be associated with a greater uncertainty of the location of the spectral
peak, as reflected by a spreading out of the contours.
134
Figure 1
Figure 2
135
Figure 3
Figure 4
136
Figure 5
Figure 6
137
Ambulatory profile in a non-ambulatory subject: a sphygmochron with gaps (when we should
measure again, not interpolate)
Harald Hörmann1
, Jarmila Siegelova, Bohumil Fiser, Germaine Cornélissen2
, Franz Halberg2
1
Medizinische Universität Innsbruck, Innsbruck, Austria
2
University of Minnesota, Minneapolis, MN, USA
Aim. To document that non-ambulatory individuals can obtain a monitoring profile over time
for a computer comparison with peer group limits, a sphygmochron, while pursuing a very active
life.
Background. Elsewhere in these proceedings, we indicate different methods for interpolation
when there are gaps in the data and the dangers arising from compressing the data when they are
included for an assessment of their time structure. Here in turn we summarize the data with large
unintended gaps occurring for technical reasons and this handicap notwithstanding, briefly indicate
the usefulness of the results for a preliminary assessment by sphygmochron.
Subject. HH, a male adult professional 46 years of age, uses a wheelchair for mobility. On
August 6th, 1991, due to a strong impact on his spine after a bicycle downhill accident, he was
diagnosed as paraplegic with a complete lesion at TH 4-6, accompanied by a haematopneumothorax
and several lesions in higher segments of the spine up to C1 without any functional restrictions
following these. The diagnosis can be compressed to complete paraplegia at TH4-6 and is up to date
until present. Functional restrictions of inner organs are within the typical restrictions for complete
paraplegia resulting from injury of higher segments of the thoracic spine. HH carried the TM-2430
ambulatory blood pressure and heart rate monitor manufactured by A&D (Tokyo, Japan) during a
visit in Minnesota in July 2008 and resumed monitoring with interruptions upon his return to
Innsbruck in August 2008.
Circadian Pattern of SBP
(HHoe001a, M, 46y)
70
80
90
100
110
120
130
140
150
160
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
SBP(mmHg)
Figure 1. Plexogram (a term used for
stacking data over an idealized day, as
done here at half-hour intervals for 24
hours, or along any other time scale) shows
acceptability of systolic (S) BP values of
HH, a male professional with paraplegia
using a wheelchair for mobility, while
active in his chosen health-related
profession revealing changes along the 24hour
scale, here confounded by
transmeridian dyschronism, since the
subject was monitoring after a flight from
Austria to Minnesota and after a return
flight. © Halberg.
138
Circadian Pattern of DBP
(HHoe001a, M, 46y)
40
50
60
70
80
90
100
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
DBP(mmHg)
Figure 2. Acceptability of diastolic (D) BP
of HH, revealing, as does Figure 1, an updown
pattern that can be tested for
circadian rhythmicity. © Halberg.
Circadian Pattern of HR
(HHoe001a, M, 46y)
30
40
50
60
70
80
90
100
110
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
HR(beats/min)
Figure 3. Acceptability of HR of HH
showing variability from well below 60
beats/min to nearly 100 beats/min. ©
Halberg.
139
Name:--------------------- Patient #: HHoe001a
Age: 46 Sex: M
To:
Patient Peer Group Patient Peer Group Patient Peer Group
Value Reference Value Reference Value Reference
Limits Limits Limits
Range Range Range
Range Range Range
Range Range Range
(hr:min) (hr:min) (hr:min)
(mmHg x hour) (mmHg x hour) (mmHg x hour)
(mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units)
Individualized bounded indices: (STD = Standard)(Min = Minimum)(Max = Maximum)(HBI = Hyperbanic Index)
INTERVENTION NEEDED MORE MONITORING NEEDED
No Annually
Yes Drug Non-Drug As soon as possible
Other specify_________________________
Prepared By_________________________________________ Date____/____/________
1) Unusually long standing or lying down during waking: unusual activity, such as exercise, emotional
loads, or schedule changes, e.g. shiftwork; etc.; 2) Salt, calories, kind and amount, other, etc.
Copyright, Halberg Chronobiology Center, University of Minnesota, Mayo Hospital, Rooms 715,
733-5 (7th floor), Minneapolis Campus, Del Code 8609, 420 Deleware Street SE,
Minneapolis, MN 55455, USA. Fax 612-624-9989.
For questions, call F. Halberg or G. Cornelissen at 612-624-6976.
SPHYGMOCHRON-TM Monitoring Profile over Time;
Computer Comparison with Peer Group Limits
Blood Pressure (BP) and Related Cardiovascular Summary.
(DOUBLE AMPLITUDE)
TIMING OF OVERALL
Monitoring From:
Comments:
CHRONOBIOLOGIC CHARACTERISTICS
ADJUSTED 24-h MEAN
28 07 2008 22:30
HIGH VALUES
(ACROPHASE) (hr:min)
SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg)
16.74 6.4-39.40 11.82 4.84-29.80
(MESOR)
PREDICTABLE CHANGE
HEART RATE (bpm)
113.5 98.4-135.1 64.4 60.3-87.2 76.2 56.4-91.2
19.44 5.26-36.20
15:59 11:48-17:40 16:18 11:08-16:48 15:03 11:44-17:20
DURING 24 HOURS
HBI*
10-YEAR CUMULATIVE
PERCENT TIME
OF ELEVATION
TIMING OF
EXCESS 00:00 00:00 00:00
EXTENT OF EXCESS
0 0 0EXCESS
09 08 2008 17:01
0 0 0
STD (MIN; MAX)* STD (MIN; MAX)* STD (MIN; MAX)*
0.0% 0.0% 0.0%
Figure 4. Sphygmochron consisting of an upper parametric and a lower non-parametric part
indicating absence of any chronobiologically detectable abnormality. © Halberg.
140
Timeplot of oscillometric readings of HHoe001a
40
60
80
100
120
140
160
7/28/08 7/30/08 8/1/08 8/3/08 8/5/08 8/7/08 8/9/08 8/11/08
Time (calendar date)
BloodPressure(mmHg)
0
20
40
60
80
100
120
140
160
HeartRate(beats/min)
SBP
DBP
HR
Figure 5. Dense record around July 30 in Minnesota and interrupted record in August in
Innsbruck. © Halberg.
Results. When non-parametrically his circadian pattern is demonstrated by stacking data from
different days at the same intended 48-hour timepoints, 30 min apart, of an idealized day, we obtain
the curve in Figure 1, in which continuous lines show the limits of acceptability for systolic (S) BP,
derived from clinically healthy peers matched by gender and age (1-3). We find that with the
exception of one measurement, all SBP mean values are within these limits for HH. Figure 2
presents corresponding data on HH's diastolic (D) BP which again, with just 5 exceptions (vs. 43
acceptable values), is within the peer group limits. Figure 3 shows the acceptability of all but one
HR mean out of 48. A summary for different days is shown for each of these three variables and
from three other derived variables in Table 1, which shows the great variability of mean values from
day to day for SBP from 106 to 123 mm Hg.
Figure 4 shows a summary by sphygmochron. All parametric endpoints also show
acceptability insofar as for the three variables summarized, the values are all within also-shown
acceptable limits. We do not recommend the pattern of measurements that underlies this
sphygmochron based on original data displayed in Figure 5. We do wish to emphasize that even a
very severely handicapped professional can use the instrumentation and that, gaps notwithstanding,
a tentative diagnosis of an acceptable BP can be postulated which in our experience, rather than
being filled in by computations, is best complemented by an uninterrupted long record to look for
infradian as well as circadian endpoints.
141
Table 1: Means, their ratios, and standard deviations of 6 vascular variables investigated
Wakeup Time = 7:00 Bed Time = 23:00
Begin Day Time = 10:00 End Day Time = 20:00
Begin Night Time = 0:00 End Night Time = 6:00
Systolic Blood Pressure (SBP)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 109.37 15.91 18 111.78 9.55 13 98.77 8.23 11.89
2 45 113.56 21.47 19 126.74 19.95 12 95.67 15.27 27.36
3 55 122.58 17.46 29 124.14 15.66 12 116.50 17.15 6.23
4 49 106.06 12.53 12 103.42 4.96 6 117.83 11.16 -13.59
5 18 109.56 14.78 5 123.60 14.57 12 104.67 11.52 17.28
6 3 116.67 8.08 1 126.00 0.00 1 112.00 0.00 12.00
Overall 213 113.02 17.77 84 119.11 16.50 56 105.45 15.29 12.09
Diastolic Blood Pressure (DBP)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 60.88 11.99 18 62.72 5.93 13 52.92 3.84 16.09
2 45 65.69 14.98 19 73.00 14.09 12 56.33 17.27 25.37
3 55 69.24 12.52 29 71.83 12.31 12 60.50 10.26 16.36
4 49 59.06 9.10 12 60.17 6.00 6 69.33 9.69 -15.52
5 18 63.11 11.89 5 72.40 14.67 12 60.50 8.52 18.86
6 3 68.67 4.16 1 70.00 0.00 1 72.00 0.00 -2.91
Overall 213 63.93 12.69 84 68.49 11.97 56 59.00 11.53 14.84
Heart Rate (HR)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 72.47 16.80 18 84.44 12.30 13 55.08 4.97 40.53
2 45 79.49 21.27 19 84.00 19.93 12 68.75 17.19 19.19
3 55 77.11 14.43 29 81.14 14.46 12 71.17 11.52 12.93
4 49 72.88 16.32 12 81.33 17.96 6 82.83 9.60 -2.06
5 18 74.17 13.05 5 80.80 15.59 12 71.50 12.12 12.54
6 3 73.00 2.00 1 71.00 0.00 1 75.00 0.00 -5.48
Overall 213 75.39 16.87 84 82.38 15.68 56 68.30 14.07 18.67
Mean Arterial Pressure (MAP)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 77.05 12.41 18 79.07 6.57 13 68.21 5.03 14.11
2 45 81.64 15.58 19 90.91 13.39 12 69.44 15.41 26.29
3 55 87.02 12.86 29 89.26 11.99 12 79.17 10.58 11.60
4 49 74.73 8.69 12 74.58 5.09 6 85.50 9.35 -14.61
5 18 78.59 11.87 5 89.47 14.46 12 75.22 7.61 18.12
6 3 84.67 4.37 1 88.67 0.00 1 85.33 0.00 3.94
Overall 213 80.30 13.17 84 85.36 12.19 56 74.48 11.41 13.55
142
Pulse Pressure (PP)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 48.49 10.87 18 49.06 6.91 13 45.85 5.64 6.62
2 45 47.87 16.49 19 53.74 19.64 12 39.33 13.26 30.09
3 55 53.35 13.52 29 52.31 13.27 12 56.00 15.93 -6.92
4 49 47.00 12.01 12 43.25 5.33 6 48.50 8.64 -11.17
5 18 46.44 10.84 5 51.20 4.82 12 44.17 12.49 15.14
6 3 48.00 8.00 1 56.00 0.00 1 40.00 0.00 33.33
Overall 213 49.09 13.26 84 50.62 13.02 56 46.45 12.81 8.50
Double Product (DP)
Day 24-Hour Day Time Night Time DNR%
N Mean StDev N Mean StDev N Mean StDev
1 43 79.50 22.43 18 93.99 13.41 13 54.35 6.37 49.86
2 45 89.90 26.73 19 103.61 15.61 12 65.95 20.24 41.89
3 55 93.99 19.93 29 100.22 19.14 12 82.44 15.99 18.92
4 49 77.67 20.81 12 84.33 19.82 6 97.74 15.64 -17.27
5 18 80.88 15.79 5 98.49 11.71 12 74.31 11.80 29.90
6 3 85.07 3.96 1 89.46 0.00 1 84.00 0.00 6.42
Overall 213 85.21 22.66 84 97.15 17.65 56 72.31 19.32 29.15
Discussion. The data and the analyses reveal that an active paraplegic can wear the cuff with
the monitor during daily activities and during sleep at night. While for the first number of days of
monitoring he noticed a reduction in the quality of sleep, he did remark that while active yet sitting,
without having to move the wheelchair around, the measurement is not much of a burden. Again,
one must not generalize from an exceptionally active and strong individual. It can be anticipated,
however, that in the foreseeable future there will be a further simplification of the instrumentation
needed for automatic ambulatory chronobiologically interpreted BP and HR monitoring. With such
affordable instrumentation, medicine will change in keeping with an extended view (4, 5). The
current view of health care is based on spotchecks in health care offices. An extended view will
prevent us from flying blind by providing a view of variability and of any rules in that variability
that reflect life as it may have evolved from the big bang, as a small part of the concomitantly
evolving cosmos. In the health care of individuals, the view will be extended by a positive definition
of health replacing health defined as the absence of disease. The endpoints from continued
monitoring will be dynamic; already today they can detect prediabetes, prehypertension and a
premetabolic syndrome (3, 6, 7). By the introduction of a sphygmochron in elementary and
secondary education (8), their discussion for medical students will then become superfluous and will
be replaced by analyses far beyond the sphygmochron here illustrated.
Conclusion. A severely handicapped professional using chronobiologically interpreted BP
monitoring, can manage to use the current available instrumentation (e.g., from A&D) to evaluate
greatly changing variables automatically, even though he is restricted to a wheelchair. Such
monitoring as a sine qua non extends the view and practice of health care by computer aided selfhelp,
as an aspect of social medicine.
143
References
1. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber M,
Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Peña S,
Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N, Borer K,
Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7-day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical Instrumentation &
Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
2. Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka K, Watanabe Y, Kumagai Y,
Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff O. Circadian HyperAmplitude-Tension,
CHAT: a disease risk syndrome of anti-aging medicine. J Anti-Aging
Med 1998; 1: 239-259. (Editor's Note by Fossel M, p. 239.)
3. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual and
proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64.
4. Kofler WW. Progress in development of a comprehensive theory of a human person as a social
being. Science without Borders, Transactions of the International Academy of Science H&E,
2003/2004; 1: 10-15.
5. Kofler WW. The need on a "critical extended evolution related view" of reality as a basis for
an "extended view" of health. Science without Borders, Transactions of the International
Academy of Science H&E, 2003/2004; 1: 27-54.
6. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
7. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633.
doi:10:1038/jhh.2008.32.
8. Halberg F, Smith HN, Cornélissen G, Delmore P, Schwartzkopff O, International BIOCOS
Group. Hurdles to asepsis, universal literacy, and chronobiology—all to be overcome.
Neuroendocrinol Lett 2000; 21: 145-160.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
144
C-ABPM reveals solar cis-halfyear and transyear signatures in human diastolic blood
pressure
George S. Katinas1
, Franz Halberg1
, Germaine Cornélissen1
, Salvador Sanchez de la Peña2
, Jerzy
Czaplicki3
, Jarmila Siegelova4
and the BIOCOS project
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
2
Chronomic Res. Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City, Mexico
3
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
4
Masaryk University, Brno, Czech Republic
Aim. To seek in human diastolic (D) blood pressure (BP) a theoretically predicted solar beat
period (1) which was amply documented in physics (2-11) and in biomedicine (12-20).
Subject, method and background. GSK, a physician-scientist, 72 years of age at the start of
automatic, chronobiologically interpreted ambulatory BP monitoring (C-ABPM) with few gaps
around the clock for >10 years (from March 31, 1998, to June 29, 2007), used a TM-2421
instrument from A&D (Tokyo, Japan). Analyses were by extended cosinor that had already
revealed the cis-half-year in sudden cardiac death in some but not in all geographic regions tested
(12-14). Earlier studies had also revealed spectral components with a period, , longer than a
calendar year, dubbed transyears (12-20).
Results. In the spectral window of data of GSK, now covering a decade, a predicted ~0.422year
component was a peak, as were a far-transyear of 1.202-year length and a near-transyear.
Discussion. Several medical scientists and opinion leaders have self-measured their BP
systematically a sufficient number of times a day for chronomic (time structural) analyses, from
the time of encountering chronobiology until their death (21, 22); they set an example for others
who also may not wish to base treatment on single spotchecks in a health care office. Cosinorinterpreted
self-measurements, advocated by many long ago (23), while helpful and currently
gaining access into practice, were not readily feasible, however, without a noteworthy interruption
of activities during waking and (what matters more) disturbance of sleep (24). New, relatively
unobtrusive instrumentation now makes C-ABPM possible and cost-effective and will save lives.
Illustrative results and problems encountered in as-one-goes self-surveys, among others (25), by
GSK (26) have been published. GSK's thorough record also revealed that both MESORhypertension
and CHAT (circadian hyper-amplitude-tension) can be intermittent conditions even
under treatment, and treatment is best adjusted based on monitoring, rather than "flying blind"
(27). Since an ~0.42-year and a transyear had been predicted based on theory about beat periods of
solar rotations (1), and had been found not only in solar-terrestrial physics but also in biology, we
anticipated such a period, and indeed found it in GSK.
Conclusion. Monitoring blood pressure and heart rate for health care can also serve
transdisciplinary science, seeking signatures of the sun's activity in the biosphere.
1. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
2. Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day periodicity in
the occurrence of hard solar flares? Nature 1984; 312: 623-625.
3. Bogart RS, Bai T. Confirmation of a 152-day periodicity in the occurrence of solar flares
inferred from microwave data. Astrophys J 1985; 299: L51-L55.
4. Bai T, Cliver EW. A 154 day periodicity in the occurrence rate of photon flares. Astrophys J
1990; 363: 299-309.
145
5. Bai T, Sturrock PA. Evidence for a fundamental period of the sun and its relation to the 154
day complex of periodicities. Astrophys J 1993; 409: 476-486.
6. Kile JN, Cliver EW. A search for the 154 day periodicity in the occurrence rate of solar
flares using Ottawa 2.8 GHz burst data, 1955-1990. Astrophys J 1991; 370: 442-448.
7. Oliver R, Ballester JL. Short-term periodicities in sunspot areas during solar cycle 22. Solar
Physics 1995; 156: 145-155.
8. Carbonell M, Ballester JL. The periodic behaviour of solar activity: the near 155-day
periodicity in sunspot areas. Astron Astrophys 1992; 255: 350-362.
9. Kiplinger AL, Dennis BR, Orwig LE. Detection of a 158-day periodicity in the solar hard Xray
flare rate. Bull Am Astronom Soc 1984; 16: 891.
10. Ballester JL, Oliver R, Carbonell M. The near 160 day periodicity in the photospheric
magnetic flux. Astrophys J 2002; 566: 505-511.
11. Ballester JL, Oliver R, Carbonell M. Return of the near 160 day periodicity in the
photospheric magnetic flux during solar cycle 23. Astrophys J 2004; 615: L173-L176.
12. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
13. Cornélissen G, Schnaiter D, Halberg F, Mitsutake G, Otsuka K, Fiser B, Siegelova J, Jozsa
R, Olah A, Bakken EE, Chibisov S (presenter). A cis-half-year characterizes the incidence of
sudden cardiac death also in and near Austria. In: Proceedings, International Symposium,
Problems of ecological and physiological adaptation, People's Friendship University of
Russia, Moscow, 30-31 Jan 2007. Moscow: People's Friendship University of Russia; 2007.
p. 545-551. Cf. also p. 542-545.
14. Hamamatsu A, Cornélissen G, Otsuka Ku, Halberg F, Chibisov S (presenter). Linearnonlinear
rhythmometry documents a transyear and a cishalfyear in sudden cardiac death
(ICD 10, code I46.1) in Tokyo. In: Proceedings, International Symposium, Problems of
ecological and physiological adaptation, People's Friendship University of Russia, Moscow,
30-31 Jan 2007. Moscow: People's Friendship University of Russia; 2007. p. 542-545.
15. Cornélissen G, Masalov A, Halberg F, Richardson JD, Katinas GS, Sothern RB, Watanabe
Y, Syutkina EV, Wendt HW, Bakken EE, Romanov Y. Multiple resonances among time
structures, chronomes, around and in us. Is an about 1.3-year periodicity in solar wind built
into the human cardiovascular chronome? Human Physiology 2004; 30 (2): 86-92.
16. Cornélissen G, Halberg F, Rostagno C, Otsuka K. A chronomic approach to cardiac
arrhythmia and sudden cardiac death. The Autonomic Nervous System 2007; 44: 251-254.
17. Mikulecky M, Florida PL. Daily birth numbers in Davao, Philippines, 1993-2003: Halberg's
transyear stronger than year. Abstract, 26th Seminar, Man in His Terrestrial and Cosmic
Environment, Upice, Czech Republic, May 17-19, 2005.
18. Mikulecky M. Reanalyza natality v jizni brazilii -- opet dominuje Halbergova parasezonalita:
International Conference on the Frontiers of Biomedical Science: Chronobiology, Chengdu,
China, September 24-26, 2006, p. 188-193.
19. Kovac M, Mikulecky M. Secular rhythms and Halberg's paraseasonality in the time
occurrence of cerebral stroke. Bratisl Lek Listy 2005; 106 (2): 423-427.
146
20. Kovac M, Mikulecky M. Time sequence of epileptic attacks from the point of view of
possible lunisolar connections. International Conference on the Frontiers of Biomedical
Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 175-179.
21. Levine H, Halberg F. Circadian rhythms of the circulatory system. Literature review.
Computerized case study of transmeridian flight and medication effects on a mildly
hypertensive subject. U.S. Air Force Report SAM-TR-72-3. Brooks AFB, Texas: USAF
School of Aerospace Medicine, Aerospace Medical Division (AFSC); April 1972. 64 pp.
22. Bartter FC, Delea CS, Baker W, Halberg F, Lee JK. Chronobiology in the diagnosis and
treatment of mesor-hypertension. Chronobiologia 1976; 3: 199-213.
23. Halberg F, Johnson EA, Nelson W, Runge W, Sothern R. Autorhythmometry—procedures
for physiologic self-measurements and their analysis. Physiol Tchr 1972; 1: 1-11.
24. Stinson SM, Cornélissen G, Scarpelli PT, Halberg F. Self-measurement and ambulatory
monitoring of blood pressure: a subject's chronobiological perspective. Biomed &
Pharmacother 2002; 56 (Suppl 2): 333s-338s.
25. Halberg F, Cornélissen G, Schack B, Wendt HW, Minne H, Sothern RB, Watanabe Y,
Katinas G, Otsuka K, Bakken EE. Blood pressure self-surveillance for health also reflects
1.3-year Richardson solar wind variation: spin-off from chronomics. Biomed &
Pharmacother 2003; 57 (Suppl 1): 58s-76s.
26. Katinas GS, Cornélissen G, Otsuka K, Haus E, Bakken EE, Halberg F. Why continued
surveillance? Intermittent blood pressure and heart rate abnormality under treatment. Biomed
& Pharmacother 2005; 59 (Suppl 1): S141-S151.
27. Fossel M. Editor's Note (to Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka
K, Watanabe Y, Kumagai Y, Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff
O. Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging
medicine. J Anti-Aging Med 1998; 1: 239-259). J Anti-Aging Med 1998; 1: 239.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
147
Pain and the cardiovascular system revisited in a long-term monitoring
George S. Katinas1
, Germaine Cornélissen1
, Franz Halberg1
, Salvador Sanchez de la Peña2
, Jerzy
Czaplicki3
, Jarmila Siegelova4
and the greater BIOCOS project
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Chronomic Res. Center, Escuela Nacional de Medicina y Homeopatía-IPN, Mexico City, Mexico
3
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
4
Masaryk University, Brno, Czech Republic
We report a perhaps individualized threshold in pain-associated systolic (S) and diastolic (D)
blood pressure (BP) elevation and the lack of a corresponding increase, instead a decrease in heart
rate (HR) in the case of an elderly man (GSK) with MESOR-hypertension (1). He used the TM-
2421 ambulatory monitor manufactured by A&D (Tokyo, Japan), recording BP and HR at halfhour
intervals around the clock with very few interruptions, by now for over 10 years, so that an
unusually thorough objective assessment is possible. The data in Figures 1-3 show first a gradual
and an abrupt increase in pain, quantified as-one-goes along a scale of 1-10 and an apparently
differing response of BP and HR. A threshold for BP elevation with pain is apparent in GSK for
BP and HR. HR may respond with a lowering rather than an increase. The responses to pain are
abrupt, but subside in response to physical therapy. A BP decrease with a lowering of pain is seen
for SBP and DBP and an increase for HR. Conceivably, BP monitoring during painful procedures
may provide an objective measure of response, and may deserve further testing in gauging the
extent of physical intervention and the response to physical and other therapy on groups, even
when such studies are noted for the given individual, in case the macroscopic changes described
herein await further quantification by parameter tests (2) and cumulative sum control charts (3).
Figure 1. Gradual increase in pain is not
associated with an increase in blood pressure
(BP) up to an abrupt pain increase associated
with an abrupt increase in systolic (S) BP which
quickly responds to a lowering of pain by return
of SBP to pre-pain values, in response to
physical therapy in an elderly man, GSK. ©
Halberg.
148
Figure 2. Diastolic blood pressure (DBP)
response to pain and to physical therapy in an
elderly man, GSK. © Halberg.
Figure 3. Changes in heart rate (HR) in
response to pain and physical therapy in an
elderly man, GSK. © Halberg.
1. Katinas GS, Cornélissen G, Otsuka K, Haus E, Bakken EE, Halberg F. Why continued
surveillance? Intermittent blood pressure and heart rate abnormality under treatment. Biomed
& Pharmacother 2005; 59 (Suppl 1): S141-S151.
2. Bingham C, Arbogast B, Cornélissen Guillaume G, Lee JK, Halberg F. Inferential statistical
methods for estimating and comparing cosinor parameters. Chronobiologia 1982; 9: 397-439.
3. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of
antihypertensive response by self-starting cumulative sums. J Medical Engineering &
Technology 1997; 21: 111-120.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
149
HARM VS. BENEFIT FROM LOSARTAN WITH HYDROCHLOROTHIAZIDE AT
DIFFERENT CIRCADIAN TIMES IN MESOR-HYPERTENSION OR CHAT
Yoshihiko Watanabe*§, Germaine Cornélissen•, Franz Halberg•, Larry Beaty•, Jarmila
Siegelova‡, Kuniaki Otsuka§, Earl E. Bakken¶
*Department of Sports Medicine, School of Sports Sciences, Waseda University, Tokorozama,
Saitawa, Japan
§Department of Medicine, Tokyo Women's Medical University, Medical Center East, Tokyo,
Japan
•Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
‡Masaryk University, Brno, Czech Republic
¶North Hawaii Community Hospital Inc., Kamuela, Hawaii, USA
Abstract. Two new male patients, Sa, 65 years of age, with MESOR-hypertension (MH), and
Su, 66 years of age, with circadian hyper-amplitude-tension, CHAT, were studied by
chronobiologically interpreted automatic ambulatory blood pressure (BP) and heart rate (HR) with
7-day/24-hour monitoring monitoring, C-ABPM 7/24. The last 7 days of a no-hypotensivetreatment
(Rx) span were monitored [1)] and compared with C-ABPM 7/24 for effects on BP and
HR at the end of several weeks on 50 mg Losartan -- (L) [2)] followed by L with 12.5 mg
hydrochlorothiazide (L+H) [3)] -- both 2. and 3. at breakfast and then on a set of 5 differently
timed treatment spans on L+H, administered (to approach 5 different circadian stages) upon
awakening or 3, 6, 9 or 12 hours after awakening [4)-8)]. At the end of each L+H Rx stage, and
earlier at the end of no Rx or L only at breakfast or L+H only at breakfast, BP was also monitored
for 7 days (C-ABPM). Circadian characteristics were assessed by cosinor on each day's data and
compared among the 5 Rx times by a 1-way analysis of variance. A circadian rhythm characterized
the responses of the MESOR (M) and circadian amplitude (A) of systolic (S) and diastolic (D) BP
and of pulse pressure (PP) of Su and the response of SBP-M and DBP-M of Sa. In Su, the effect
was desired at the two late test times (9 and 12 hours after awakening) but at 3 earlier test times,
the circadian overswing was actually increased. The effect of L+H in the morning in Su was
harmful; in the evening beneficial. Such undesirable effects are currently not picked up in data that
are not collected and/or analyzed chronobiologically. Care providers who collect data that do not
lend themselves to a chronobiologic analysis or refrain from using C-ABPM, offered cost-free by
BIOCOS, may in very many people unintentionally induce a risk greater than a high BP, and hence
may do harm. Ignorance is no excuse, certainly not in the face of a series of prior consensus
meetings advocating an indispensable chronobiologic approach in keeping with "first do no harm"
(1).
Introduction. Chronobiologically interpreted ambulatory blood pressure (BP) monitoring
(C-ABPM) underlies an individualized approach for reliably diagnosing vascular variability
disorders, VVDs, such as MESOR-hypertension (MH), or CHAT, short for circadian hyperamplitude-tension
(1, 2) or an above-threshold pulse pressure, and once the diagnosis is
ascertained, C-ABPM is best continued for finding the appropriate timing for the administration of
non-drug or drug treatment. By a C-ABPM one may avoid harm due to timing that escapes notice
in current practice, but if detected can be readily corrected, sometimes only by changing the timing
of drug administration.
Background. For 240 mg of diltiazem, a change of treatment from 08:30 to 04:30 reduced
both the MESOR and the circadian amplitude (3). CHAT, associated with sotalol 80 mg given
150
twice daily, can be avoided by omitting the evening dose (4). More generally, a long series of
studies in the laboratory shows gains from chronotherapy summarized in Table 1.
Subjects and methods. For the patients investigated, the schedule of monitoring with a device
(TM-2421 or TM-2430) for ambulatory monitoring from A&D (Tokyo, Japan) and their laboratory
determinations are shown in Tables 2 and 3. Methods of analysis are given with their results in
Tables 4-6 and in Figures 1-12.
Results. Figure 1 illustrates for SBP that the kinds of time series investigated cannot be
readily quantified and compared by the unaided eye, just as most cells are not seen without
microscopes. Figures 2 and 3 show results for the SBP M and A, analyzed in Figure 4: both effects
(upon M and upon A) are circadian rhythmic. Figures 2 and 3 also show that the SBP MESOR had
been lowered at all test times by L+H, but not the circadian amplitude. What is most important, at
3 of the 5 treatment times, CHAT, a risk of stroke greater than a high BP (2), is exacerbated rather
than reduced.
Figures 5-7 show results for Su's DBP M and A and a rhythm is again present, indicating that
treatment can and should be optimized by timing. Figures 8-10 summarize the statistically
significant circadian rhythms in the response of the SBP-M of patient Sa and one of lesser
(borderline) statistical significance in Sa's SBP-A. Sa's DBP-M also responds rhythmically to
L+H, as seen in Figure 11, as does the pulse pressure of Su but not of Sa in Figure 12.
Discussion. The failure of current health care to diagnose and treat risks greater than that of
MH such as a 7-day CHAT (1) -- that may need only a change in the timing of medication to be
eliminated (1-6) and that can be exacerbated by unmonitored and/or chronobiologically
uninterpreted treatment -- can be compared historically with the resistance to antisepsis and
asepsis (7).
We paraphrase Oliver Wendell Holmes, who had recognized the problem of puerperal fever
before Semmelweis and Lister (8) did, and hope that chronomic facts (Holmes referred to "medical
logic"), will be further checked, considered and taught in modern-day schools (9, 10). A single
office BP measurement is no longer regarded as reliable by opinion leaders (11), and even an
around-the-clock profile (1) cannot reliably detect a VVD, nor can a day-night ratio do equally so
with statistical significance in the light of outcomes (12-16). An international project on The
BIOsphere and the COSmos, BIOCOS (17), provides participants with an 80% reduction in the
purchase price of automatic monitors of BP and HR for ambulatory use and with chronomic
analyses in the light of an accumulating reference data base, qualified by gender and age in
exchange for the data. Some readers may use this opportunity for their own health care and/or that
of their family, friends and acquaintances. Some may decide to monitor themselves in the long
term for basic science as well. Treatments at different times are not equivalent. Just as does the
marker rhythm of tumor temperature in the treatment of cancer, Table 1 (18), C-ABPM offers an
opportunity for increasing therapeutic benefit and preventing harm. Moreover, C-ABPM allows 1.
an optimal diagnosis, 2. optimal timing and 3. an ongoing check of treatment effects and 4.
indications for change when needed.
151
TowardIndividualizedChronotherapyofCircadianHyper-Amplitude-Tension(CHAT)
SystolicBloodPressure(mmHg)(M,66y)DiastolicBloodPressure(mmHg)
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Figure1.OriginaldataofSu,amalepatient66yearsofage,withCHAT(circadianhyper-amplitude-tension)before(ontop)andaftertreatment(Rx)with50mgofLosartan(L)
aloneorLwith12.5mgofhydrochlorothiazide(L+H),atbreakfastinthesecondandthirdrows,respectively.Thenext5rowsshowdatawithRxatawakeningandat3,6,9and
12hoursthereafter.Albeitnotshown,similardataforothervariablesofthesamepatientandforanothermalepatient,Sa,65yearsofage,werealsoobtained.7-daycosine
curveswerefittedtoalldatafrombothpatients,butasinglevalueforeach,theMESOR,M,andamplitude,A,fromthefittothe7-dayseriesasawholedidnotallowdetectionof
thecircadianorcircaseptanrhythmstage-dependenceoftheresponsewhetherevaluatedbyANOVAorasinglecosinor(notshown).Asummaryofseparatefitsofa24-hour
cosinetoeach24-hour(ratherthanasingle168-hour)datasectionsufficedtogetstatisticallysignificantresults,obtainedfromtestsofthezeroAassumption(wheneachtime
seriesinthelastweekofoneofthe5treatmenttimesyielded7separatedailyMsandAs).Similarcalculationsforacircaseptanresponsewouldrequiredataover7ormore
circaseptancycles.©Halberg.
152
Figure 2. All treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg lowered circadian systolic blood pressure
MESOR at all test times in analyses in Figure 4, but this response was not quantitatively the same, Tables 4 and 5 and Figure 4. ©
Halberg.
Chronomic (time-structural) surveillance starts with a chronobiologically interpreted 7-day
around-the-clock record (C-ABPM) which (until affordable automatic monitors become available
for everybody's continuous surveillance) suffices only to rule out, but not to rule in and to treat a
VVD. When the 7-day record is repeatedly abnormal and confirms the VVD, it serves to recognize
and treat any risk elevation as well as overt disease, but again not blindly. Monitoring is to be
continued to ascertain whether and, if so, for how long treatment effects last, be it for lowering an
increased risk and/or in surveilling the success or failure of BP M or A lowering or raising, as need
be. Once longitudinal records are available, statistical inference can be obtained for the individual
patient by means of parameter tests (19) and by sequential testing such as that by the self-starting
cumulative control chart (20).
An initial decline in M coincides with the start of treatment (21 and Figure 15 therein).
Relying on an N-of-1 chronobiologic pilot design, treatment time in relation to clock-time was
then advanced by 4 hours, initially every 17 days, and at shorter intervals thereafter. Rx at 12:00
was associated with a reversal of the up-to-then continuous decrease. For that subject, TT in (21),
treatment in the evening was associated with an elevation in the circadian amplitude of BP. It is
clear that treatment has to be individualized when in Su treatment in the morning elevated the
153
Figure 3. Very different responses to treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg of the circadian
amplitude of patient Su's blood pressure, analyzed in Table 5 and Figure 4. © Halberg.
amplitude, inducing or exacerbating CHAT, while treatment in the evening eliminated CHAT.
Such an increase in circadian amplitude of BP may induce iatrogenic CHAT in many other,
possibly millions of patients, thereby increasing cardiovascular disease risk unknowingly.
Against this background, it must be re-emphasized that in Su, who had (mild) CHAT to start
with, treatment with L+H exacerbated CHAT in the morning, but not when the same dose was
given in the evening, Figures 4 and 7 (cf. also 21 for the difference in patient TT). We must not
generalize, but individualize by monitoring, so that we do not fly blind (22) to the possibility that
by eliminating the lower risk of MH, we acquire the higher risk of CHAT. The large risk of CHAT
is illustrated elsewhere (6 and Figure 2 IIA-C therein). It was shown in another study that
switching the timing of medication every day was too fast a schedule (23). In the present study, the
intervals between spans of treatment at different clock-hours were of several weeks, and only the
last week was monitored. During this final monitoring week, there were trends, Table 6. The asone-goes
weekly analysis of the monitoring may be used for deciding on the interval between
changes in medication, while also accounting for trends (21). In the case of Su and Sa, a week's
monitoring after several weeks on the drug has allowed the detection of response rhythms. Shorter
yet uninterrupted monitoring, e.g., with initial changes every 17 days, has also worked (21) and
when a first cycle of treatments is repeated to once more reascertain the best time, the interval
between changes may be shortened (21).
Conclusion. The monitoring of Su and Sa and much earlier background information should
suffice to recommend that any patient on treatment for high BP should be monitored to find out the
best treatment, apart from ruling out that other VVDs are not traded for a lower BP average.
154
Chronotherapy Individualized by Monitoring of a Patient (Su, M, 66y) with
Circadian Overswing (CHAT*) Finds Best Treatment Times for Lowering both
MESOR (top) and an Excessive Circadian Amplitude (bottom)
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00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Treatment Time (hours from awakening, AW)
SBP-M(mmHg)
1-way ANOVA: F=9.225; P<0.001
Cosinor: PR=43%; P<0.001
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for SBP-M
based on clinically healthy peers
matched by gender and age
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1-way ANOVA: F=5.666; P=0.002
Cosinor: PR=32%; P=0.002
AW +3h +6h +9h +12h
No Treatment:
CHAT diagnosed
Treatment Effect
CHAT exacerbated
CHAT eliminated
Upper limit of acceptability
for SBP-A based on
clinically healthy peers
matched by gender and age
HARM
BENEFIT
* CHAT: Circadian Hyper-Amplitude-Tension, a vascular variability disorder. Bottom: Note that a
treatment can be useful when given in the evening, but is actually harmful when taken on awakening and
later in the morning, when it exarcerbates CHAT, a condition that carries a risk of morbid events greater
than an elevated mean value of blood pressure.
Figure 4. Monitoring of patient Su reveals for his systolic blood pressure a good time for both a hypotensive effect and a
lowering of an excessive circadian amplitude by treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg when
medication is taken 9 or 12 hours after awakening. Note from the lower graph on amplitude, A, that the same treatment given on
awakening or 3 or 5 hours thereafter can actually do harm, further raising an already elevated circadian A. Neither CHAT nor the
effect of treatment upon this condition are conventionally detectable in office visits and escape a 24-hour profile as well when it is
155
not interpreted in the light of chronobiologic reference standards, and even when it is so interpreted, the record is not long enough
to rule out a transient abnormality that may be only a physiological response.
Changing the timing of medication during consecutive spans shows differences in the efficacy of treatment. An empirical
approach to chronotherapy, here implemented immediately after diagnosis, should ascertain that the treatment is effective and not
harmful. Optimization of treatment effects by timing can be achieved for the individual patient by systematically changing, e.g.
advancing the clock-hour of treatment on a standardized routine of activity and sleep. Successful treatment of MESORhypertension
assessed by a self-starting cumulative sum (control) chart was aimed earlier to optimize hypotensive treatment for a
then-just-diagnosed 24-year-old individual (TT) who switched his Rx first every 17 days by 4 hours and then mostly at shorter
intervals. A statistically significant decrease in MESOR was indicated by the breakout outside the decision interval of a negative
(CUSUM) line (21). With continued Rx, the blood pressure MESOR leaves the decision interval, indicating a statistically significant
decrease in overall blood pressure. At a certain timepoint, the amplitude is increased, and this can be immediately detected by CABPM
with CUSUM when monitoring is continuous, as shown elsewhere (17 and Figures 15 and 16 therein). © Halberg.
Figure 5. All treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg lower the MESOR of patient Su's diastolic blood
pressure but again not equally, Table 5. In this patient, treatment in the evening lowers the excessive SBP amplitude. © Halberg.
156
Figure 6. Treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg affect the circadian amplitude, A, of diastolic blood
pressure of patient Su in different ways, raising the high normal amplitude further, at 3 hours after awakening, including CHAT, vs.
lowering the A as desired (see Table 5) when the same dose is given in the evening. © Halberg.
65
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85
90
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
DBP-M(mmHg)
1-way ANOVA: F=8.447; P<0.001
Cosinor: PR=40%; P<0.001
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for DBP-M
based on clinically healthy peers
matched by gender and age
0
4
8
12
16
20
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Time (hours from awakening)
DBP-A(mmHg)
1-way ANOVA: F=5.589; P=0.002
Cosinor: PR=38%; P<0.001
AW +3h +6h +9h +12h
No Treatment
Treatment Effect
Iatrogenic CHAT
CHAT eliminated
Upper limit of acceptability
for DBP-A based on
clinically healthy peers
matched by gender and age
Figure 7. Patient Su: Effects of Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg upon the diastolic blood pressure MESOR and
amplitude show a very great circadian time-dependence, whether by analysis of variance or cosinor (P<0.001). A MESORhypotensive
effect is greater 9 and 12 hours after awakening than at earlier times in the day, and CHAT at these times is eliminated
while it was induced with the same treatment taken 3 hours after awakening. © Halberg.
157
Figure 8. All treatments with Losartan (L) 50 mg and hydrochlorothiazide 12.5 mg lower the systolic blood pressure M of patient Sa
(Tables 4 and 5). © Halberg.
Figure 9. Along the 24-hour time scale, there are differences in the response to Losartan (L) 50 mg and hydrochlorothiazide 12.5
mg of the circadian amplitude of patient Sa's systolic blood pressure. A marked circadian blood pressure response rhythm is of
borderline statistical significance (Table 4). © Halberg.
158
105
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120
125
130
135
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145
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
SBP-M(mmHg)
1-way ANOVA: F=3.135; P=0.029
Cosinor: PR=25%; P=0.012
AW +3h +6h +9h +12h
Treatment Effect
No Treatment: MESOR-hypertension diagnosed
Upper limit of acceptability
for SBP-M based on
clinically healthy peers
matched by gender and age
0
3
6
9
12
15
18
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
SBP-A(mmHg)
1-way ANOVA: F=2.829; P=0.043
Cosinor: PR=15%; P=0.075
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability
for SBP-A based on
clinically healthy peers
matched by gender and age
Figure 10. Patient Su: A cosinor and an analysis of variance show a circadian periodic response of the systolic MESOR to Losartan
(L) 50 mg and hydrochlorothiazide 12.5 mg. The analysis of variance also shows a difference in response of the circadian
amplitude of systolic blood pressure of patient Sa. © Halberg.
65
70
75
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85
90
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
DBP-M(mmHg)
1-way ANOVA: F=5.013; P=0.003
Cosinor: PR=33%; P=0.002
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for DBP-M
based on clinically healthy peers
matched by gender and age
0
3
6
9
12
15
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
DBP-A(mmHg)
1-way ANOVA: F=0.785; P=0.544
Cosinor: PR=8%; P=0.295
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability
for DBP-A based on
clinically healthy peers
matched by gender and age
Figure 11. Patient Sa. A cosinor and an analysis of variance show a circadian periodic response of the systolic MESOR to Losartan
(L) 50 mg and hydrochlorothiazide 12.5 mg. The analysis of variance also shows a difference in response of the circadian
amplitude of systolic blood pressure of patient Sa. © Halberg.
30
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00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
PP(mmHg)
1-way ANOVA: F=4.756; P=0.004
Cosinor: PR=3%; P=0.605
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for PP
Fitted cosine curve
30
35
40
45
50
55
60
65
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Time (hours from awakening)
PP(mmHg)
1-way ANOVA: F=7.258; P<0.001
Cosinor: PR=32%; P=0.002
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for PP
Figure 12. Patient Sa (left) and patient Su (right): Losartan 50 mg combined with hydrochlorothiazide 12.5 mg reduce, with
circadian stage dependence, a somewhat elevated pulse pressure which is still within the physiologic range for patient Sa, with a
time effect validated by ANOVA (top), but no rhythm is seen by cosinor. There is again a statistically highly significant circadian
response rhythm in pulse pressure, validated by cosinor and ANOVA for patient Su, with circadian hyper-amplitude-tension (bottom
half). © Halberg.
159
1. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group:
Resolution from a meeting of the International Society for Research on Civilization Diseases
and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995:
Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18
figures. URL http://www.msi.umn.edu/~halberg/
2. Cornélissen G, Delcourt A, Toussaint G, Otsuka K, Watanabe Y, Siegelova J, Fiser B, Dusek
J, Homolka P, Singh RB, Kumar A, Singh RK, Sanchez S, Gonzalez C, Holley D, Sundaram
B, Zhao Z, Tomlinson B, Fok B, Zeman M, Dulkova K, Halberg F. Opportunity of detecting
pre-hypertension: worldwide data on blood pressure overswinging. Biomedicine &
Pharmacotherapy 2005; 59 (Suppl 1): S152-S157.
3. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber
M, Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la
Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N,
Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical
Instrumentation & Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
4. Shinagawa M, Kubo Y, Otsuka K, Ohkawa S, Cornélissen G, Halberg F. Impact of circadian
amplitude and chronotherapy: relevance to prevention and treatment of stroke. Biomedicine
& Pharmacotherapy 2001; 55 (Suppl 1): 125s-132s.
5. Kumagai Y, Cornélissen G, Fujimura A, Halberg F, Kharlitskaya EV, Ikonomov O,
Blagonravov ML, Chibisov SM, Radysh IV. Chronotherapy of vascular variability disorders:
a challenge for the clinic. Proceedings, 1st International Workshop, Physiology of adaptation
and quality of life: problems of traditional medicine and innovation, People's Friendship
University of Russia, Moscow, Russia, May 14-16, 2008. p. 404-407.
6. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
7. Halberg F, Cornélissen G, Delmore P, Schwartzkopff O, International Womb-to-Tomb
Chronome Group: The costs of ignoring a long-overdue chronomedicine: the chronome
initiative emerging from the catacombs. Neuroendocrinol Lett 2003; 24 (Suppl 1): 247-256.
8. Sutcliffe J, Duin N. A History of Medicine. New York: Barnes & Noble; 1992. 256 pp.
9. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
10. Kiser K. Father Time. Minnesota Medicine 2005 [November]: 26-29, 42-43.
11. Pickering TG. Masked hypertension and white-coat hypertension. In: Proceedings, 59th
Annual Meeting, Japan Society of Neurovegetative Research, Tokyo, November 1-3, 2006.
p. 32.
12. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633.
doi:10:1038/jhh.2008.32.
13. Schaffer E, Cornélissen G, Rhodus N, Halhuber M, Watanabe Y, Halberg F. Outcomes of
chronobiologically normotensive dental patients: a 7-year follow-up. JADA 2001; 132: 891-
899.
14. Otsuka K, Cornélissen G, Halberg F. Predictive value of blood pressure dipping and
swinging with regard to vascular disease risk. Clinical Drug Investigation 1996; 11: 20-31.
160
15. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual
and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64.
16. Bingham C, Cornélissen G, Chen C-H, Halberg F. Chronobiology works when day-night
ratios fail in assessing cardiovascular disease risk from blood pressure profiles. Abstract, III
International Conference, Civilization diseases in the spirit of V.I. Vernadsky, People's
Friendship University of Russia, Moscow, Oct. 10-12, 2005, p. 111-113.
17. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A,
Gorgo Y, Zhao ZY, Weydahl A, Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV,
Perfetto F, Tarquini R, Singh RB, Rhees B, Lofstrom D, Lofstrom P, Johnson PWC,
Schwartzkopff O, International BIOCOS Study Group. Cross-spectrally coherent ~10.5- and
21-year biological and physical cycles, magnetic storms and myocardial infarctions.
Neuroendocrinol Lett 2000; 21: 233-258.
18. Halberg Francine, Cornélissen G, Ulmer W, Halberg Franz. Radiation treatment aimed at
exploiting weekly rhythms. These proceedings.
19. Bingham C, Arbogast B, Cornélissen Guillaume G, Lee JK, Halberg F. Inferential statistical
methods for estimating and comparing cosinor parameters. Chronobiologia 1982; 9: 397-439.
20. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of
antihypertensive response by self-starting cumulative sums. J Medical Engineering &
Technology 1997; 21: 111-120.
21. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: Part II, chronomics for an immediately applicable biomedicine. J
Applied Biomedicine 2006; 4: 73-86. http://www.zsf.jcu.cz/vyzkum/jab/4_2/halberg2.pdf.
22. Fossel M. Editor's Note [to Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka
K, Watanabe Y, Kumagai Y, Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff
O. Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging
medicine]. J Anti-Aging Med 1998; 1: 239.
23. Prikryl P, Cornélissen G, Neubauer J, Prikryl P Jr, Karpisek Z, Watanabe Y, Otsuka K,
Halberg F. Chronobiologically explored effects of telmisartan. Clinical and Experimental
Hypertension 2005; 2 & 3: 119-128.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
161
Table 1: Susceptibility rhythms leading to
individualized inferential statistical chronopharmacology and chronotherapy
Year Description Author(s)
1952, 1953 2800-fold increase in sensitivity of a corticosteroid assay by
accounting for circadian stage (Figure 1 in 2 vs. 1)
Halberg (1, 2)
1955 Circadian susceptibility rhythm to noise Halberg, Bittner, Gully, Albrecht &
Brackney (3)
1955 - - - - - - - - - - " - - - - - - - - - - - - an endotoxin Halberg, Spink, Albrecht & Gully (4)
1958 Manipulability of a susceptibility rhythm by lighting regimen Halberg, Jacobson, Wadsworth &
Bittner (5)
1958 Detection of (growth) hormone effect on mitoses depends
on circadian stage
Litman, Halberg et al. (6)
1959 Effect of ethanol depends on circadian stage Haus, Hanton & Halberg (7)
1959 Individualized sequential testing Johnson, Haus, Halberg & Wadsworth
(8)
1959 Circadian susceptibility rhythm to a drug (ouabain) Halberg & Stephens (9)
1960 LD50 to whole-body X-irradiation depends on circadian
stage
Halberg (10, discussion)
1961 Circadian susceptibility rhythm to Librium Marte & Halberg (11)
1963 - - - - - - - - - - " - - - - - - - - - - - - acetylcholine Jones, Haus & Halberg (12)
1964 - - - - - - - - - - " - - - - - - - - - - - - fluothane Matthews, Marte & Halberg (13)
1967 Cosinor method Halberg, Tong & Johnson (14)
1969 Methodological and conceptual context Halberg (15)
1969 Chronotherapy with penicillin Reinberg et al. (16)
1970, 1972 Chronotherapy with arabinosyl cytosine (ara-C) Cardoso et al. (17), Haus et al. (18)
1973 Rhythm in chronotherapeutic indices of hydrochlorothiazide
and adriamycin
Halberg et al. (19), Levine et al.
(20), Shiotsuka et al. (21)
1974, 1975 Formulation of rules of chronopharmacology and
chronotherapy; demonstration of shift of susceptibility
rhythm to adriamycin by meal timing
Halberg (22-24)
1977 Doubling of 2-year survival by timing radiotherapy Halberg (25)
1979 Ara-C chronotherapy brings about cancer cures Halberg, Nelson, Cornélissen, Haus,
Scheving & Good (26)
1979 More antihypertensive chronotherapy Güllner, Bartter & Halberg (27)
1992 Individualized cancer marker-guided chronochemotherapy Halberg et al. (28)
1995 More antihypertensive chronotherapy and its optimization
by timing
Halberg et al. (29)
1997 Individualized sequential testing of chronotherapy Cornélissen, Halberg, Hawkins,
Otsuka & Henke (30)
2004 "Tree of life" Halberg et al. (31)
2006 Toxicity marker-guided chronochemotherapy Halberg et al. (32)
1. Halberg F. Some correlations between chemical structure and maximal eosinopenia in adrenalectomized and
hypophysectomized mice. J Pharmacol exp Ther 1952; 106: 135-149.
2. Halberg F. Some physiological and clinical aspects of 24-hour periodicity. Journal-Lancet (Minneapolis) 1953;
73: 20-32. See Figure 1.
3. Halberg F, Bittner JJ, Gully RJ, Albrecht PG, Brackney EL. 24-hour periodicity and audiogenic convulsions in
I mice of various ages. Proc Soc exp Biol (NY) 1955; 88: 169-173.
4. Halberg F, Spink WW, Albrecht PG, Gully RJ. Resistance of mice to brucella somatic antigen, 24-hour
periodicity and the adrenals. J clin Endocrinol 1955; 15: 887.
5. Halberg F, Jacobson E, Wadsworth G, Bittner JJ. Audiogenic abnormality spectra, 24-hour periodicity and
lighting. Science 1958; 128: 657-658.
6. Litman T, Halberg F, Ellis S, Bittner JJ. Pituitary growth hormone and mitoses in immature mouse liver.
Endocrinology 1958; 62: 361-364.
7. Haus E, Hanton EM, Halberg F. 24-hour susceptibility rhythm to ethanol in fully-fed, starved and thirsted mice
and the lighting regimen. Physiologist 1959; 2: 54.
162
8. Johnson EA, Haus E, Halberg F, Wadsworth GL. Graphic monitoring of seizure incidence changes in epileptic
patients. Minn Med 1959; 42: 1250-1257.
9. Halberg F, Stephens AN. Susceptibility to ouabain and physiologic circadian periodicity. Proc Minn Acad Sci
1959; 27, 139-143.
10. Halberg F. Temporal coordination of physiologic function. Cold Spr Harb Symp quant Biol 1960; 25: 289-310.
Discussion on LD50, p. 310.
11. Marte E, Halberg F. Circadian susceptibility rhythm of mice to librium. Fed Proc 1961; 20, 305.
12. Jones F, Haus E, Halberg F. Murine circadian susceptibility-resistance cycle to acetylcholine. Proc Minn Acad
Sci 1963; 31: 61-62.
13. Matthews JH, Marte E, Halberg F. A circadian susceptibility-resistance cycle to fluothane in male B1 mice.
Canadian Anaesthetists' Society J 1964; 11: 280-290.
14. Halberg F, Tong YL, Johnson EA. Circadian system phase—an aspect of temporal morphology; procedures
and illustrative examples. Proc. International Congress of Anatomists. In: Mayersbach H v, ed. The Cellular
Aspects of Biorhythms, Symposium on Biorhythms. New York: Springer-Verlag; 1967. p. 20-48.
15. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
16. Reinberg A, Zagula-Mally ZW, Ghata J, Halberg F. Circadian reactivity rhythm of human skin to house dust,
penicillin and histamine. J Allergy 1969; 44: 292-306.
17. Cardoso SS, Scheving LE, Halberg F. Mortality of mice as influenced by the hour of the day of drug (ara-C)
administration. Pharmacologist 1970; 12: 302.
18. Haus E, Halberg F, Scheving L, Pauly JE, Cardoso S, Kühl JFW, Sothern R, Shiotsuka RN, Hwang DS.
Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system.
Science 1972; 177: 80-82.
19. Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE, Runge W,
Spalding JF, Lee JK, Good RA. Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon
host rhythms. Experientia (Basel) 1973; 29: 909-934.
20. Levine H, Thompson D, Shiotsuka R, Krzanowski M, Halberg F. Autorhythmometrically determined blood
pressure ranges and rhythm of 12 presumably healthy men during an 18-day span. Int J Chronobiol 1973; 1:
337-338.
21. Shiotsuka R, Halberg F, Haus E, Lee JK, McHugh R, Simpson H, Levine H, Ratte J, Najarian J. Results
bearing on the chronotherapy of hypertension: saluresis and diuresis without kaluresis can be produced by
properly timing chlorothiazide administration according to circadian rhythms. Int J Chronobiol 1973; 1: 358.
22. Halberg F. Protection by timing treatment according to bodily rhythms: an analogy to protection by scrubbing
before surgery. Chronobiologia 1974; 1 (Suppl. 1): 27-68.
23. Halberg F. Quando trattare /When to treat. Hæmatologica (Pavia) 1975; 60: 1-30.
24. Halberg F. When to treat. Indian J. Cancer 1975; 12: 1-20.
25. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc. 30th Ann. Cong.
Rad., January 1977, Post-Graduate Institute of Medical Education and Research, Chandigarh, India, 8 pp.
26. Halberg F, Nelson W, Cornélissen G, Haus E, Scheving LE, Good RA. On methods for testing and achieving
cancer chronotherapy. Cancer Treatment Rep 1979; 63: 1428-1430.
27. Güllner HG, Bartter FC, Halberg F. Timing antihypertensive medication. The Lancet, September 8, 1979: 527.
28. Halberg F, Cornélissen G, Bingham C, Fujii S, Halberg E. From experimental units to unique experiments:
chronobiologic pilots complement large trials. in vivo 1992; 6: 403-428.
29. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group: Resolution from a
meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE
Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology
Seminar #8, April 1995, 12 pp. text, 18 figures. URL http://www.msi.umn.edu/~halberg/
30. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of antihypertensive
response by self-starting cumulative sums. J Medical Engineering & Technology 1997; 21: 111-120.
31. Halberg F, Otsuka K, Katinas G, Sonkowsky R, Regal P, Schwartzkopff O, Jozsa R, Olah A, Zeman M,
Bakken EE, Cornélissen G. A chronomic tree of life: ontogenetic and phylogenetic 'memories' of primordial
cycles - keys to ethics. Biomedicine & Pharmacotherapy 2004; 58 (Suppl 1): S1-S11.
32. Halberg F, Prem K, Halberg F, Norman C, Cornélissen G. Cancer Chronomics I: Origins of timed cancer
treatment: early marker rhythm-guided individualized chronochemotherapy. J Exp Ther Oncol 2006; 6: 55-61.
163
Table 2: Monitoring spans on patients investigated and timings on treatment (Rx)*
Su: 66-year-old man, height 167 cm, body weight 70 kg, BMI 25.1, with circadian hyper-amplitude-tension (CHAT)
Patient start end medication timing medication start
1 20071128 20071205 No hypotensive drug start
20071226 20080102 Losartan50mg* after breakfast 20071206
20080123 20080130 L+H1Tab* after breakfast 20080110
20080312 20080318 0 h 20080131
20080416 20080423 3 h 20080320
20080604 20080611 6 h 20080423
20080709 20080716 9 h 20080612
20080806 20080813 12 h 20080717
Sa: 65-year-old man, height 163 cm, body weight 58 kg, BMI 21.8, with MESOR-hypertension
Patient start end medication timing medication start
2 20071213 20071220 No hypotensive drug start
20080103 20080110 Losartan50mg* after breakfast 20071221
20080125 20080201 L+H1Tab* after breakfast 20080111
20080314 20080321 0 h 20080202
20080415 20080421 3 h 20080322
20080520 20080527 6 h 20080423
20080624 20080701 9 h 20080528
20080729 20080805 12 h 20080702
*L: Losartan 50mg; L+H: Losartan 50mg + hydrochlorothiazide 12.5mg
164
Table3:LaboratorydataofpatientsinvestigatedduringtreatmentwithLosartan50mgandLosartan50mg+
hydrochlorothiazide12.5mg*
Su:66-year-oldman,height167cm,bodyweight70kg,BMI25.1,withcircadianhyper-amplitude-tension(CHAT)
PtstartendNaClUalbUVNorAdAdBNPPRAAldCrUANaKT-chTGHDL-chLDL-chBSHbA1C
1200711282007120511.2440.121005253315.48.5106
200712262008010212.111760
200801232008013012.457.81960818246.812099.50.934.41394.218570651061636.1
200803122008031812.737.41950451267.42246.70.874.917213762832046.2
200804162008042310.911800267249.62366.50.875.513941769956961636.2
200806042008061116.5717.8161037714.61671.50.813.718017163951586.3
200807092008071613.3894041011.43172.60.814.31404.317210755941416.3
200808062008081311.39.21150335208.10.814.11404.117694531042206.4
Sa:65-year-oldman,height163cm,bodyweight58kg,BMI21.8,withMESOR-hypertension
PtstartendNaClUalbUVNorAdAdBNPPRAAldCrUANaKT-chTGHDL-chLDL-chBSHbA1C
2200712132007122014.94270055512014.0270.20.862.71414.221013855132112
200801032008011015.722970
20080125200802017.94527007211978.03198.50.873.61424.3208127491281075.3
20080314200803218.4419308051166.02601090.883.31384.2213214481291125.1
200804152008042110.233050639697.0581370.894.31394.322985571561065.3
20080520200805279.39322805871229.0301170.893.41404.221494551361065.3
200806242008070110.72526405728810.01101050.883.51384.1200171441181025.3
200807292008080514.5626503378715.0871080.913.61393.8214128491401035.3
*L=Losartan50mg;L+H=Losartan50mg+hydrochlorothiazide12.5mg
NaCl=Sodiumintake(g/day),Ualb=urinaryalbumin(mg/day),UV=urinaryvolume(ml/day)NorAd=Noradrenaline(pg/ml),Adrenaline
(pg/ml)
BNP=brainnatriureticpeptide(pg/ml),PRA=plasmareninactivity(pg/ml),Ald=aldosterone(pg/ml),UA=uricacid,NaandKserum
concentrations,Tch=totalcholesterol,TG:triglycerides,HDL:highdensitylipoprotein,LDL:lowdensitylipoprotein,HbA1C=A1C
hemoglobin.
165
Table 4: Summary of effects investigated by analysis of variance in two men, Su, 66 years of
age, and Sa, 65 years of age*
SBP DBP HR PP HR/SD
ANOVA F P F P F P F P F P
M 9.23 6.18 8.45 <0.01 1.36 0.27
Su
A 5.67 <0.01 5.59 <0.01 0.44 0.78
7.26 <0.01 1.47 0.24
M 3.14 0.03 5.01 <0.01 3.57 0.02
Sa
A 2.83 0.04 0.78 0.54 0.32 0.86
4.76 <0.01 0.32 0.86
*S: systolic; D: diastolic; BP: blood pressure (mm Hg); HR: heart rate (beats/min); PP: pulse
pressure; HR/SD: standard deviation (SD) of HR; M: MESOR (midline-estimating statistic of
rhythm), a chronome (time structure)-, in this case circadian rhythm-adjusted mean; A: Amplitude
(one-half of the total change accounted for by the fitted cosine curve); F: F-test; P: P-value from
test of equality of parameters.
166
Table5:Summaryofeffectsinvestigatedbycosinorintwomen,Su,66yearsofage,andSa,65yearsofage*
VariablePRPMESOR±SEAmplitude(95%CI)Acrophase(95%CI)
SBP-M43<0.001113.8±2.1010.6(5.2,16.1)-154˚(-116,-176)
SBP-A320.00215.5±1.76.6(2.4,11.2)-153˚(-101,-181)
DBP-M40<0.00173.9±1.15.5(2.6,8.5)-158˚(-120,-180)
DBP-A38<0.0019.9±1.04.3(1.9,6.6)-147˚(-99,-174)
HR-M30.65871.5±0.70.8()-162˚()
HR-A50.4546.8±0.91.5()-172˚()
PP32<0.0139.9±1.35.1(1.8,8.4)-149˚(-95,-179)
Su(patientwithcircadian
hyper-amplitude-tension,
CHAT)
HR-SD40.51513.0±0.91.0()-324˚()
SBP-M250.012113.8±0.763.5(1.1,5.9)-175˚(-135,-198)
SBP-A150.0758.4±1.03.2()-217˚()
DBP-M330.00269.7±0.53.2(1.5,4.9)-183˚(-161,-200)
HR-M270.00774.6±0.94.2(1.5,6.9)-176˚(-140,-197)
HR-A40.53910.1±1.11.7()-173˚()
DBP-A80.2955.6±0.71.5()-219˚()
PP30.60544.2±0.60.6()-121˚()
Sa(patientwithMESOR-
hypertension)
HR-SD30.64111.3±0.81.2()-186˚()
*S:systolic;D:diastolic;BP:bloodpressure(mmHg);HR:heartrate(beats/min);PP:pulsepressure;HR-SD:standarddeviation
(SD)ofHR;M:MESOR(midline-estimatingstatisticofrhythm),achronome(timestructure)-,inthiscasecircadianrhythm-adjusted
mean;A:Amplitude(one-halfofthetotalchangeaccountedforbythefittedcosinecurve);PR:percentrhythm;P:P-value.
167
Study Stage slope (mmHg/day) r P slope (mmHg/day) r P
Patient Sa
NoRx -1.558 -0.226 <0.001 -0.592 -0.145 0.008
Losa 0.136 0.019 0.727 -0.263 -0.061 0.255
PBkft -0.319 -0.049 0.376 0.052 0.012 0.822
P-00 -0.469 -0.053 0.336 -0.378 -0.075 0.169
P-03 0.957 0.111 0.056 0.211 0.036 0.532
P-06 -0.790 -0.095 0.083 -0.514 -0.088 0.110
P-09 0.032 0.004 0.940 0.364 0.073 0.189
P-12 0.703 0.089 0.110 0.245 0.044 0.432
Patient Su
NoRx -1.984 -0.193 0.001 -0.876 -0.111 0.064
Losa -2.148 -0.201 <0.001 -1.338 -0.165 0.003
PBkft -0.179 -0.016 0.780 -0.239 -0.027 0.646
P-00 -1.172 -0.091 0.127 -1.408 -0.153 0.010
P-03 0.074 0.006 0.914 -0.366 -0.040 0.495
P-06 2.337 0.176 0.002 0.182 0.021 0.711
P-09 -0.237 -0.023 0.681 -0.267 -0.035 0.535
P-12 -0.707 -0.063 0.265 -0.174 -0.024 0.665
Systolic BP Diastolic BP
Table 6. TRENDS AS A FUNCTION OF TIME
168
Time-specified norms reveal full systolic but incomplete diastolic early MESORhypertension,
MH
Yoshihiko Watanabe12
, Germaine Cornélissen3
, Kuniaki Otsuka2
, Miguel Revilla4
, Jerzy
Czaplicki5
, Othild Schwartzkopff3
, Jarmila Siegelova6
, Franz Halberg3
and the broader BIOCOS
project
1
Dept Sports Medicine, School of Sports Sciences, Waseda Univ, Tokorozama, Saitawa, Japan
2
Dept of Medicine, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
4
Department of Applied Mathematics and Computer Science, University of Valladolid, Spain
5
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
6
Masaryk University, Brno, Czech Republic
Aim. Relatively unobtrusive, (on a family-and-friends basis easily) affordable
instrumentation for relatively dense (e.g., half-hourly) automatic blood pressure (BP) and heart
rate (HR) monitoring has become available, serving for ambulatory use (ABPM) in the hands of an
international project on The BIOsphere and the COSmos, BIOCOS (corne001@umn.edu), for a
chronobiologic (C) parametric (cosines-fit-based) and non-parametric (time-qualified stackingbased)
interpretation, i.e., for C-ABPM. With C-ABPM for at least 7 days/24 hours, a reliable
Circadian Stage-Dependence of Infradian Modulation of
Systolic Blood Pressure (SBP) Reveals Transyears Primarily by Night*
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0 5 10 15 20 25 30 35 40 45 50
Frequency (cycles/15 years)
SBP-A(mmHg)
02:30-05:30 06:30-09:30 10:30-13:30
14:30-17:30 18:30-21:30 22:30-01:30
* Results by population-mean cosinor summarizing data collected during 6 different 4-hour intervals (data at separate clock hours analyzed separately);
Data from YW (M, born 23 Nov 1952), cardiologist who monitoed himself around the clock mostly at 30-min intervals with only few short interruptions
from August 1987 to Jan 2003 (between ages 35 and 50).
12.5[10.0,16.7]y
1.47[1.34,1.65]y
Period (years [95% confidence limits]
1.013[0.980,1.079]y
0.507[0.495,0.534]y
Figure 1. Data collected around-the-clock for 15 years by YW at half-hour intervals were averaged hourly. Data from each clock
hour (24 separate time series) were analyzed by least squares spectra. Results from 4 consecutive clock hours (assigned at
midpoints) were summarized by population-mean cosinor and compared among the six 4-hour circadian stages (shown as six
curves in this graph). © Halberg.
169
Nam e:--------------------- Patient #: YW
Age: 55 Sex: M
To:
Patient Peer Group Patient Peer Group Patient Peer Group
Value Reference Value Reference Value Reference
Lim its Lim its Lim its
Range Range Range
Range Range Range
Range Range Range
(hr:m in) (hr:m in) (hr:m in)
(m m Hg x hour) (m m Hg x hour) (m m Hg x hour)
(mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units) (mmHg x hour)(in 1,000's units)
Individualized bounded indices: (STD = Standard)(Min = Minim um )(Max = Maxim um )(HBI = Hyperbanic Index)
INTERVENTIO N NEEDED M ORE M ONITO RING NEEDED
No Annually
Yes Drug Non-Drug As soon as possible
Other specify_________________________
M ESOR-Hypertension
Prepared By_____G erm aine Cornelissen________________ Date_19_/_Aug_/_2008____
1) Unusually long standing or lying down during waking: unusual activity, such as exercise, em otional
loads, or schedule changes, e.g. shiftwork; etc.; 2) Salt, calories, kind and am ount, other, etc.
Copyright, Halberg Chronobiology Center, University of Minnesota, Mayo Hospital, Room s 715,
733-5 (7th floor), Minneapolis Cam pus, Del Code 8609, 420 Deleware Street SE,
Minneapolis, MN 55455, USA. Fax 612-624-9989.
For questions, call F. Halberg or G. Cornelissen at 612-624-6976.
8/18/2008 2:30
65 1 0
STD (M IN; M AX)* STD (M IN; M AX)* STD (M IN; M AX)*
78.3% 3.1% 0.0%
236 4 0EXCESS
22:46 23:30 0:00
EXTENT OF EXCESS
DURING 24 HOURS
HBI*
10-YEAR CUM ULATIVE
PERCENT TIM E
OF ELEVATION
TIM ING OF
EXCESS
10.43 5.26-36.20
16:05 11:48-17:40 15:22 11:08-16:48 16:14 11:44-17:20
HEART RATE (bpm )
142.5 98.4-135.1 87.3 60.3-87.2 74.6 56.4-91.2
HIGH VALUES
(ACROPHASE) (hr:m in)
SYSTOLIC BP (m m Hg) DIASTOLIC BP (m m Hg)
23.61 6.4-39.40 11.83 4.84-29.80
(M ESOR)
PREDICTABLE CHANGE
(DOUBLE AM PLITUDE)
TIM ING OF OVERALL
M onitoring From :
Com m ents:
CHRONOBIO LOG IC CHARACTERISTICS
ADJUSTED 24-h M EAN
1/4/2008 9:30
SPHYGM OCHRON-TM
M onitoring Profile over Tim e;
Com puter Com parison w ith Peer Group Lim its
Blood Pressure (BP) and Related Cardiovascular Sum m ary.
Figure 2. The top section of the sphygmochron, between the first two heavy horizontal lines, shows that the MESOR of SBP is
outside the limit of acceptability for peers, as is the MESOR of DBP. For SBP in Figure 3, most single mean values by clock-hour
and -minute are within peer-group limits, albeit very close to the upper continuous line limit in Figure 3. In Figure 4, the stacking of
the data can mislead to call "normal" what is already abnormal. The DBP MESOR's deviation from the upper limit is small, 0.1
mmHg. It may seem far-fetched to base decisions on a difference of a small fraction of 1 mmHg for individuals used to judge at
best a few 24-hour profiles or single values. In the case of YW in turn, there are sets of values for over half a year, here
summarized in Figures 2-5, and further information in the light of 21 years of previous sphygmochrons. We conclude, from the
upper parametric part of the sphygmochron in this figure, that we detect earliest abnormality in DBP as well as SBP, at variance
with the lower half of the sphygmochron providing results from the inspection of a non-parametric stacking section with an
abnormality only of SBP. © Halberg.
diagnosis of MESOR-hypertension (MH) can be more thoroughly approximated than in the nowconventional
approaches, but eventually dense monitoring from birth to death is advocated. Nondrug
treatment, including relaxation and diet, notably a reduction of sodium intake, if and only if
documented as desirable by monitoring, is then pertinent (1, 2). When non-drug intervention fails,
170
drug treatment can be considered again with continued monitoring and an optimization of any
effect by timing, in keeping with an international consensus meeting (3).
Background. A physician-scientist, YW, has been using C-ABPM for over 2 decades (4-10).
He started at 35 years of age in August 1987 with half-hourly measurements around-the-clock with
the aim (in August 2008) of continuing the monitoring. He has used and plans to further use the
accumulating time series for the analysis of aging as it may differ in various circadian and other
rhythm stages (11), and, as the case may be, to detect any anomaly seen as a vascular variability
disorder (VVD) (12). At the same time, YW has been seeking and finding signatures of
heliogeomagnetic and/or of any other non-photic environmental factors (5), including those of the
about (~) 10-year Schwabe cycle (13). The half-hour density of the data also allows the study of
interactions between circadian stages and different infradian rhythms that are dependent upon or
are demonstrable only during certain limited stages of the about-daily cycle (10, 11, 14). Different
time series, each limited to a specific fraction of the 24-hour day, used to approximate different
circadian stages (10, 11), can lead to inferences different from each other and from those drawn
from around-the-clock data, Figure 1.
In addition to cardiologic and transdisciplinary research, we here explore or demonstrate, as
the case may be, the practical merits in an improved health care by an individualized computeraided
self-surveillance of one's cardiovascular variability. This aim was clearly stated in Ignaz
Zadek's doctoral thesis for his medical degree in Berlin in 1880 (15) and published one year later
(16). Zadek wanted to focus on BP variability in a given patient (15, 16). His concept was
extended by Theodore C. Janeway of Johns Hopkins University in 1904 (17). It should be noted
that Janeway, an opinion leader in his time, before examining a patient insisted on gathering
enough data to study periodic variations (we emphasize his use of the plural "variations",
indicating his interest not just in the change from day to night along the 24-hour scale, but also in
variability from day to day and along longer time series such as years [18]). There are many
rhythmic variations of BP in addition to circadians (18-22). Beyond finding periodicities
mimicking the Schwabe cycle on himself noted above, YW has also already demonstrated aboutyearly
cycles that drift and can be absent for long spans (of years), replaced by transyears, cycles
with periods, , longer than a year, mimicking the s found in the solar wind's speed and proton
content (20, 21).
Method. While the extended cosinor (23-25) and cross-spectral analyses were used for
research, a sphygmochron, as a BP and related cardiovascular summary, Figure 2, was prepared on
the continuously accumulating data as discussed elsewhere (18, 26) and as a screen for a VVD that
was found, namely systolic and diastolic MESOR-hypertension, based on a computer comparison
with peer group limits of YW's last over-7-month long section of his 21-year monitoring profile
over time.
Results. Figures 3-5 are plexograms, showing 48 averages of data stacked at intervals of 30
minutes along an idealized 24-hour scale, irrespective of day of sampling. Each point corresponds
to the average of many values at roughly the same clock-hour and minute within a bin on different
consecutive days from January 4 to August 18, 2008. It is clear from Figure 3 for SBP that the
majority of these plexogram values are (as yet) only very slightly, yet clearly outside the normal
range, delineated on the basis of data from clinically healthy peers of the same gender and age. For
diastolic BP in Figure 4, only three of 48 average values are unacceptable (3.1%), yet they all
approach the upper limit of acceptability. All HR values in Figure 5 are well within the range of
peers matched by gender and age.
171
Circadian Pattern of SBP
(YW, M, 55y)
70
80
90
100
110
120
130
140
150
160
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
SBP(mmHg)
SBP
SBP-lo
SBP-hi
Figure 3. Data covering 7.5 months stacked around the clock at half-hour intervals. Most of the SBP values lie slightly but clearly
outside the upper limit of peers of the same gender and age. See discussion in Figure 2 legend. © Halberg.
In the upper parametric portion of Figure 2, the conclusion that SBP was abnormal is derived
first from an abnormal MESOR of 142.5 mmHg for SBP. The abnormality of SBP is also seen
from stacking, a nonparametric approach (summarized in the section between the second and third
heavy horizontal lines): the extent of excess for this variable exceeded the upper limit of
acceptability of 50 mmHg x hour for a basic index (limit not shown). Furthermore, the percentage
time above the upper limit was found more than three-fourths of the time (78.3%), a further
nonparametric result.
172
Circadian Pattern of DBP
(YW, M, 55y)
40
50
60
70
80
90
100
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
DBP(mmHg)
DBP
DBP-lo
DBP-hi
Figure 4. DBP values are high, close to but mostly below the upper limit of acceptability. Nonetheless, as seen in Figure 2, their
MESOR is abnormal. The cosinor detects abnormality in the time-qualified normal range. © Halberg.
By contrast, in the lower part of the sphygmochron DBP abnormality is observed only 3.1%
of the time and excess is practically zero (1 mmHg x hour rather than over 50 as for SBP). In this
case, however, the upper parametric portion is the decisive diagnosis: the DBP MESOR, a rhythmadjusted
average, is above the upper limit by 0.1 mmHg, a difference which will seem trivial for
anyone used to looking at the "true" (imaginary) single BP measurement or even at the mean of a
24-hour profile. The merit of this diagnosis cannot be suggested based on a single case, but it is in
keeping with the assumption that, on a population basis, for each mmHg, an increase in risk does
occur when the population size is large enough, and if a population is still larger, the increase of
0.1 mmHg will also count. If a line is to be drawn somewhere, the sphygmochron shows that most
systolic values are above and most diastolic values are high yet below the prediction limit of peers.
173
The point of a sphygmochron in the case of YW at this time is that there is a double systolic and
diastolic BP disorder that constitutes a solid warning and is best treated and that can be picked up
by cosinor while DBP is still in the range of peers.
Circadian Pattern of HR
(YW, M, 55y)
30
40
50
60
70
80
90
100
110
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Time (Clock Hours)
HR(beats/min)
HR
HR-lo
HR-hi
Figure 5. HR values are well within the normal range of peers, distant from both upper and lower limits. © Halberg.
Whether drug or non-drug treatment is indicated must remain the decision of the
cardiologist/scientist/subject, who at this time prefers to lower his salt intake, fully aware that the
lowering of sodium intake must not be done blindly, without monitoring. This dietary
manipulation can raise rather than lower BP-M in a small number of subjects, whereas it is
apparently not pertinent on still other subjects (2). Only testing again while monitoring BP and
manipulating sodium intake can provide an answer that has to be sought for each given individual.
Discussion. Garages are monitored continuously to prevent crime, including rape.
Experimental animals are being monitored to develop new drugs. Those for whom the drugs are
174
being developed should also be monitored to find out when non-drug treatment should start as well
as when drug treatment should begin, once non-drug approaches are documented by C-ABPM to
have failed. In the case of YW, the stage has been detected when, on an over half-yearly C-ABPM
basis, both SBP and DBP became parametrically abnormal, something that summaries and
displays of stacked data could confirm for SBP but not (yet) for DBP. This inspection of stacked
data fails to indicate abnormality in DBP, as compared to peers of the same gender and age, but
not values close to the upper limit. Do we witness the moment when the MESORs have become
abnormal, but not yet the underlying single values? Did an increase in circadian amplitude precede
that in MESORs, as in the case of an Okamoto rat (27), and did an increase in LVMI (28) precede
the MESOR-increases? All of these questions await further scrutiny in YW's database and in time
series of others.
A methodological point to be emphasized for both variables is that, in the case of YW with
an assessment of cosinor yielded parameters, abnormality can be detected early before a
nonparametric approach detects it in DBP as well as SBP.
Conclusion. C-ABPM, when continued as a tool of preventive cardiology, can detect an
earliest individualized VVD and can prompt intervention while the same data serve for
transdisciplinary research (29).
1. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A,
Gorgo Y, Zhao ZY, Weydahl A, Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV,
Perfetto F, Tarquini R, Singh RB, Rhees B, Lofstrom D, Lofstrom P, Johnson PWC,
Schwartzkopff O, International BIOCOS Study Group. Cross-spectrally coherent ~10.5- and
21-year biological and physical cycles, magnetic storms and myocardial infarctions.
Neuroendocrinol Lett 2000; 21: 233-258.
2. Cornélissen G, Kawasaki T, Uezono K, Delea C, Halberg F. II: Blood pressure rhythms and
salt. Ann Ist Super Sanità 1993; 29: 667-677.
3. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group:
Resolution from a meeting of the International Society for Research on Civilization Diseases
and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995:
Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18
figures. URL http://www.msi.umn.edu/~halberg/
4. Watanabe Y, Cornélissen G, Halberg F. Thousands of blood pressure and heart rate
measurements at fixed clock hours may mislead. Neuroendocrinol Lett 2003; 24: 339-340.
5. Watanabe Y, Cornélissen G, Halberg F, Otsuka K, Ohkawa S-I. Association by signatures
and coherences between the human circulation and helio- and geomagnetic activity.
Biomedicine & Pharmacotherapy 2001; 55 (Suppl 1): 76s-83s.
6. Watanabe Y, Cornélissen G, Katinas G, Sothern RB, Halberg F, Watanabe M, Watanabe F,
Otsuka K. Non-photic, non-thermic circadecadal solar cycle interaction with cardiovascular
circannual and circasemiannual variation in heated air-conditioned habitat. Biomedicine &
Pharmacotherapy 2003; 57 (Suppl 1): 55s-57s.
7. Watanabe Y, Otsuka K, Watanabe H, Asahi Y, Sato C, Murayama M, Sugai J, Halberg F.
Circannual rhythm of blood pressure and heart rate in ambulatory blood pressure monitoring.
The Autonomic Nervous System 1992; 29: 17-23.
175
8. Watanabe Y, Cornélissen G, Halberg F, Otsuka K, Ohkawa S-i, Kikuchi T, Siegelova J.
Need for chronobiologic reference values (chronodesms) smoothed over age: a problem
awaiting a BIOCOS solution. Scripta medica (Brno) 2000; 73: 105-110.
9. Watanabe Y, Katinas G, Cornélissen G, Sothern RB, Siegelova J, Fiser B, Dusek J, Homolka
P, Prikryl P, Singh RB, Schwartzkopff O, Halberg F. Time course of blood pressures over 18
years analyzed separately by day and by week. In: Halberg F, Kenner T, Fiser B, Siegelova J,
eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic:
Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk
University; 2006. p. 42-46.
10. Watanabe Y, Halberg F, Cornélissen G, Katinas G, Watanabe F, Otsuka K, Bakken EE,
Sothern RB, Sothern SB. Various modulations by the seasons and by paraseasonality at
different circadian stages. The Autonomic Nervous System 2007; 44: 255-258.
11. Halberg F, Sothern RB, Cornélissen G, Czaplicki J. Chronomics, human time estimation and
aging. Submitted.
12. Halberg F, Cornélissen F, Schwartzkopff O, Blagonravov ML, Chibisov SM, Otsuka K,
Siegelova J, Beaty L, Nolley E, Sanchez de la Peña S, Zaslavskaya R, Radysh IV. Vascular
variability disorders (VVDs) and syndromes (VVSs): MESOR-hypertension, CHAT and
other. Proceedings, 1st International Workshop, Physiology of adaptation and quality of life:
problems of traditional medicine and innovation, People's Friendship University of Russia,
Moscow, Russia, May 14-16, 2008. p. 401-403.
13. Schwabe H. Sonnen-Beobachtungen im Jahre 1843. Astronomische Nachrichten 1844; 21:
254-256 (no. 495).
14. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clockhour
in long-term investigation is no panacea. Proceedings, International Conference on the
Frontiers of Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006,
p. 208-211.
15. Zadek I. Die Messung des Blutdrucks am Menschen mittelst des Basch'chen Apparates.
Berlin, med. F., Diss., 25. Nov 1880. Berlin: Schumacher; 1880. 48 p.
16. Zadek I. Die Messung des Blutdrucks am Menschen mittelst des Basch'chen Apparates. Z
klin Med 1881; 2: 509-551.
17. Janeway TC. The clinical study of blood pressure. New York: D. Appleton & Co.; 1904. 300
pp.
18. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber
M, Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la
Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N,
Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical
Instrumentation & Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
19. Cornélissen G, Masalov A, Halberg F, Richardson JD, Katinas GS, Sothern RB, Watanabe
Y, Syutkina EV, Wendt HW, Bakken EE, Romanov Y. Multiple resonances among time
structures, chronomes, around and in us. Is an about 1.3-year periodicity in solar wind built
into the human cardiovascular chronome? Human Physiology 2004; 30 (2): 86-92.
176
20. Cornélissen G, Halberg F, Breus T, Syutkina EV, Baevsky R, Weydahl A, Watanabe Y,
Otsuka K, Siegelova J, Fiser B, Bakken EE. Non-photic solar associations of heart rate
variability and myocardial infarction. J Atmos Solar-Terr Phys 2002; 64: 707-720.
21. Halberg F, Cornélissen G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka
P, Prikryl P, Chibisov SM, Holley DC, Wendt RW, Bingham C, Palm SL, Sonkowsky RP,
Sothern RB, Pales E, Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R,
Konradov AA, Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov
AV, Faraone P, Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T,
Pantaleoni GC, Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki
EA, Bathina S, Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M.
Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks,
near-decades, phylogenetic and ontogenetic memories. Biomedicine & Pharmacotherapy
2004; 58 (Suppl 1): S150-S187.
22. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
23. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
24. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T, editors. Encyclopedia
of Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
25. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
26. Halberg F, Cornélissen G, Otsuka K, Sanchez de la Peña S, Schwartzkopff O, Watanabe Y,
Pati AK, Wall DG, Delmore P, Borer K, Beaty LA, Nolley ES, Adams C, Siegelova J,
Homolka P, Dusek J, Fiser B, Prikryl P. Why and how to implement 7-day/24-hour blood
pressure monitoring? Int J Geronto-Geriatrics 2005; 8 (1): 1-31.
27. Halberg J, Halberg E, Hayes DK, Smith RD, Halberg F, Delea CS, Danielson RS, Bartter
FC. Schedule shifts, life quality and quantity modeled by murine blood pressure elevation
and arthropod lifespan. Int J Chronobiol 1980; 7: 17-64.
28. Kumagai Y, Shiga T, Sunaga K, Cornélissen G, Ebihara A, Halberg F. Usefulness of
circadian amplitude of blood pressure in predicting hypertensive cardiac involvement.
Chronobiologia 1992; 19: 43-58.
29. Halberg F, Schwartzkopff O, Cornélissen G, Otsuka K. Life's waves in space-time in and
around us. Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary
Symposium 2007, What is Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute
for Theoretical Physics, Kyoto University, October 15-20, 2007. p. 45-47.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
177
Differing far-transyear/calendar year amplitude ratios in blood pressure vs. heart rate in
adolescence
Fumihiko Watanabe1
, Germaine Cornélissen2
, Yoshihiko Watanabe1
, Jarmila Siegelova3
, Jerzy
Czaplicki4
, Franz Halberg2
and the broader BIOCOS project
1
Dept Sports Medicine, School of Sports Sciences, Waseda Univ, Tokorozama, Saitawa, Japan, and
Dept of Medicine, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
2
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
3
Masaryk University, Brno, Czech Republic
4
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
Abstract. We mapped the time structure during childhood and adolescence of systolic (S) and
diastolic (D) blood pressure (BP) and heart rate (HR) to find that a far-transyear dominated over the
calendar year in a boy's (FW) spectra of BP and vice versa in the spectrum of HR. Only transyears
and no calendar year components were found in the BP and HR of the boy's father (YW) in a record
starting at 35 years of age and continuing for over a decade around the clock at 30-minute intervals.
Background, Subject and Method. The extended cosinor (1-3) was used on data from FW, a
clinically healthy boy who had been monitored for the first 40 days of life at half-hour intervals,
revealing a gradual transition from dominant (non-photic) infradian (about half-weekly and weekly)
components to a (photic) circadian rhythm (4). Here, we examine the relative prominence of nonphotic
infradians in the para-annual spectral region, also mapped in the boy's father (5, 6). Neartransyears
(1.00 year < [ {period} - CI {95% confidence interval}] < [ + CI] < 1.20 years) and fartransyears
(1.2 years [ -CI < [ + CI] < 1.9 years) have been documented elsewhere (7).
Results. Figure 1 describes for FW the well-known trends during childhood and adolescence
of BP and HR self-measured daily on awakening. As anticipated, the trend is ascending in systolic
(S) BP and diastolic (D) BP (top two rows) and descending in HR (bottom row). The trends in BP
appear linear, those in HR curvilinear. Hence the two BP series were linearly detrended, whereas a
second-order polynomial was used to detrend the HR data. Results from the extended cosinor on the
residuals are shown in Figures 2 and 3 and are partly summarized further in Table 1. The data
suffice to assess, with uncertainties, a transyearly component that is more prominent than the yearly
(circannual) component for SBP and DBP, while a calendar year dominates the spectrum of HR. All
three variables reveal a component longer than a year in the category of a far-transyear (7). A 7-day
synchronized circaseptan rhythm and a precise 3.5-day rhythm are seen for the HR of FW (Figure
3), whereas only a circasemiseptan component is societally synchronized in SBP but not in DBP,
and a circaseptan peak differs from precisely 7 days in both SBP and DBP.
Discussion. Information from series of single measurements at a fixed clock-hour is not
necessarily the same as that based on around-the-clock profiles and can mislead, as shown on
himself by YW, the father of FW (5) and by others elsewhere (8, 9). Results on infradians can differ
as a function of circadian stage to the extent that a circasemiannual component of probable
geomagnetic origin is apparent in BP measurements taken in the evening for 22 years by a father
(SBS) starting measurements in his 60s, whereas in the spectrum of his measurements taken in the
morning, there is a valley at the 0.5-year trial period (8). SBS's son, RBS, started self-measurements
in his early 20s and is still self-measuring in his own 60s (10). An alignment of measurements from
two generations provides a perspective over most of a lifetime, yet remains to be qualified in that
inferences remain tentative. With this background, it is noteworthy that in data collected at
awakening, in the BP of FW, a transyear prevails, whereas an about-yearly change is statistically
significant but of lower amplitude, Table 1. The reverse is true overall for HR in FW, Table 1.
178
Figure 1. Time course of systolic (S) and diastolic (D) blood pressure and heart rate (HR)
measured daily upon awakening by a boy (FW) 8 to 15 years of age, participating in familial
autorhythmometry. © Halberg.
179
Figure 2. Components in a spectral window of the systolic (S) and diastolic (D) blood pressure
(BP) and heart rate (HR) of FW. Note that as compared to the calendar year component's
amplitude, A, numerically, the A of the also-present transyears is larger for SBP and DBP and
smaller for HR (see also Table 1). © Halberg.
180
Figure 3. Spectral components in a window complementing that in Figure 2 of the systolic (S) and
diastolic (D) blood pressure (BP) and heart rate (HR) of FW. Note the 7-day synchronized
circaseptan component with a circasemiseptan in HR but no corresponding prominent societallysynchronized
component in BP. © Halberg.
181
In the case of FW's father, between 35 and 55 years of age, transyears replace any calendar-yearly
component in BP and HR. It remains to be clarified whether the spectral structure of measurements
taken at other clock-hours differs from that in the morning, as shown for SBS (8) and YW (6, 11).
Transyears are also found in the incidence of natality as a population phenomenon in some
geographic locations such as the Philippines (12) and Brazil (13), but not in Japan (14) or Italy (15).
In a spectrum, transyears characterize the incidence of sudden cardiac death in some
geographic locations, where they can replace the calendar year, but not in other locations (7, 16),
where there is only a calendar year, and at still other sites, both a calendar year and a transyear
coexist. Transyears are also reported in spectra of the incidence of strokes (17) and epilepsy (18) in
Slovakia. The mapping of the infradian aspects in physiology and pathology opens new perspectives
in the otherwise neglected range of infradian cycles, as yet ignored by reference only to timeunspecified
normal values.
Conclusion. Transyears, signatures of the solar wind's speed, can characterize the human
circulation on awakening, during a span bracketing puberty in an 8-15-year-old boy (FW). Without
extrapolating the details here recorded to other clock-hours and other individuals, it seems
worthwhile to extend the monitoring of the circulation to families in order to recognize early
infradian as well as circadian abnormality and to attempt to treat it (cf. 6).
1. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
2. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T, editors. Encyclopedia
of Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
3. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
4. Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T,
Schwartzkopff O, Bakken E, Halberg F. Methodology: partial moving spectra of postnatal
heart rate chronome. Neuroendocrinol Lett 2003; 24 (Suppl 1): 139-144.
5. Watanabe Y, Cornélissen G, Halberg F. Thousands of blood pressure and heart rate
measurements at fixed clock hours may mislead. Neuroendocrinol Lett 2003; 24: 339-340.
6. Watanabe Y, Cornélissen G, Siegelova J, Halberg F. Far- and near-transyears, but no calendar
year in infradian blood pressure dynamics before MESOR-hypertension. These proceedings.
7. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla
M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G,
Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P,
Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress:
season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and
site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38.
http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
8. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clockhour
in long-term investigation is no panacea. Proceedings, International Conference on the
Frontiers of Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006, p.
208-211.
9. Halberg F, Sothern RB, Cornélissen G, Czaplicki J. Chronomics, human time estimation and
aging. Submitted.
10. Sothern RB, Katinas GS, Cornélissen G, Halberg F. A 38-year record, albeit informative, is
not yet enough: womb-to-tomb monitoring is overdue. Appendix 2 of Halberg F, Cornélissen
G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka P, Prikryl P, Chibisov
SM, Holley DC, Wendt HW, Bingham C, Palm SL, Sonkowsky RP , Sothern RB, Pales E,
Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R, Konradov AA,
182
Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov A V, Faraone P ,
Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T, Pantaleoni GC, Watanabe
Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki EA, Bathina S, Haus E,
Hillman D, Schwartzkopff O, Bakken EE, Zeman M. Chronoastrobiology: proposal, nine
conferences, heliogeomagnetics, transyears, near-weeks, near-decades, phylogenetic and
ontogenetic memories. Biomed & Pharmacother 2004; 58 (Suppl 1): S179- S186.
11. Watanabe Y, Halberg F, Cornélissen G, Katinas G, Watanabe F, Otsuka K, Bakken E, Sothern
RB, Sothern SB. Differing modulations by seasons, Halberg's paraseasonality, and
geomagnetics found at different circadian stages. In: Proceedings, 59th
Annual Meeting, Japan
Society of Neurovegetative Research, Tokyo, November 1-3, 2006. p. 61-63.
12. Mikulecky M, Florida PL. Daily birth numbers in Davao, Philippines, 1993-2003: Halberg's
transyear stronger than year. Abstract, 26th Seminar, Man in His Terrestrial and Cosmic
Environment, Upice, Czech Republic, May 17-19, 2005.
13. Mikulecky M. Reanalyza natality v jizni brazilii -- opet dominuje Halbergova parasezonalita:
International Conference on the Frontiers of Biomedical Science: Chronobiology, Chengdu,
China, September 24-26, 2006, p. 188-193.
14. Yamanaka T, Cornélissen G, Kazuma M, Kazuma N, Murakami S, Otsuka K, Siegelova J,
Dusek J, Sosikova M, Halberg F. Further mapping of the natality chronome, in Toda City
(Japan) Maternity Hospital. Scripta medica 2005; 78: 99-106.
15. Cornélissen G, Halberg F, Mikulecky M, Florida P, Faraone P, Yamanaka T, Murakami S,
Otsuka K, Bakken EE. Yearly and perhaps transyearly human natality patterns near the
equator and at higher latitudes. Biomed & Pharmacother 2005; 59 (Suppl 1): S117-S122.
16. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, Johnson P,
Gigolashvili M, Breus T, Sonkowsky R, Chibisov SM, Katinas G, Siegelova J, Dusek J, Singh
RB, Berri BL, Schwartzkopff O. Incidence of sudden cardiac death, myocardial infarction and
far- and near-transyears. Biomed & Pharmacother 2005; 59 (Suppl 1): S239-S261.
17. Kovac M, Mikulecky M. Secular rhythms and Halberg's paraseasonality in the time
occurrence of cerebral stroke. Bratisl Lek Listy 2005; 106 (2): 423-427.
18. Kovac M, Mikulecky M. Time sequence of epileptic attacks from the point of view of possible
lunisolar connections. International Conference on the Frontiers of Biomedical Science:
Chronobiology, Chengdu, China, September 24-26, 2006, p. 175-179.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
183
Table1:Transyeardominatesovercalendar-yearinbloodpressure,andviceversainheartrateforaboy(FW)*
Variable(units)
Trialperiod
(years)
Period(years)
(95%CI)
Amplitude(A)
(95%CI)
Amplituderatios(%)
(vs.1-yearA)
1.301.45(1.41,1.50)3.56(2.58,4.54)137
1.001.006(0.977,1.035)2.60(1.59,3.61)SBP(mmHg)
0.400.384(0.377,0.390)1.68(0.68,2.67)65
1.301.47(1.42,1.53)2.05(1.38,2.71)133
1.000.996(0.953,1.028)1.54(0.86,2.22)DBP(mmHg)
0.400.377(0.368,0.386)0.83(0.17,1.50)54
1.301.28(1.20,1.36)0.99(0.33,1.65)69
1.000.983(0.950,1.016)1.43(0.79,2.07)HR(beats/min)
0.400.346(0.340,0.351)1.11(0.47,1.75)78
*Extendedcosinoranalysesofdailysystolic(S)anddiastolic(D)bloodpressure(BP)andheartrate(HR)self-measurementsupon
awakeningbyaboyduringabout8yearsfrom8to15yearsofage(13Oct2001-16Aug2008).95%CI:95%confidenceinterval;
amplitude:measureofone-halfoftheextentofchangewithinonecyclepredictablebythefittedcosinemodel.InYW,thefatherof
FW,noyearlycomponentisdemonstrableduringadecadeofdataobtainedduringaspanwhenhewas35to46yearsofage,
precedingbyanotherdecadethediagnosisofMESOR-hypertension.Aligningtheresultsfrommonitoringofbothfatherandson
alongthescaleofagemayprovideinformationbutwilleventuallyhavetobecheckedbylifetimemonitoringoffamilies.Untilthen,
thebestthatcanbedoneistomonitormoresubjectsopportunistically.
184
Transyears, no calendar-year in blood pressure decades before MESOR-hypertension:
normal or abnormal?
Yoshihiko Watanabe12
, Germaine Cornélissen3
, Franz Halberg3
, Dewayne Hillman3
, Jerzy
Czaplicki4
, Robert B. Sothern3
, Kuniaki Otsuka2
, Jarmila Siegelova5
and the broader BIOCOS
project
1
Dept Sports Medicine, School of Sports Sciences, Waseda Univ, Tokorozama, Saitawa, Japan
2
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
4
Institute of Pharmacology and Structural Biology, CNRS UMR 5089, Toulouse, France
5
Masaryk University, Brno, Czech Republic
Aim. To map, in a clinically healthy cardiologist/scientist (YW) (1-7), any infradian cycles
that characterize the blood pressure (BP) and heart rate (HR) for a possible diagnostic use of their
alterations during a decade preceding the parametric diagnosis of both systolic (S) and diastolic
(D) MESOR-hypertension.
Subject. The first section (August 26, 1987, to August 4, 1998) of a 21-year record of YW, is
analyzed herein by the extended cosinor, in retrospect after the diagnosis of MESOR-hypertension
(MH) was established on the basis of YW's data from January to August 2008, both parametrically
and nonparametrically for SBP and parametrically for DBP by a sphygmochron, a summary over
time of BP and related variables, interpreted in the light of reference values from peers matched by
gender and age (8).
Methods. Original data from 1987 to 1998 are shown in Figure 1 between two horizontal
lines that correspond to the mean ± 3 standard deviations for SBP, mean arterial pressure (MAP)
and DBP, all based on oscillometric measurements, and HR. Values outside these lines are
compressed to fit within the lines and the rest of the ordinate. The unaided eye sees ups and downs
but cannot quantify the time structure (chronome) of these variations. Daily averages, shown in
Figure 2 (left), are analyzed by linear least-squares spectra (9-14), with results shown in Figure 2
(right).
Results. Both a near-transyear and a far-transyear are seen in the spectra of SBP, DBP and
HR, demonstrated in Figure 2 (right). Their 95% confidence intervals also given in Table 1 do not
overlap the precise calendar year, which actually corresponds to a trough rather than a peak for the
case of SBP and DBP and is on the descending slope (no peak) for HR.
Discussion. Two other subjects with treated MESOR-hypertension, FH (15) and GSK (16),
documented earlier that transyears can replace the calendar yearly component. The latter in turn, in
a record of self-measurements of BP by a clinically healthy normotensive subject (RBS), who
monitored himself about 5 times a day from 20 to 60 years of age, was prominent and dominated
over transyears that were also present (17). An about 1.3-year transyear component was invariably
detected in all of several dozen decades-long series examined thus far (18, 19). Whether or not a
MESOR-hypertensive subject has an alteration in the para-annual range of the BP and HR spectra,
e.g., in one or several infradian amplitude ratios, is currently only a basic question. It will have to
be examined in data from many subjects in health and disease. It may gain practical meaning once
affordable unobtrusive automatic instrumentation becomes available for lifetime automatic
sequentially chronobiologically analyzed monitoring for which the analytical procedures are
available (10-15, 20).
185
Figure 1. Display of original truncated data. © Halberg.
Conclusion. Whether or not the dominance of transyears over calendar years in the human
adult constitutes an infradian aspect of pre-hypertension, found thus far in one subject by
longitudinal BP monitoring, remains to be clarified on additional subjects.
1. Watanabe Y, Cornélissen G, Halberg F. Thousands of blood pressure and heart rate
measurements at fixed clock hours may mislead. Neuroendocrinol Lett 2003; 24: 339-340.
2. Watanabe Y, Cornélissen G, Halberg F, Otsuka K, Ohkawa S-I. Association by signatures
and coherences between the human circulation and helio- and geomagnetic activity.
Biomedicine & Pharmacotherapy 2001; 55 (Suppl 1): 76s-83s.
3. Watanabe Y, Cornélissen G, Katinas G, Sothern RB, Halberg F, Watanabe M, Watanabe F,
Otsuka K. Non-photic, non-thermic circadecadal solar cycle interaction with cardiovascular
circannual and circasemiannual variation in heated air-conditioned habitat. Biomed &
Pharmacother 2003; 57 (Suppl 1): 55s-57s.
186
Figure 2. Daily means, computed from data in Figure 1, are shown on the left. Results from least
squares spectra show the relative prominence of anticipated spectral components on the right and
in Table 1. © Halberg.
Table 1: Para-annual infradians in the pre-MESOR-hypertensive circulation at ages 35-46 y
(YW, male physician-scientist)*
Period Far-transyear (95% CI) Near-transyear (95% CI) Half-year (95% CI) ~0.36-year (95% CI)
Variable
Systolic BP 1.47 (1.42, 1.52) 1.103 (1.078, 1.129) 0.505 (0.497, 0.514) 0.360 (0.356, 0.364)
Diastolic BP 1.52 (1.47, 1.57) 1.071 (1.048, 1.094) 0.508 (0.502, 0.515) 0.359 (0.354, 0.365)
Heart rate 1.53 (1.48, 1.58) 1.038 (1.013, 1.064) 0.513 (0.501, 0.525) 0.365 (0.361, 0.369)
*BP: blood pressure; CI: confidence interval of point: near-transyear: 1.00 y < [ {period} - CI
{95% confidence interval}] < [ + CI] < 1.20 y; far-transyear: 1.2 y [ - CI] < [ + CI] < 1.9 y.
187
4. Watanabe Y, Otsuka K, Watanabe H, Asahi Y, Sato C, Murayama M, Sugai J, Halberg F.
Circannual rhythm of blood pressure and heart rate in ambulatory blood pressure monitoring.
The Autonomic Nervous System 1992; 29: 17-23.
5. Watanabe Y, Cornélissen G, Halberg F, Otsuka K, Ohkawa S-i, Kikuchi T, Siegelova J.
Need for chronobiologic reference values (chronodesms) smoothed over age: a problem
awaiting a BIOCOS solution. Scripta medica (Brno) 2000; 73: 105-110.
6. Watanabe Y, Katinas G, Cornélissen G, Sothern RB, Siegelova J, Fiser B, Dusek J, Homolka
P, Prikryl P, Singh RB, Schwartzkopff O, Halberg F. Time course of blood pressures over 18
years analyzed separately by day and by week. In: Halberg F, Kenner T, Fiser B, Siegelova J,
eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic:
Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk
University; 2006. p. 42-46.
7. Watanabe Y, Halberg F, Cornélissen G, Katinas G, Watanabe F, Otsuka K, Bakken EE,
Sothern RB, Sothern SB. Various modulations by the seasons and by paraseasonality at
different circadian stages. The Autonomic Nervous System 2007; 44: 255-258.
8. Watanabe Y, Cornélissen G, Otsuka K, Revilla M, Czaplicki J, Schwartzkopff O, Siegelova
J, Halberg F and the broader BIOCOS project. Time-specified norms reveal full systolic but
incomplete diastolic early MESOR-hypertension, MH. These proceedings.
9. Halberg F, Tong YL, Johnson EA. Circadian system phase—an aspect of temporal
morphology; procedures and illustrative examples. Proc. International Congress of
Anatomists. In: Mayersbach H v (Ed.) The Cellular Aspects of Biorhythms, Symposium on
Biorhythms. New York: Springer-Verlag; 1967. p. 20-48.
10. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
11. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T, editors. Encyclopedia
of Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
12. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
13. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
14. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber
M, Müller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la
Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N,
Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical
Instrumentation & Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
15. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
188
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
16. Katinas GS, Cornélissen G, Otsuka K, Haus E, Bakken EE, Halberg F. Why continued
surveillance? Intermittent blood pressure and heart rate abnormality under treatment. Biomed
& Pharmacother 2005; 59 (Suppl 1): S141-S151.
17. Sothern RB, Katinas GS, Cornélissen G, Halberg F. A 38-year record, albeit informative, is
not yet enough: womb-to-tomb monitoring is overdue. Appendix 2 of Halberg F, Cornélissen
G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka P, Prikryl P, Chibisov
SM, Holley DC, Wendt HW, Bingham C, Palm SL, Sonkowsky RP , Sothern RB, Pales E,
Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R, Konradov AA,
Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov A V, Faraone P ,
Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T, Pantaleoni GC,
Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki EA, Bathina S,
Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M. Chronoastrobiology: proposal,
nine conferences, heliogeomagnetics, transyears, near-weeks, near-decades, phylogenetic and
ontogenetic memories. Biomed & Pharmacother 2004; 58 (Suppl 1): S179- S186.
18. Cornélissen G, Masalov A, Halberg F, Richardson JD, Katinas GS, Sothern RB, Watanabe
Y, Syutkina EV, Wendt HW, Bakken EE, Romanov Y. Multiple resonances among time
structures, chronomes, around and in us. Is an about 1.3-year periodicity in solar wind built
into the human cardiovascular chronome? Human Physiology 2004; 30 (2): 86-92.
19. Cornélissen G, Halberg F, Rostagno C, Otsuka K. A chronomic approach to cardiac
arrhythmia and sudden cardiac death. The Autonomic Nervous System 2007; 44: 251-254.
20. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007; 120: e19-e20.
doi:10.1016/j.amjmed.2006.02.045.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
189
Chronomics: Anxiety disorder in adolescence and
heart rate asynchronized with weekly schedule
Yoshihiko Watanabe1
, Germaine Cornélissen2
, George S. Katinas2
,
Fumihiko Watanabe1
, Bohumil Fiser, Jarmila Siegelova, Othild Schwartzkopff2
, Franz Halberg2
1
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
2
Halberg Chronobiology Center, Univ. of Minnesota, Minneapolis, MN, USA
Abstract
Circadian rhythms that are not synchronized by the environment have been associated with
emotional disorders. Automatic hourly around-the-clock measurements of blood pressure (BP) and
heart rate (HR) of a 14-year-old Japanese boy for 38 days allow a test for asynchronization with
the daily and/or weekly routines. Transient, barely synchronized about 7-day (circaseptan)
components in BP and the lack of an external circaseptan synchronization of HR were found in
this boy. Findings may relate to his history of transient sweating and palpitations that prevented
him from attending school at 13 years of age and/or to his family history of vascular disorders.
Introduction
Evidence for a lack of synchronization with the environmental routine of the about 24-hour
core temperature rhythm had led to the coining of circadian (1) and to a Ross Pediatric Conference
(2). Circadian desynchronization of adrenocortical function from the societal routine, specifically
with a view of emotional disorders, including mania and depression, was reviewed in 1968 (3) and
continues to be actively investigated in the laboratory as in the clinic (4-8). Focus upon circaseptan
and other infradian rhythms is not new. Our meta-analyses of BP and HR in a thesis published in
1880 and republished in 1881 allow us to demonstrate about 3.5- and about-7-day rhythmicity in
addition to changes along the 24-hour scale. Janeway in 1904 wrote about BP periodicities in
plural; he could have been referring to about 24-hour and about 7-day rhythms (1).
Automatic longitudinal vascular monitoring on an adult patient during an episode of
depression revealed differential systolic (S) vs. diastolic (D) BP vs. HR behavior in the spectral
region of one week, Figure 1 (9). Here, we show partial lack of circaseptan synchronization of HR,
if not of BP with the societal 7-day routine, of interest in particular in a 14-year-old Japanese boy
who had episodes of anxiety in school. Such a spectral finding has been earlier related to an
episode of depression in an adult (9) and the symptoms of transient sweating and palpitations at 13
years of age in this boy came to mind. Adolescents with anxiety disorders are reportedly at an
increased risk of subsequent anxiety, depression, illicit drug dependence and educational underachievement
as young adults (10; cf. 11). This boy's data are also of particular interest from the
viewpoint of earliest BP rhythm alterations and high BP later in life (12). He has a family history
of vascular disease, and from this viewpoint his BP and HR had been monitored every 30 minutes
during the first 40 days of his life (12).
Case report
The boy's paternal grandfather died at 47 years of age of renal failure with malignant
hypertension associated with a pheochromocytoma. His maternal grandfather took medication for
high BP; his maternal grandmother had breast, gastric and uterine cancer by the time of her death.
His paternal grandmother underwent six surgeries for uterine cancer, colonic cancer and
degeneration of the spine and on each knee joint. His mother had surgery for breast cancer in the
summer of 2006. The boy's BP and HR were monitored around the clock, mostly at 30-minute
intervals for 40 days (October 20-November 28, 1992).
190
Figure1.Contourmapfromamovingperiodogramondataofa42-year-oldwomanwithbipolaremotionalillness.Theperiodisplottedonthe
abscissaandtimeontheordinate.Adifferentbehaviorisevidentinthecircadianbandofsystolicbloodpressure(SBP),ascomparedwiththe
behaviorofdiastolicbloodpressure(DBP)andheartrate(HR),duringtheepisodeofdepressionoccurringaroundOctober26.During
depression,thecircadianbandofSBPfadesgreatly(itpracticallydisappears)andthemainvariancemovestotheinfradianregion(tothe
right),whereasacomparablechangeisnotapparentforDBPandHR.©Halberg.
191
Thereafter, once a week, he monitored BP and HR for 24 hours at 60-minute intervals for 8 weeks,
until April 4, 1993. At 9 years of age on October 13, 2001, he started to monitor his BP and HR
once daily in the morning.
Problems arose at 13 years of age: In February 2005, he passed his junior high school
entrance examination. In March, he graduated from elementary school; in April he entered a
private junior high school, but during this month he could not attend school because of feelings of
anxiety about the school. From April to July he spent most of his time at home. In July, he started
to attend a public junior high school, where he made good friends. In 2006, when his best friend
moved out of town, he made new friends in his new class, and in April 2006 he started swimming
school. At 14 years of age, he was monitored again. His BP and HR were measured automatically
with a TM-2430 monitor from A&D (Tokyo, Japan), mostly every hour by day and night from
July 26 to September 10, 2006. Figures 2-4 show a circadian rhythm's consistent predominance in
a gliding spectral window, while Figures 5-7 show combined gliding (left) and global spectral
windows ("global" only in the sense of summarizing the entire series). The 24-hour synchronized
circadian rhythm stands out for all three variables in all of the gliding and global displays. The 24hour
synchronization is apparent numerically on the right, in that the 95% confidence interval of
the period overlaps 24 hours and that of the 12-hour harmonic overlaps 12 hours, the latter
component likely an expression of a nonsinusoidal circadian waveform. In Figure 7, the nonoverlap
of 168 hours by the 95% confidence interval of the circaseptan period of HR indicates a
lack of synchronization of the subject's pulse with a weekly schedule.
CIRCADIAN DOMINANCE OVER EXTRACIRCADIANS
IN GLIDING SPECTRUM OF HUMAN SYSTOLIC BLOOD
PRESSURE WITH PERSISTING CIRCASEPTANS AND
CIRCASEMISEPTANS (14-YEAR-OLD JAPANESE BOY)*
* Born 19.10.1992; his systolic blood pressure was measured at mostly 60-minute
intervals from 26 July 2006 for the ensuing 38 days and analyzed as a gliding
(moving) spectrum in separate weekly intervals, displaced in 12-hour increments
through the data set. A great prominence of circadians, shown by height and darker
shading, corresponds to larger amplitudes.
Amplitude(mmHg)
13.6
10.2
6.8
3.4
0.0
10
12
16
24
84
168
29-Jul
2-Aug
6-Aug
10-Aug
14-Aug
18-Aug
22-Aug
26-Aug
30-Aug
~1/2-week-c
~1-week-component (c)
(circaseptan)
~1/2-day-c
~1-day-c
(circadian)
Time
(calendar
date)
Period
(hours)
Figure 2. Time structure of systolic blood
pressure showing circadian dominance and
infradian intermittency while an about half-day
component may reflect variability in the
circadian waveform of a 14-year-old Japanese
boy. © Halberg.
192
CIRCADIAN DOMINANCE OVER EXTRACIRCADIANS
IN GLIDING SPECTRUM OF HUMAN DIASTOLIC BLOOD
PRESSURE WITH PERSISTING CIRCASEPTANS AND
CIRCASEMISEPTANS (14-YEAR-OLD JAPANESE BOY)*
* Born 19.10.1992; his diastolic blood pressure was measured at mostly 60-minute
intervals from 26 July 2006 for the ensuing 38 days and analyzed as a gliding
(moving) spectrum in separate weekly intervals, displaced in 12-hour increments
through the data set. A great prominence of circadians, shown by height and darker
shading, corresponds to larger amplitudes.
Amplitude(mmHg)
11.2
8.4
5.6
2.8
0.0
10
12
16
24
84
168
29-Jul
2-Aug
6-Aug
10-Aug
14-Aug
18-Aug
22-Aug
26-Aug
30-Aug
~1/2-week-c
~1-week-component (c)
(circaseptan)
~1/2-day-c
~1-day-c
(circadian)
Time
(calendar
date)
Period
(hours)
Figure 3. Time structure of diastolic blood
pressure showing circadian dominance and
infradian intermittency while an about halfday
component may reflect variability in the
circadian waveform of a 14-year-old
Japanese boy. © Halberg.
CIRCADIAN DOMINANCE OVER EXTRACIRCADIANS
IN GLIDING SPECTRUM OF HUMAN HEART RATE WITH
INTERMITTENTLY PERSISTING CIRCASEPTANS
(14-YEAR-OLD JAPANESE BOY)*
* Born 19.10.1992; his heart rate was measured at mostly 60-minute intervals from
26 July 2006 for the ensuing 38 days and analyzed as a gliding (moving) spectrum
in separate weekly intervals, displaced in 12-hour increments through the data set.
A great prominence of circadians, shown by height and darker shading,
corresponds to larger amplitudes.
Amplitude(beats/min)
11.2
8.4
5.6
2.8
0.0
10
12
16
24
84
168
29-Jul
2-Aug
6-Aug
10-Aug
14-Aug
18-Aug
22-Aug
26-Aug
30-Aug
~1-week-component (c)
(circaseptan)
~1/2-day-c
~1-day-c
(circadian)
Time
(calendar
date)
Period
(hours)
Figure 4. Time structure of heart rate
showing circadian dominance and infradian
intermittency while an about half-day
component may reflect variability in the
circadian waveform of a 14-year-old
Japanese boy. © Halberg.
193
Figure 5. Gliding spectrum (left) aligned with global spectrum (right) of systolic blood pressure of a 14-yearold
Japanese boy. Note that the 95% confidence intervals of the period of three components cover the
week, day and half-day, respectively. © Halberg.
Figure 6. Gliding spectrum (left) aligned with global spectrum (right) of diastolic blood pressure of a 14-yearold
Japanese boy. Note that 95% confidence interval of an infradian peak does not cover the precise halfweek
(= 84 hours). © Halberg.
194
Figure 7. Gliding spectrum (left) aligned with global spectrum (right) of heart rate of a 14-year-old Japanese
boy. Note lack of circaseptan synchronization by 95% confidence interval of a circaseptan component not
covering a precise week (= 168 hours). © Halberg.
Table 1: Nonlinear estimation of about 7-day and about 21-day periods ( , in days)
in the circulation of a Japanese boy (14 years of age)
Spectral region Circaseptan Circavigintan
Variable Kind of data Original Daytime means Original
Systolic blood pressure (SBP) 7.64* (6.78-8.50)
Not statistically
significant
21.97* (16.7-27.2)
Mean arterial pressure (MAP)c
Not assessed 7.41* (6.67-8.15)
Diastolic blood pressure (DBP) 7.45† (6.53-8.37) 7.37* (6.74-8.00)
Heart rate (HR) 8.19* (7.39-8.99) 8.05* (7.29-8.81)
SBP x HRc
Not assessed
*P<0.05; †borderline statistical significance; c
calculated
Note (in bold) that for variables involving heart rate, the 95% confidence intervals (given
in parentheses) of the circaseptan period do not cover the precise week.
195
Table 1 shows again that the 95% confidence interval of the circaseptan period of HR does
not cover the precise week, as do the corresponding 95% confidence intervals of SBP and DBP,
yet the confidence intervals of these variables also barely cover 7 days. The external circaseptan
asynchronization of HR is further supported and extended in analyses restricted to the daytime
means: in these time series, the circaseptan periods not only of HR but also of the double product
both have a 95% confidence interval that does not overlap precisely 7 days. The corresponding
confidence intervals of the circaseptan periods of DBP and mean arterial pressure barely cover
precisely 168 hours. Longer series would have been required to detect for the boy's BP any
probable external circaseptan asynchronization with the societal routine.
Table 2: Larger cardiovascular prominence of circaseptans in neonates and of
circadians in adults, gauged by amplitude ratios (AR)*
Mean AR and 95% confidence interval Comparison
Variable Neonates (40) Adults (15) Student t (P)
Systolic BP 2.23 (1.66, 2.99) 0.15 (0.09, 0.24) 9.545 (<0.001)
Diastolic BP 1.57 (1.18, 2.09) 0.13 (0.08, 0.21) 9.024 (<0.001)
HR 2.32 (1.78, 3.01) 0.16 (0.11, 0.25) 11.848 (<0.001)
*Data series on BP and HR analyzed by the least-squares (cosinor) fit of 24-hour and
7-day cosine curves to data series each covering at least 7 days around-the-clock.
The prominence of circaseptans early in extrauterine life raises the question whether this
chronome component may have evolved by resonance with solar wind-related
(geomagnetic) disturbance and/or may (also) currently constitute a response to our
cosmos. The endogenicity of BP and HR circaseptans is supported by their free-running
under conditions of an isolette for prematures or in social isolation for adults or for SBP in
an afebrile boy (with intermittent fever) on a daily routine in the presence of a 24-hour
synchronized circadian of locomotor activity.
Discussion
In the BP and HR of a clinically healthy-appearing newborn with a family history of vascular
disorders and cancer, about 7-day and other infradian (with a period longer than 28 hours) cycles
dominate during the first several weeks of life in terms of a much larger double amplitude (extent
of predictable change) as compared to that of the circadian variation (12). This finding is in
keeping with Table 2, summarizing earlier studies on 40 newborns by comparison to data on 15
adults. Circadian variations, initially less prominent than infradians, Figures 8-10, become
dominant only after the third week of life for the ensuing weeks (and until late in maturity). Again
at 14 years of age, we find about 7-day variations persisting in SBP and DBP and HR. In these
variables, circaseptans can disappear and reappear. Their behavior is quasi-persistent, revealed as
intermittent for all three variables and showing an alternation of circaseptans with
circasemiseptans in SBP and DBP during adolescence, Figures 2 and 3, as they did postnatally
(12).
The subject was monitored during vacation. In the presence of a fully 24-hour synchronized
circadian rhythm, a circaseptan asynchronization with the societal week of HR (and of the double
product) characterizes an adolescent who happened to exhibit a transient anxiety disorder,
consisting of sweating and palpitation, at 13 years of age, while attending school. As noted, after
graduation from elementary school in March 2005 (at 13 years of age), in April he entered a
private junior high school but anxiety prevented him from attending it. From April to July he spent
196
most of the time in his home. In July, he started to go to a public high school, could soon socialize,
made friends there and at the time of this writing seems to be content. Whether his circaseptan
asynchronization of HR was a residual from an anxiety disorder comes to mind in view of a prior
association between alterations of circaseptan rhythms during an episode of depression in an adult
(9), but to our knowledge control data on other adolescents covering weeks are not available.
There is evidence, however, for altered HR variability in patients with panic disorder (13).
0.00
1.45
2.90
4.35
5.80
7.25
8.70
10.15
11.60
13.05
0-1.45 1.45-2.9 2.9-4.35 4.35-5.8 5.8-7.25 7.25-8.7 8.7-10.15 10.15-11.6 11.6-13.05
** in a healthy boy, born 19.10.1992, whose blood pressure was measured at mostly 30-minute
intervals from 20.10 for the ensuing 40 days, and analyzed as a moving spectrum in separate weekly
intervals, displaced in 12-hour increments through the data set. An initially greater relative
prominence of infradians, shown by height and darker shading, corresponding to a larger percentage
rhythm, contrasts with the relative prominence of circadians and circasemidians in later weeks of life,
while any ultradians with still higher frequencies and any trends and chaos, two other chronome
elements, are here unassessed.
168
24
16
12
10
Period (hours)
24-Oct
28
1-Nov
5
9
13
17
21
25
Time
(calendar
date)
!
*PercentageRhythm(%)
~ 1-week-component (c)
~ 12-hour c
~ 1-day c
Figure 8. Changing relative prominence* of some
components in a partial spectral element of the
postnatal human systolic blood pressure
chronome**. Infradian-to-circadian moving systolic
blood pressure spectrum of a boy at term: side view
of relative prominence. © Halberg.
0.00
0.62
1.24
1.87
2.49
3.11
3.73
4.35
4.98
5.60
* in a healthy boy, born 19.10.1992, whose blood pressure was measured at mostly 30-minute intervals
from 20.10 for the ensuing 40 days, and analyzed as a moving spectrum in separate weekly intervals,
displaced in 12-hour increments through the data set. An initially greater prominence of infradians
(see ~ 1 week c, left), shown by height and color, corresponding to a larger amplitude, contrasts with
the prominence of circadians and circasemidians in later weeks of life, while any ultradians with still
higher frequencies and any trends and chaos, two other chronome elements, are here unassessed.
Amplitude(mmHg)
168
24
16
12
10
Period (hours)
24-Oct
28
1-Nov
5
9
13
17
21
25
Time
(calendar
date)
~ 12-hour c
~ 1-week-component (c)
~ 1-day c
Figure 9. Changing relative prominence* of some
components in a partial spectral element of the
postnatal human diastolic blood pressure
chronome**. Infradian-to-circadian moving diastolic
blood pressure spectrum of a boy at term: side view
of relative prominence. © Halberg.
197
0.00
1.09
2.18
3.27
4.36
5.45
6.54
7.63
8.72
9.81
0-1.09 1.09-2.18 2.18-3.27 3.27-4.36 4.36-5.45 5.45-6.54 6.54-7.63 7.63-8.72 8.72-9.81
* in a healthy boy, born 19.10.1992, whose heart rate was measured at mostly 30-minute intervals from
20.10 for the ensuing 40 days, and analyzed as a moving spectrum in separate weekly intervals,
displaced in 12-hour increments through the data set. An initially greater prominence of infradians
(see ~ 1 week c, left), shown by height and color, corresponding to a larger amplitude, contrasts with
the prominence of circadians and circasemidians in later weeks of life, while any ultradians with still
higher frequencies and any trends and chaos, two other chronome elements, are here unassessed.
Amplitude(beats/min)
168
24
16
12
10
Period (hours)
24-Oct
28
1-Nov
5
9
13
17
21
25
Time
(calendar
date)
~ 1-week-component (c)
~ 3-day c
~ 1-day c
~ 12-hour c
Figure 10. Changing relative prominence* of some
components in a partial spectral element of the
postnatal human heart rate chronome**. Infradianto-circadian
moving heart rate spectrum of a boy at
term: side view of relative prominence. © Halberg.
Figure 11. Circaseptan acrophases, , in the 17-ketosteroids and volume of urine excreted by a healthy
man*. Different behavior of the about-weekly variation in urinary excretion of 17-ketosteroids (top) and urine
volume (bottom) recorded by a clinically healthy man after self-administration of androgen. The acrophase
(phase of maximum) of a 7-day cosine curve is plotted on the ordinate, expressed in (negative) degrees,
with 360˚ equated to 7 days, and 0˚ (reference) set to midnight between Saturday and Sunday prior to start
of data collection. Analyses performed on data in a 182-day interval progressively displaced in 28-day
increments throughout the 15-year record (abscissa). © Halberg.
198
Figure 12. About 21-day component in
spectrum of systolic blood pressure of a 14year-old
Japanese boy. © Halberg.
In addition to the social routine's precise 7-day schedule, physical environmental conditions
also involve cyclic counterparts to a near-week such as a near 7-day oscillation in geomagnetic
activity (1) and in rainfall (14). Components corresponding in period length to those detected for
the subject were not found in the geomagnetic index Kp during the 38 days of his monitoring. His
HR is asynchronized with the geomagnetic variation as well as from the societal routine.
Circaseptan asynchronization, in the presence of a social weekly schedule in urine volume was
demonstrated earlier for the urinary excretion of 17-ketosteroids in a healthy man treated with a
heavy dose of androgen, Figure 11 (15).
Figure 12 shows that the SBP of this 14-year-old boy also exhibits an about 23-day
(circavigintan) spectral component. The nonlinearly estimated period is of 21.3 days with a 95%
confidence interval extending from 16.0 to 26.7 days, when accounting for the prominent circadian
rhythm, Figure 12. A similar component has been reported in the 17-ketosteroid excretion of a
clinically healthy adult man who collected and analyzed his 24-h urinary 17-ketosteroid excretion
over 15 years (15). Hence this component has been tentatively interpreted as the gauge of a
possible male sex cycle (the subject does not yet shave). Much additional mapping with
unobtrusive affordable instrumentation will be necessary to diagnose asynchronization and other
variability disorders of BP and HR at birth or during adolescence, an important task since
alteration of variability in the range of acceptable values represents risks greater than hypertension
in adults and can be detected by a time structural (chronomic) analysis (16, 17). Toward this goal,
Figures 2-7 and 12 constitute first maps that include infradian as well as circadian physiologic
variability and show changes in their relative prominence differing in adolescence as compared to
analyses of data collected neonatally (12).
Figures 1-10 illustrate an approach by a computer-implemented temporal microscopy of
physiological variables. In that context, they introduce an inferential statistical methodology for
the study of psychiatric time series in the context of transdisciplinary ones with aeolian wobbly
spectral components. The long-term aim is the detection of earliest disease risks at birth and in
adolescence by broadening the perspective from now-useful circadians (16-19) to other assessable
variations already sought in 1904 and found in data published in 1880 and 1881 (1). The Phoenix
Project, a group of Minnesota engineers (http://www.phoenix.tc-ieee.org), aims to build
unobtrusive, generally applicable non-cuff, electrode-independent inexpensive instrumentation for
199
monitoring BP and HR automatically and to provide analytical software for a time-structural
analysis in the light of reference values from peers matched by gender and age
(http://www.sphygmochron.org/). The analytical service is available cost-free from a project on
The BIOsphere and the COSmos, BIOCOS, by contacting corne001@umn.edu.
As to about 3.5- and 7-day cycles, they usually complement the almost-ubiquitous
circadians, along with other spectral components including about 20- and 30-day and about 5- and
~6-month rhythms, as well as annual and paraannual ones (20). The recognition that a seemingly
free-running about-weekly schedule resides in part in living matter came first from the breakdown
products of the very adrenocortical and gonadal hormones (17-ketosteroids = 17-KS) that are
important for survival and reproduction; the circadian story repeated itself.
First found was an apparently free-running rhythm in 17-KS with a period close to yet
different from precisely 7 days. On weekends, the subject (CH) drank an extra cup of tea and a
bottle of beer, a schedule that synchronized the volume he excreted and measured, but not the
steroid metabolites contained in his urine which he determined for 15 years by the same method,
with the same reagents bought at the outset (15). In other words, the precise 7-day period found for
CH in the urine volume in which the metabolites had been determined, coexisted with a period of
about (but different from precisely) 7 days in the excreted steroidal metabolite and was also
different (desynchronized) from another near-7-day period in the planetary geomagnetic index Kp
during the urine's collection span (1, 15).
Second, there was the observation that circaseptans appear after the administration of a single
stimulus that carries no 7-day information, as in the case of a partial hepatectomy studied by
Hübner (21) in rats and by us after kidney or heart transplantation in rodents and humans (22-24).
Single stimulus induction of circaseptans, or rather their manifestation after a single stimulus,
traced back to antiquity, was also the topic of a classic book on circaseptans by Günther
Hildebrandt and Ingrid Bandt-Reges (25; see also 26).
Third, as to ontogeny, a dominant weekly pattern, much more prominent than the alsopresent
circadian component in the same data, was seen in a survey of more than 181 profiles of
BP, each profile on a separate baby, each measured every 30 minutes for 48 hours on different 2
consecutive days of the first week of life (27), and in several hundred additional longitudinal
monitorings for several weeks during the first months of life (28). By the fourth week of life, the
circadian component usually dominated the human spectrum (12). In a crayfish, the circaseptan
dominated the activity pattern at the age of 6 months (29). In the case studied herein, aeolian
circaseptans persisted into adolescence, albeit they came and went and were only quasi-persistent.
Fourth, again as to ontogeny, the circaseptans regain relative prominence with elderly age,
concurrently with a circadian decrease in amplitude (30).
Fifth, as to phylogeny, the giant unicell Acetabularia acetabulum, standardized in light and
darkness alternating every 12 hours, thereafter released into continuous light, after signal
averaging of electrical activity, shows a circaseptan rhythm with a free-running near-one-week
period, with a much larger amplitude than that of the also free-running circadian rhythm (20).
Assuming that this alga has not changed in the interim, this eukaryote may tell us about the
environmental cycles it adapted to when it developed, perhaps 500 million years ago (31) at a time
that physical instruments cannot yet readily trace and the length of the day was several hours
shorter than today.
Sixth, like Acetabularia, tumor cell cultures, as spheroids or as monolayer, also show a
major circaseptan peak in -ATP concentration, with a superposed circadian in amplitude that is
barely one-third of the circaseptan (32, 33). While Acetabularia shows free-running circadians and
circaseptans, the tumor cells are 1- and 7-day synchronized and when Acetabularia shows a
200
dispersion of periods after a first cycle or so, the tumor cells remain 1- and 7-day synchronized for
six consecutive cycles. Tumor cell kill by radiation was much better at the circadian and
circaseptan peak of the -ATP marker, as compared to radiation administered at the circaseptan
and circadian minimum (32, 33), but the synchronizing stimulus is not identified in this case.
Seventh, remove-and-replace approaches, that led over half a century ago to mechanisms of
circadian rhythms (1) also served in the case of circaseptans. About 7-day rhythms opened a new
chapter in chronomics, the aligned recording of variables in and around us. Again a remove-andreplace
approach proved to be helpful, but it was not via an interference with the organism, such as
eye removal leading to free-running or bilateral adrenalectomy or suprachiasmatic nuclear
lesioning leading to different consequences in the case of different biological variables. This time
it was the cosmos, notably the sun, not the surgeon (in blinding) or genetics (in the case of
congenitally blind ZRD mice; 1), that did the removal and the cosmos also was responsible for the
replacement: when solar activity had 7-day components in its (Walsh) spectra (computed in St.
Petersburg by Vernova et al. (34), human HR (in Minnesota and Connecticut) had these
components amplified in its spectrum, and vice versa when these components were lacking in the
sun's record, the corresponding components in heart rate were damped, but not lost, showing that
they were also partly built in (35; cf. also 15). This coding of the circaseptans in our genes is
compatible with resonance. Hence it is hardly surprising to find an occasional pull of a biological
circaseptan acrophase by a geomagnetic cycle with a proximal frequency, e.g., for one variable but
not for another. While in the case of circadian rhythms the assumption that free-running indicated
the built-in nature of rhythms led to successes at the molecular level, in that case and more so in
the case of infradians, we must remember that organisms are open systems to their environments
and there is in any case a complementary system of the cosmos, that influences along infradian as
well as circadian scales the difference between survival and sudden cardiac death (36), suicide (37)
and being killed by the hand of others (38-40).
201
References
1. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
2. Halberg F. Circadian desynchronization. In: Fomon SJ, ed. Circadian Systems: Report of the
39th Ross Conference on Pediatric Research. Columbus, Ohio: Ross Laboratories; 1961. p.
18-19.
3. Halberg F. Physiologic considerations underlying rhythmometry, with special reference to
emotional illness. Symposium on Biological Cycles and Psychiatry. In: Symposium Bel-Air
III. Cycles biologiques et psychiatrie / publié sous la direction du professeur J. de
Ajuriaguerra. Geneva: Georg / Paris: Masson et Cle; 1968. p. 73-126.
4. Kripke DF, Youngstedt SD, Elliott JA, Tuuainen A, Rex KM, Hauger RL, Marler MR.
Circadian phase in adults of contrasting ages. Chronobiology International 2005; 22: 695-
709.
5. Van Reeth O. Sleep and circadian disturbances in shift-work: strategies for their
management. Hormone Research 1998; 49: 158-162.
6. Penev PD, Kolker DE, Zee PC, Turek FW. Chronic circadian desynchronization decreases
the survival of animals with cardiomyopathic heart disease. Am J Physiol1998; 275 (6 Pt 2):
H2334-H2337.
7. Tsai LL, Tsai YC, Hwang K, Hwang YW, Tzeng JE. Repeated light-dark shifts speed up
body weight gain in male F344 rats. Am J Physiol Endocrinol Metab 2005; 289 (2): E212-
E217.
8. Bartol-Munier I, Gourmelen S, Pevet P, Challet E. Combined effects of high-fat feeding and
circadian desynchronization. Int J Obesity 2006; 30: 60-67.
9. Cornélissen G, Halberg F, Schwartzkopff O, Delmore P, Katinas G, Hunter D, Tarquini B,
Tarquini R, Perfetto F, Watanabe Y, Otsuka K. Chronomes, time structures, for
chronobioengineering for "a full life". Biomed Instrum Technol 1999; 33: 152-187.
10. Woodward LJ, Fergusson DM. Life course outcomes of young people with anxiety disorders
in adolescence. J Am Acad Child Adolescent Psychiatry 2001; 40: 1086-1093.
11. Prior M, Smart D, Sanson A, Oberklaid F. Does shy-inhibited temperament in childhood lead
to anxiety problems in adolescence? J Am Acad Child Adolescent Psychiatry 2000; 39 (4):
461-468.
12. Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T,
Schwartzkopff O, Bakken E, Halberg F. Methodology: partial moving spectra of postnatal
heart rate chronome. Neuroendocrinol Lett 2003; 24 (Suppl 1): 139-144.
13. McCraty R, Atkinson M, Tomasine D, Stuppy WP. Analyses of twenty-four-hour heart rate
variability in patients with panic disorder. Biological Psychology 2001; 56: 131-150.
14. Abbot CG. Solar variation and weather, a summary of the evidence, completely illustrated
and documented. Washington DC: Smithsonian Miscellaneous Collections 146, No.3 (Publ.
4545); 1963. 67 pp. + 4 plates.
15. Halberg F, Engeli M, Hamburger C, Hillman D. Spectral resolution of low-frequency, smallamplitude
rhythms in excreted 17-ketosteroid; probable androgen induced circaseptan
desychronization. Acta endocrinol (Kbh) 1965; 50 (Suppl 103): 5-54.
16. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual
and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239.
doi:10.1161/01.HYP.0000250392.51418.64.
202
17. Halberg F, Cornélissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other
variabilities also await treatment. Am J Medicine 2007, doi:10.1016/j.amjmed.2006.02.045.
18. Halberg F, Cornélissen G, Bingham C, Tarquini B, Mainardi G, Cagnoni M, Panero C,
Scarpelli P, Romano S, März W, Hellbrügge T, Shinoda M, Kawabata Y. Neonatal
monitoring to assess risk for hypertension. Postgrad Med 1986; 79: 44-46.
19. Halberg F, Cornélissen G, Bakken E. Caregiving merged with chronobiologic outcome
assessment, research and education in health maintenance organizations (HMOs). Progress in
Clinical and Biological Research 1990; 341B: 491-549.
20. Halberg F, Cornélissen G, Schwartzkopff O, Otsuka K. The cosmos with aeolian cycles,
tipping the scale between death and survival: an indispensable control., in preparation.
21. Hübner K. Kompensatorische Hypertrophie, Wachstum und Regeneration der Rattenniere.
Ergebnisse der allgemeinen Pathologie und pathologischen Anatomie 1967; 100: 1-80.
22. Ratte J, Halberg F, Kühl JFW, Najarian JS. Circadian variation in the rejection of rat kidney
allografts. Surgery 1973; 73: 102-108.
23. DeVecchi A, Halberg F, Sothern RB, Cantaluppi A, Ponticelli C. Circaseptan rhythmic
aspects of rejection in treated patients with kidney transplant. In: Walker CA, Winget CM,
Soliman KFA (Eds.) Chronopharmacology and Chronotherapeutics. Tallahassee, Florida:
Florida A & M University Foundation; 1981. p. 339-353.
24. Liu T, Cavallini M, Halberg F, Cornélissen G, Field J, Sutherland DER. More on the need
for circadian, circaseptan and circannual optimization of cyclosporine therapy. Experientia
1986; 42: 20-22.
25. Hildebrandt G, Bandt-Reges I. Chronobiologie in der Naturheilkunde: Grundlagen der
Circaseptanperiodik. Heidelberg: Haug; 1992. 102 pp.
26. Cornélissen G, Halberg F. The biological week and broader time structures (chronomes): In
memory of Gunther Hildebrandt. Percept Motor Skills 2000; 90: 579-586.
27. Cornélissen G, Halberg F, Tarquini B, Mainardi G, Panero C, Cariddi A, Sorice V, Cagnoni
M. Blood pressure rhythmometry during the first week of human life. In: Tarquini B (Ed.)
Social Diseases and Chronobiology: Proc. III Int. Symp. Social Diseases and Chronobiology,
Florence, Nov. 29, 1986. Bologna: Società Editrice Esculapio; 1987. p. 113-122.
28. Cornélissen G, Engebretson M, Johnson D, Otsuka K, Burioka N, Posch J, Halberg F. The
week, inherited in neonatal human twins, found also in geomagnetic pulsations in isolated
Antarctica. Biomed & Pharmacother 2001; 55 (Suppl 1): 32s-50s.
29. Fanjul Moles ML, Cornélissen G, Miranda Anaya M, Prieto Sagredo J, Halberg F. Larger
infradian vs. circadian prominence of locomotor activity in young vs. older crayfish.
Abstract, 6° Convegno Nazionale de Cronobiologia, Chianciano, Italy, November 27-28,
1998. p. 65.
30. Gubin D, Cornélissen G, Halberg F, Gubin G, Uezono K, Kawasaki T. The human blood
pressure chronome: a biological gauge of aging. In vivo 1997; 11: 485-494.
31. Berger S, Kaever MJ. Dasycladales: An Illustrated Monograph of a Fascinating Algal Order.
Stuttgart: Thieme-Verlag; 1992. 247 pp.
32. Ulmer W, Cornélissen G, Revilla M, Siegelova J, Dusek J, Halberg F. Circadian and
circaseptan dependence of the beta-ATP peak of four different cancer cell cultures:
implications for chronoradiotherapy. Scripta medica (Brno) 2001; 74: 87-92.
33. Cornélissen G, Ulmer W, Halberg F. Basic research on cancer cell cultures for circadiancircaseptan
optimization of radiotherapy. PS-001, Proceedings, 2nd World Congress of
Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 62.
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34. Vernova YeS, Pochtarev VI, Ptitsyna NG, Tyasto MI. Short-period variations in the rate of
change of solar activity as a geosensitive parameter. Geomagnetism and Aeronomy 1983;
23: 425-427.
35. Cornélissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E,
Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD,
Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar
activity change. Biologia (Bratislava) 1996; 51: 749-756.
36. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, Johnson P,
Gigolashvili M, Breus T, Sonkowsky R, Chibisov SM, Katinas G, Siegelova J, Dusek J,
Singh RB, Berri BL, Schwartzkopff O. Incidence of sudden cardiac death, myocardial
infarction and far- and near-transyears. Biomed & Pharmacother 2005; 59 (Suppl 1): S239-
S261.
37. Cornélissen G, Halberg F. Chronomics of suicides and the solar wind. Br J Psychiatry 2006;
189: 567-568.
38. Wendt HW. Interplanetary magnetic field (IMF) polarity, collective emotions and entropy
changes of random event generators. Proceedings, 8th
International Congress "Health and
education millennium", Moscow, Russia, November 14-17, 2007, pp. 81-84.
39. Halberg F, Cornélissen G, Sothern RB, Chibisov SM, Wendt HW. Do unseen, very weak
magnetic mechanisms contribute to terrorism in wobbly spectral windows? Proc. 8th
International Congress "Health and education millennium", Moscow, Russia, November 14-
17, 2007, p. 63-66.
40. Cornélissen G, Halberg F, Wendt HW, Sothern RB, Chibisov SM, Kulikov SI, Agarwal RK.
Weak magnetoperiodism rather than socio-photo-thermoperiodism characterizes human
terrorism detection of about 1.3-year aeolian transyear but not precise 1.0-year cycle. Proc.
8th
International Congress "Health and education millennium", Moscow, Russia, November
14-17, 2007, p. 77-80.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
204
A transtridecadal cycle in human heart rate: Selective infradian, notably multidecadal solarphysiologic
BEL congruences
Robert B. Sothern, George S. Katinas, Bohumil Fiser, Jarmila Siegelova, Germaine Cornélissen,
Franz Halberg
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
Abstract
Noninvasive cardiology surveys vascular variability to detect earliest prehypertension,
prediabetes and a premetabolic syndrome. The data obtained for such prehabilitation can also be
used to monitor space weather. Thereby, we detect, in the human circulation as in a mental function,
genetically coded signatures of irregular nonstationary and hence questioned environmental cycles.
By inferential statistical methods and by transdisciplinary counterparts, we here validate a cycle
originally documented by plots of data for the unaided eye by three scientists -- Eduard Brückner,
Charles Egeson and William J.S. Lockyer -- hence dubbed the BEL cycle, from their last-name
initials. A set of analytical methods resolves solar-terrestrial-biospheric associations, good or bad, in
individuals', populations' and ecosystems' health and illness.
Figure 1. Brückner at an advanced age. Courtesy of Dr.
Reinhold Steinacker, O.Univ.-Prof., Head, Vice-Dean; Mag.
Walter Lang and Dr. Franz Holawe, Department of
Meteorology and Geophysics, Faculty of Geosciences,
Geography and Astronomy, University of Vienna, Austria.
Background
In an 1877 book on the history of astronomy, Rudolf Wolf (1) cites observation of meteor
showers in the Leonids that have a period of 33 ¼ years, "meaning that a maximum happens only
about every 33 years (i.e., 1799, 1833, 1866)". In a 324-page monograph published in 1890, Eduard
Brückner (2), Figure 1, very thoroughly compiled extensive data over several centuries in the case
of severe winters from 1000 to 1775. He suggested cycles of 34.87 years, which he documented
with many tables and figures and an overall chart, aligning variation in environmental temperature,
rainfall, ice-free rivers, cold winters and the wine harvest with Zürich relative sunspot (Wolf)
numbers. He reported that his cycle was independent of that in sunspots (which he assumed to
undergo an about 55-year cycle). Human migrations from Europe to North America and westward
within North America were associated by Brückner with his wet-dry cycle (3, 4). Alternations of
wet and dry climate and their possible signatures were highly variable from one cycle to the next,
205
yet when Brückner averaged them for consecutive spans of about 2 centuries each, he arrived at the
34.8-year length; we here refer to an over- (beyond = trans) tridecadal, i.e., transtridecadal or
circaquinseptennian cycle.
A few months before Brückner (in 1889), Charles Egeson (5) published his research on solar
meteorology, reporting a trans-tridecadal weather cycle in rainfall, thunderstorms and westerly
winds in the month of April for Sydney, Australia, with the length of the period varying from 33 to
34 years. William J.S. Lockyer (6) deserves credit for finding an ~35-year period in the length of the
sunspot cycle and for aligning this cycle with terrestrial weather. In 1901, William Lockyer (6)
concluded that the time between consecutive minima in sunspots underwent an about 35-year
variation, as did the total spotted area between any two consecutive minima, all in keeping, per
Lockyer (6), with Brückner (2): "The climate variations indicated by Professor Brückner are
generally in accordance with the 35-year period" (6). W.J.S. Lockyer added that the frequency of
aurorae and magnetic storms also shows indications of a 35-year period (6).
Based largely on the details in (1), the story of solar-terrestrial meteorology since antiquity
was given 2 years later in the journal Science by William Lockyer's father, Sir Norman Lockyer
(discoverer of helium in the sun's atmosphere and founder of the journal Nature) (7). Sir Norman
began with a statement in 1903 that remains timely in 2008: "There are very many cases recorded in
the history of science in which we find that the most valuable and important applications have arisen
from the study of the ideally useless. Long period weather forecasting, which at last seems to be
coming into the region of practical politics as a result of the observation of solar changes, is another
example of this sequence" (7). Sir Norman Lockyer then traced the history of solar-terrestrial
variables to ancient China, which was aware of sunspots and of "a magnetic force which acts upon a
needle" (7).
The BEL reports were documented by no more than curves for visual inspection by the
unaided eye, a circumstance prompting Arthur Schuster in 1914, at his time the leading numerical
investigator of hidden periods in his field, to examine Brückner's data and to question the
justification of calling the Brückner cycle a periodicity: he explicitly indicated, however, that he did
not wish to detract from the phenomenon's importance (8). Subsequently, S.I. Kostin questioned any
"Brückner or 'Brikner''' cycle explicitly (in 1965; 9), while Felix Sigel in 1979 referred to the
"Brikner" cycle as a multiple of Schwabe's circadecadal periodicity in Zürich relative sunspot
(Wolf) numbers (10). In 2003, in an article on fire cycling, there is again a misspelled reference to
"Brikner's climatic cycle", described as "minor" yet properly identified in the range from 36-41
years (11). Since 2000, the GKSS-Forschungszentrum (Geesthacht, Germany) has awarded the
Eduard Brückner Prize every three years for outstanding interdisciplinary work in climate research
(12); yet several investigators in solar-terrestrial atmospheric physics and/or geophysics in the USA,
when asked by one of us in 2008, said they had never heard of the "Brikner" or Brückner cycle.
Thus, in 2008 the original discoverers of trans-tridecadals are, at least in the USA, mostly forgotten.
Without citation to Egeson, Brückner or the Lockyers, and without reference to a
transtridecadal cycle, the close relation of changes in the length of the solar cycle to climate (11)
was documented in 1991 (13); other pertinent papers had been reviewed in a historical context by
1995 (14). A possible 35.6-year variation was reported early in the 21st
century in coronal holes
(15), yet in a spectrogram, it was a transient. It was not a peak in a (global) analysis of the entire
series by the extended cosinor analysis method. 33-year variations were found "... in all the solarterrestrial
parameters ..." in 2006 by Nayar, who applied wavelet decomposition analysis to sunspot
numbers and solar wind velocity, among other variables (16).
For cases of both accepted and questioned cycles in or around us, we had proposed that, as
three highly desirable steps, a test of the zero-amplitude (no cycle) assumption combined with
point-and-interval estimation should be carried out first. Second, we advocated the search for a
206
Figure 2. Congruence or similarity in characteristics such as the period or phase of a spectral component in
two or more concomitantly sampled time series of the same variables or of different variables within
intracellular entities, cells, tissues, organs, organ systems, individuals, populations, disciplines and, most
interestingly, when they are transdisciplinary, as are transyears or trans- and cis-half-years. © Halberg.
207
transdisciplinary counterpart, i.e, a component with a corresponding cycle length, defined as
congruent by overlapping or overlying CIs (95% confidence intervals) of the periods, s, involved,
Figure 2 (17; cf. 18-20). Third, we advocate, when possible, a remove-and-replace approach (17).
These criteria apply when the period of one data series is mimicked transdisciplinarily in another; it
then provides strong support in transdisciplinary terms for the reality of aeolians (see below),
notably when the intermittent nature of the phenomena in a given discipline prompt "lingering
doubts", to cite verbatim a physicist (C. Wolff) questioning his own report of an 0.42-year period.
The cycle of about 5 months length was predicted by Charles Wolff (21-24) and found to
characterize hard solar flares by Rieger (25) and others (26-34) in other aspects of solar activity; it
was biospherically validated in sudden cardiac death (ICD10, code I46.1) in Minnesota, the Czech
Republic, Hungary, Austria and Tokyo (35-37), and in suicide (38-40), in circulating melatonin
(20), in the 17-ketosteroid excretion of a clinically healthy man during 15 years and in the diastolic
blood pressure of a treated MESOR-hypertensive man, GSK, with an intermittent circadian
overswing, CHAT (41). The intermittent and otherwise nonstationary waxing and waning in
amplitude to the point of disappearing and reappearing, bifurcating and rejoining, and drifting in
frequency, found in the solar wind's speed, was dubbed "aeolian".
Results
In a clinically healthy man, RBS, a transtridecadal cycle characterizes his heart rate measured
for 40 years about 2-7 times daily (on the average about 5 times daily). A cycle of about 32.9 years
stands out clearly in a spectrum (Figure 3 right) and is visualized in a model fitted to the display of
original data as a function of time (Figure 3 left). It is congruent with a cycle in Zürich (Wolf)
numbers during the same span, which is visualized in Figure 4. The CIs in Figures 3 and 4 give
quantitative details (in parentheses) of uncertainties in heart rate and Zürich numbers. The
circadecadal congruence differs among the 3 vascular variables in Figure 5. Selective infradian
congruence is also seen for circaseptan components in Figure 6.
There is further selective mental-environmental congruence in the transyear window of
bioresonance. In a relatively small spectral window of a 36-year series of the around-the-clock
estimation of 1 minute (TE), we find four cases of congruent spectral components in this mental
function matching those in both solar wind speed (S) and a geomagnetic index, aa (E). There were
another four cases of congruence between TE and S only (not E) and two added cases of congruence
between aa (E) only (not S) and TE. This may be interpreted as in keeping with both direct effects
of S or E and/or of S acting via E.
Selective congruence may be limited to certain circadian stages. This is the case of a human
mental function (TE) which is modulated by BEL in a 36-year-long time series, as discussed
elsewhere in these proceedings. Congruence may vary in time, i.e., may be transient or intermittent,
as in the case of a cis-half-year in 17-ketosteroid excretion vs. that in the planetary magnetic
disturbance index Kp, suggesting that the biological counterpart is partly built-in since it persists
when the environmental counterpart is not detected.
208
Figure 3. *Weekly averages of data from RBS, clinically healthy man, 21 years of age at start of selfmeasurements
5-7 times per day during 1967-2006 (N=1978). Transtridecadal Brückner-Egeson-Lockyer
cycle (BEL) of 32.9 years in human heart rate of RBS given with its 95% confidence interval in the spectral
window (right), derived from original data shown on the left with the fitted model. Note that numerically the
BEL cycle has the largest amplitude in the window examined, while it is the smallest in Figure 4 in Zürich
numbers. © Halberg.
Figure 4. Composite 3-cmponent model fitted to data (bottom right), with contribution by each separate
component also shown (top and bottom left) with nonlinearly resolved period (in years) and 95% confidence
interval in person. Minor transtridecadal BEL aspect of Zürich sunspot numbers, top left, as compared to
other components with much larger amplitude (top right and bottom left) and by contrast to the prominent
BEL in heart rate in *RBS (clinically healthy man, about 20.5-years of age at start of monitoring) shown in
Figure 3. Entire model shown at the bottom on the right. © Halberg.
209
Gaa
BSC
WN
SBP
DBP
HR
* BSC = Hale's Bipolarity Sunspot Cycle (odd cycles coded negative); WN =
Schwabe's relative sunspot numbers (Wolf Numbers); Gaa = Geomagnetic aaIndex;
SBP = Systolic Blood Pressure; DBP = Diastolic Blood Pressure; HR = Heart
Rate. Cardiovascular data collected during 38 y by RBS, a MESOR-normotensive
man, 20.5 y old at start of ongoing ~5 daily self-measurements. Width of horizontal
bars = 95% confidence intervals (CIs) for all s. All series in same span (May 11
1967 to Nov 07 2005). Thin connecting lines and shading indicate overlapping CIs.
Conclusion (tentative; based on limited data): CIs of s of some
cardiovascular spectral components overlap (when driven ?) or do
not overlap (but are near) environmental reciprocal s (when they are
endogenous ?); alternatives, including chance, not ruled out.
TRANSDISCIPLINARY MAPPING: ENVIRONMENTAL
RECIPROCALS TO PHYSIOLOGICAL CYCLES;
SOLAR SIGNATURES IN THE HUMAN CIRCULATION:
MULTIDECADAL - MULTIANNUAL CONGRUENCE *
Frequency (cycles per 40 y, log scale)
1 2 3 4 5 6 7 8
Period ( , years, y)
40 30 1020 5715
95% CI
C
O
S
M
O
S
M
A
N
= Small lack of overlap: endogenous, driven or chance ?
Figure 5. Differential congruence of environmental and physiological peaks in RBS, a clinically healthy man
who self-measured blood pressure and heart rate about 5 times a day from the age of ~20 to about 60
years. On top, Hale's bipolarity sunspot cycle (BSC) is congruent by the criterion of overlapping, if not
overlying 95% confidence intervals of periods with systolic (S) and diastolic (D) blood pressure at some
frequencies and with heart rate at a different frequency. Differential congruences are also seen between
Zürich relative sunspot numbers or geomagnetics and the physiological variables and further among
environmental or physiological variables themselves. Congruences are a first step for the study of
biospheric variables by the consequences of subtraction vs. replacement of an environmental frequency.
This figure, summarizing 40 years of physiological data, should point first to the need for replicating
congruence studies on populations of self-monitoring subjects, since a replication on the same individual is
lengthy and involves interactions with age. By the same token, congruence studies are desirable at shorter
infradian periods, as in Figure 6. © Halberg.
210
CIRCASEPTAN CONGRUENCE IN CERTAIN ENVIRONMENTAL SPECTRAL
COMPONENTS AND IN SOME CARDIOVASCULAR COUNTERPARTS
6.706.806.907.007.107.20
Period (days, d)
SOLAR WIND's (SW)
SPEED
HEART RATE (HR)
SYSTOLIC BLOOD
PRESSURE (SBP)
DIASTOLIC BLOOD
PRESSURE (DBP)
Point estimation
95% CI**
6.78 d
7.00 d
****
***
Dst
Kp
Ap
6.82 d7.01 d
7.03 d
* All peaks are statistically significant (P<0.001) by linear-nonlinear least squares cosinor
spectra (not corrected for multiple testing). HR, SBP and DBP (N=124,263 each): half-hourly
records of GSK, a 72-year old man at start of around-the-clock monitoring; SW (N=69,845)
hourly values from http://omniweb.gsfc.nasa.gov/ ; Dst, Ap and Kp 3-hourly data (N=23,376
each) from http://spidr.ngdc.noaa.gov/ .
** CI: confidence interval. *** Two separate spectral peaks without CI-overlapping.
**** All available daily SW data during 1963-2005.
Figure 6. Human heart rate monitored around the clock for over 8 years is characterized by an about 6.78day
circaseptan component with a 95% confidence interval congruent with a matching component found in
solar wind speed for the corresponding span as well as for a much longer span of over 40 years of all data
available at the time of analysis. A similar component is also found to characterize several indices of
geomagnetic activity (Dst, Ap, Kp). A similar component is not found, however, for blood pressure
measured concomitantly, characterized by a 7-day synchronized and several other non-7-day circaseptans,
two of which are congruent with the periods of indices of helio- and at least 2 indices of geomagnetic
activity, of which only one also has a congruence with a period of heart rate. Another period of blood
pressure and heart rate, is congruent with geo- but not with heliomagnetic activity. The closeness of the
spectral bumps if not hills, however, does not yield the same opportunity for emphasizing selectivity as
compared to similar congruences among spectrally well-separated peaks such as those in the decadal and
transyearly ranges, Figures 4 & 5. Precisely because of the much better demonstrability of
heliogeobiocongruence in the case of distant peaks, those in a crowded very narrow spectral range must
not be dismissed by questioning the validity of very many circaseptan components, some of which
demonstrably (by chronomic serial section) occur at different times during the observation span. Rules
based on lessons learned from congruence among different distant peaks may or may not be found to
apply to peaks, e.g., in the circaseptan spectral region. One such rule is that blood pressure and heart rate
can be congruent, each with a different spectral component of the same environmental variable in a subject
studied over nearly 4 decades, Figure 5. This rule is confirmed and extended by data only over 8 years in
the circaseptan range, where the 8 years cover 416 cycles, many more than the 40 years can cover in a
circadecadal range (a minimum of 4 decadal cycles and hardly more than a tridecadal cycle). Moreover,
any global summary such as those in Figures 5 and 6 is best extended by a chronobiologic-chronomic
211
serial section that reveals the time courses of the spectral components. Global congruences await analysis
of variations in congruence with time. © Halberg.
Conclusion
In all cases of congruence, time courses of corresponding serial data covering preferably the
longest available documented spans of the variables involved have to be aligned and examined for
any consistent reproducible consequences associated with a remove-and-replace or at least
subtraction-and-addition approach (35-40, 42). This requirement does not detract from the basic fact
that each of the cycles in and around us, notably those that are found in many disciplines constitute
the indispensable control for any endeavor involving a mapped variable along a corresponding time
scale. Non-invasive cardiology can use the data collected for prehabilitation as invaluable reference
values instead of fictitious, albeit popular baselines (43, 44).
1. Wolf R. Geschichte der Astronomie. Münich: Druck und Verlag von M. Oldenbourg; 1877. 815 pp.
2. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die Klimaschwankungen der
Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A, Hrsg. Geographische
Abhandlungen, Band IV.)
3. Brückner E. The settlement of the United States as controlled by climate and climatic oscillations. In:
Memorial Volume of the Transcontinental Excursion of 1912 of the American Geographical Society of
New York. New York: American Geographical Society; 1915. p. 125-139.
4. Rain Affects Emigration. New York Times, October 12, 1912. http://query.nytimes.com /mem/archive-
free/pdf?res=9C05E1DC133CE633A25751C2A9669D946396D6CF
5. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar and
terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
6. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
7. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
8. Schuster A. On Newcomb's method of investigating periodicities and its application to Brückner's
weather cycle. Proc Roy Soc Lond A 1914; 90: 349-355.
9. Kostin SI. Is the Brikner (Brueckner) cycle real? Directorate of Scientific Information Services Ottawa
(Ontario), May 1965. 4 pp.
http://stinet.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0615768
10. Sigel F (Dreier W, Lerche D, Übers.; Göring H, Wissenschaftl. Red. der deutschsprachigen). Schuld ist
die Sonne. Thun/Frankfurt am Main: Harri Deutsch; 1979. 215 pp.
11. Khanuk VI, Dvinskaya ML, Ranson KJ. Fire cycling in the larch-dominated communities. In:
Geoscience and Remote Sensing Symposium, 2003. IGARSS '03. Proceedings, IEEE International, 21-
25 July 2003, volume 2: 1296-1298. ISBN: 0-7803-7929-2. doi: 10.1109/IGARSS.2003.1294088.
12. Award of the third Eduard Brückner Prize. November 16, 2006.
http://www.gkss.de/institute/coastal_research/news/news/005107/index_0005107.html.en
13. Friis-Christensen E, Lassen K. Length of the solar cycle: an indicator of solar activity closely
associated with climate. Science 1991; 254: 698-700.
14. Lassen K, Friis-Christensen E. Variability of the solar cycle length during the past five centuries and
the apparent association with terrestrial climate. J Atmos Solar-Terr Phys 1995; 57: 835-845.
15. Maravilla D, Lara A, Valdés Galicia JF, Mendoza B. An analysis of polar coronal hole evolution:
relations to other solar phenomena and heliospheric consequences. Solar Phys 2001; 203: 27-38.
16. Prabhakaran Nayar SR. Periodicities in solar activity and their signature in the terrestrial environment.
ILWS Workshop, Goa, February 19-24, 2006. 9 pp.
17. Halberg F, Bakken EE, Katinas GS, Cornélissen G, Zaslavskaya RM, Blank MA, Syutkina EV, Breus
TK, Watanabe Y, Masalov A, Chibisov SM. Chronoastrobiology: Vernadsky's future science ?
Benefits from spectra of circadians and promise of a new transdisciplinary spectrum of near-matching
cycles in and around us. Opening keynote, Proceedings, III International Conference, Civilization
diseases in the spirit of V.I. Vernadsky, People's Friendship University of Russia, Moscow, Oct. 10-12,
2005, p. 4-22.
212
18. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P, Bakken E,
International Womb-to-Tomb Chronome Initiative Group: Chronobiology in space. Keynote, 37th Ann.
Mtg. Japan Soc. for Aerospace and Environmental Medicine, Nagoya, Japan, November 8-9, 1991.
University of Minnesota/Medtronic Chronobiology Seminar Series, #1, December 1991, 21 pp. of text,
70 figures.
19. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A, Gorgo Y,
Zhao ZY, Weydahl A, Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV, Perfetto F, Tarquini R,
Singh RB, Rhees B, Lofstrom D, Lofstrom P, Johnson PWC, Schwartzkopff O, International BIOCOS
Study Group. Cross-spectrally coherent ~10.5- and 21-year biological and physical cycles, magnetic
storms and myocardial infarctions. Neuroendocrinol Lett 2000; 21: 233-258.
20. Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. About 5-month cycle in
human circulating melatonin: signature of weather in extraterrestrial space? Poster presentation, Fourth
UN/ESA/NASA/JAXA Workshop on the International Heliophysical Year 2007 and Basic Space
Science: "First Results from the International Heliophysical Year 2007", Sozopol, Bulgaria, June 2-6,
2008.
21. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
22. Wolff CL. Distinctive patterns on the surface of slowly rotating stars whose oscillations are nonlinearly
coupled. Astrophys J 1974; 193: 721-727.
23. Mayr HG, Mengel JG, Wolff CL. Wave-driven equatorial annual oscillation induced and modulated by
the solar cycle. Geophys Res Lett 2005; 32: L20811. doi:10.1029/2005GL023090. 5 pp.
24. Wolff CL, O'Donovan AE. Coupled groups of g-modes in a sun with a mixed core. Astrophys J 2007;
661: 568-585.
25. Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day periodicity in the
occurrence of hard solar flares? Nature 1984; 312: 623-625.
26. Bogart RS, Bai T. Confirmation of a 152-day periodicity in the occurrence of solar flares inferred from
microwave data. Astrophys J 1985; 299: L51-L55.
27. Bai T, Cliver EW. A 154 day periodicity in the occurrence rate of photon flares. Astrophys J 1990;
363: 299-309.
28. Bai T, Sturrock PA. Evidence for a fundamental period of the sun and its relation to the 154 day
complex of periodicities. Astrophys J 1993; 409: 476-486.
29. Kile JN, Cliver EW. A search for the 154 day periodicity in the occurrence rate of solar flares using
Ottawa 2.8 GHz burst data, 1955-1990. Astrophys J 1991; 370: 442-448.
30. Oliver R, Ballester JL. Short-term periodicities in sunspot areas during solar cycle 22. Solar Physics
1995; 156: 145-155.
31. Carbonell M, Ballester JL. The periodic behaviour of solar activity: the near 155-day periodicity in
sunspot areas. Astron Astrophys 1992; 255: 350-362.
32. Kiplinger AL, Dennis BR, Orwig LE. Detection of a 158-day periodicity in the solar hard X-ray flare
rate. Bull Am Astronom Soc 1984; 16: 891.
33. Ballester JL, Oliver R, Carbonell M. The near 160 day periodicity in the photospheric magnetic flux.
Astrophys J 2002; 566: 505-511.
34. Ballester JL, Oliver R, Carbonell M. Return of the near 160 day periodicity in the photospheric
magnetic flux during solar cycle 23. Astrophys J 2004; 615: L173-L176.
35. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M,
Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov
SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE,
Czaplicki J, International BIOCOS Group. Chronobiology's progress: season's appreciations 2004-
2005. Time-, frequency-, phase-, variable-, individual-, age- and site-specific chronomics. J Applied
Biomedicine 2006; 4: 1-38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
36. Cornélissen G, Schnaiter D, Halberg F, Mitsutake G, Otsuka K, Fiser B, Siegelova J, Jozsa R, Olah A,
Bakken EE, Chibisov S (presenter). A cis-half-year characterizes the incidence of sudden cardiac death
also in and near Austria. In: Proceedings, International Symposium, Problems of ecological and
physiological adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan 2007. Moscow:
People's Friendship University of Russia; 2007. p. 545-551.
213
37. Hamamatsu A, Cornélissen G, Otsuka Ku, Halberg F, Chibisov S (presenter). Linear-nonlinear
rhythmometry documents a transyear and a cishalfyear in sudden cardiac death (ICD 10, code I46.1) in
Tokyo. In: Proceedings, International Symposium, Problems of ecological and physiological
adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan 2007. Moscow: People's
Friendship University of Russia; 2007. p. 542-545.
38. Halberg F, Cornélissen G, Berk M, Dodd S, Henry M, Wetterberg L, Nolley E, Beaty L, BIOCOS
Project. Solar signatures in Australian suicide incidence: gender differences in prominence of photic vs.
nonphotic spectral components. These proceedings.
39. Halberg F, Cornélissen G, Panksepp J, Otsuka K, Johnson D. Chronomics of autism and suicide.
Biomedicine & Pharmacotherapy 2005; 59 (Suppl 1): S100-S108.
40. Cornélissen G, Halberg F. Chronomics of suicides and the solar wind. Br J Psychiatry 2006; 189: 567-
568.
41. Katinas GS, Halberg F, Cornélissen G, Sanchez de la Peña S, Czaplicki J, Siegelova J, BIOCOS
Project. C-ABPM reveals solar cis-halfyear and transyear signatures in human diastolic blood pressure
(BP). These proceedings.
42. Halberg F, Schwartzkopff O, Cornélissen G, Otsuka K. Life's waves in space-time in and around us.
Invited presentation, Nishinomiya-Yukawa International & Interdisciplinary Symposium 2007, What is
Life? The Next 100 Years of Yukawa's Dream, Yukawa Institute for Theoretical Physics, Kyoto
University, October 15-20, 2007. p. 45-47.
43. World Hypertension League. Self-measurement of blood pressure. Bull WHO 1988; 66(2): 155-159.
44. Sothern SB, Sothern RB, Katinas GS, Cornélissen G, Halberg F. Sampling at the same clock-hour in
long-term investigation is no panacea. Proceedings, International Conference on the Frontiers of
Biomedical Science: Chronobiology, Chengdu, China, Sept 24-26, 2006, p. 208-211.
Support GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH), MSM
0021622402
214
EFFECTS of Phase II CARDIAC REHABILITATION on INSULIN
RESISTANCE and MYOCARDIAL REMODELLING in PATIENTS with
ACUTE MYOCARDIAL INFARCTION
Kohzuki M, Nagasaka M, *Dobšák P, *Sva inová H, *Siegelová J.
Department of Internal Medicine and Rehabilitation Science,
Tohoku University and Graduate School of Medicine, SENDAI, JAPAN
* Department of Functional Diagnostics and Rehabilitation, Dept. Physiotherapy and
rehabilitation, Masaryk University and St.Anna Faculty Hospital of Brno, Czech Republic
Abstract
Objective. We have designed a new 2-week hospitalized phase II Cardiac Rehabilitation (CR)
program in Japan. The purpose of the present study is to determine long-term effects on physical
parameters; especially insulin resistance and myocardial remodeling in patients with acute
myocardial infarction. Methodology Twenty-five patients (20 men, 5 women, mean age:
52±11years, peak CK 2378±1881 IU/l, mean EF 60±18%) with AMI were enrolled in this
program. Plasma propeptide of type I procollagen (PICP), HOMA-R and proinsulin were
evaluated. The physical status was assessed by the exercise tolerance (AT and peak VO2),
exercise frequency, serum lipid profiles and BMI. All the parameters were evaluated before, 1, 6
and 12 months after the participation in the program. Results Serum lipid profiles (HDL
cholesterol, triglyceride), BMI, peak VO2 and AT were improved significantly, PICP was stable
at the 1, 6 and 12 months follow-up. Eighty percent of patients had regular exercise activity
(REA). There was no significant difference in PICP between REA and the sedentary subjects.
Pro-insulin and HOMA-R were stable at the 1, 6 and 12 months follow-up. The change in
HOMA-R was not related to exercise tolerance; it strongly correlated with the change in BMI
215
(r=0.61). Conclusion These results suggest that Phase II CR program do not accelerate
myocardial remodeling and our 2-week hospitalized Phase II CR program contributes to not only
maintain insulin sensitivity but also improve in the management of other cardiac risk factors.
Key words
diabetes – rehabilitation – cardiovascular risk – myocardial infarction – exercise
Introduction
While the mortality from acute myocardial infarction (AMI) has fallen, it remains a
leading cause of mortality and morbidity in the Western world. Approximately 50% of deaths
from AMI occur in the first hour prior to admission to hospital which emphasizes the importance
of primary and secondary prevention. In the past decade several studies suggested that there are
some ways to go in this regard, especially the lifestyle changes and risk factor modification in the
post-AMI patients. Cardiovascular diseases are the leading cause of death in people with type 2
diabetes (non-insulin dependent – NIDDM). Compared to people without diabetes, people with
diabetes have strongly increased risk of coronary heart disease (1, 2). People with type 2 diabetes
without prior myocardial infarction have as high a risk of death from coronary heart disease as
non-diabetic patients with a previous history of myocardial infarction (3, 4). Effective
management of patients after AMI through lifestyle modification can delay the onset of
complications, including cardiovascular and metabolic disorders. However, there are several
problems which are not completely solved. First of all, the period of hospitalization during Phase
I cardiovascular rehabilitation (CR) becoming shorter as a result of recent advances in medical
interventions (stent, PTCA) and also for economic reasons. The lifestyle modification,
particularly in terms of daily exercise, cessation of smoking and a balanced food intake, should
be acquired during Phase II CR (or so-called recovery stage, since discharge from hospital until
return to work) and maintained thereafter. But according to numerous recent reports the
participation in the Phase II CR remains still very low - only 9-15% in U.S.A., 14-23% in U.K.
and 5-12% in Japan of all the patients after AIM participate in Phase II CR. The main reasons
why the participation ratio in Phase II CR is low, are the lack of the primary physician’s
216
recommendation for participation, long commute time (frequent visit rate and long distance to
visit local hospitals, so that the patients have a hard time to modify their life-style), patient
“denial” of severity of illness and history of depression (5). A new 2-week hospitalized phase II
cardiac rehabilitation program (2-WCR) has been designed and administered by a
multidisciplinary team. The objective of this pilot study was to evaluate the effectiveness of 2WCRP
on insulin resistance and cardiac remodeling in non-insulin dependent (NIDDM) patiens
and to clarify whether the physical and psychological status of these patients improved after
participation in the program.
Patiens and methods
Twenty-five patients with AMI and NIDDM (age 52.2 ± 11 years, 20 men, 5 women,
mean EF 60 ± 18%, peak creatinkinase 2378 ± 1881 IU/l) referred from primary care were
enrolled in the 2 weeks lasting rehabilitation program. This program consisted of exercise
training, education and counseling, and another 34 patients with AMI who did not participate in
the program served as the control group. The physical status was assessed by symptom-limited
spiroergometry and determination of exercise tolerance (AT and peak VO2). Spiroergometry was
performed by all patients according to a standardized protocol by Wasserman et al. (1999) (6).
The test was done at progressively increasing working rate (10 W/min) to the maximal tolerance
level on an electromagnetically braked bicycle ergometer. Heart rate was monitored continuously
using 12-lead electrocardiograph and blood pressure was measured non-invasively every 2min.
The peak workload was recorded; oxygen uptake and carbon dioxide production were calculated
breath by breath (CPX/D system, Medical Graphics Corporation, St. Paul, Minneapolis),
interpolated, and averaged over 10-s periods. Peak oxygen uptake (VO2peak) and oxygen uptake at
anaerobic threshold ( VO2AT) were determined according to the method by Wasserman et al.
(1999). Individual Body Mass Index was calculated according to the formula BMI = weight (kg)/
height2
(m2
).
Rehabilitation protocol
Two-week non-pharmacological rehabilitation program in hospital was performed as a
group based exercise and group (individual) education training. Exercise training consisted of
bicycle ergometry (for 2 x 30 min/day at the 80-100% of heart rate at the level of individually
217
determined anaerobic threshold), walking (1-2 km/day) and stretching performed every day in
group classes supervised by a physiotherapist. Education program was done in group classes
taught by nurse, physiotherapist and dietitian, and consisted of group lecture (30 - 60 min/day),
individual nutrition counseling (60 min/day) and individual discharge instruction (60 min/day).
Biochemical parameters
HOMA-R. The HOmeostasis Model Assessment (HOMA) Ratio is a mathematical model which
can estimate an individual's degree of insulin sensitivity and level of beta cell function from
simultaneous measurements of fasting plasma glucose and fasting plasma insulin concentrations.
HOMA-R models the physiologic glucose-insulin feedback system and estimates an individual's
insulin sensitivity based on the assumption that any one combination of glucose and insulin is
associated with a given insulin sensitivity, or, conversely, their insulin resistance. HOMA-R has
become a much used method for estimating insulin sensitivity and beta cell function in people
with non-insulin treated type 2 diabetes.
PPIICCPP ((carboxyterminal propeptide of type I procollagen)). Collagen type I and III are the major
fibrillar collagen in the myocardium. PICP is cleaved from the pro-collagen molecule during
collagen synthesis and released into the bloodstream. Some studies demonstrated that plasma
PICP level in 2-3 weeks after AIM were significantly higher in the group with dilation of
myocardium than in the group with no dilation (8).
Proinsulin. Proinsulin is a predictor of insulin that is enzymatically cleaved from insulin. Several
studies have suggested that proinsulin concentrations are strongly related to cardiovascular risk
factors and carotid wall thickness than are insulin concentrations. Increased proinsulin
concentrations predict death and morbidity caused by CHD over a period of 27 years,
independent of other major cardiovascular risk factors (9).
The changes in exercise performance, BMI and selected biochemical parameters were evaluated
after 1, 6 and 12 months after discharge home. The physical activity lasting over 20 min and
realized more than 2 times per week was considered as home-based regular physical activity.
218
Ethics
Before inclusion in the study all the subjects provided informed consent. The study was
approved by the local Ethics Committee, and conformed with the principles outlined in the
Declaration of Helsinki and to the GCP guidelines of the European Community.
Statistics
All data are presented as mean ± SD. Statistical analysis was performed using the
McNemar test of symmetry and Wilcoxon paired test. The P value < 0.05 was considered as
significant.
Results
The evaluation of exercise habits revealed, that 17 patients (70%) maintained regular
exercise activity (REA group) during long-term follow-up (> 2 times per week), while 8 patients
(30%) had lower level of exercise activity (LEA group; < 2 time per week). After participation in
the 2-WCRP, the exercise tolerance (VO2peak) increased significantly (Fig.1)
Fig.1
Exercise tolerance - peak VO2 was improved
significantly in the REA group after 6 and 12 months
0
10
20
30
40
50
1M 6M 12M
(ml/kg/min)
peakVO2
・ * *
* P ＜ 0.05
0
10
20
30
40
50
1M 6M 12M
(ml/kg/min)
peakVO2
・
NS
REA group LEA group
219
Also the BMI and serum lipid profiles of the patients in REA group were significantly
improved (Fig.2 and 3).
Fig.2
Changes in BMIChanges in BMI
0
10
20
30
40
pre 1M 6M 12M
BMI
(kg/m２）
ANOVA - NS
total BMI improved significantly in the REA group after 12 months of follow-up
BMI
0
10
20
30
40
Pre 1M 6M 12M
(kg/m２）
REA group (n = 17)
LEA group (n = 8)
*
* P＜0.05
both
groups
Fig.3
Serum lipid profiles (triglycerides and HDL cholesterol were
improved significantly in REA group after 1, 6 and 12 months
* ｐ＜0.05
** P＜0.01
（mean±SD）
(mg/dl)
TG
0
50
100
150
200
250
300
Pre 1M 6M 12M
ＡＮＯＶＡ，ＮＳ
HDL
0
20
40
60
80
100
Pre 1M 6M 12M
(mg/dl)
**
** **
LEA
REA(mg/dl)
** P＜0.01
**
**
At the 6-month follow-up these parameters remained improved and regular physical activity was
maintained. Even at the 12-month follow-up, lipid profiles remained improved and also the
220
intensity and frequency of regular physical activity was kept. PICP and proinsulin remained
stable at 1, 6 and 12 months follow-up and these changes were without statistical significance
(Fig.4 and 5). The parameter HOMA-R improved significantly at the long-term follow-up (Fig.4).
Fig.4
Proinsulin level remained stable, and HOMA-R improved
significantly (*P� 0.05) at the 6 and 12 months follow-up
HOMA-R
0
1
2
3
4
5
6
7
8
1M 6M 12M
LEA
REA
0
5
10
15
20
25
30
1M 6M 12M
(pmol/L)
LEA
REA
proinsulin
ANOVA - NS
ANOVA - NS
* P＜0.05
*
Fig.5
* p＜0.05
** p＜0.01
Changes in PICPChanges in PICP
0
50
100
150
pre 1M 6M 12M
(µg/l)
PICP
REA group (n = 17)
LEA group (n = 8)
0
50
100
150
1M 6M 12M
(µg/l)
PICP
ANOVA - NSANOVA - NS
both
groups
PICP was stable at the 1, 6 and 12 months follow-up and there
were no significant difference between both groups
221
The changes in HOMA-R were not related to exercise tolerance but strongly correlated with the
change in BMI (Fig.6).
Fig.6
ΔBMI
ΔHOMA-R
-4
-3
-2
-1
0
1
2
3
-3 -2 -1 0 1 2 3 4
r ＝ 0.64
P < 0.01
ΔHOMA-R
BMI ΔAT/Kg
ΔHOMA-R
-4
-3
-2
-1
0
1
2
3
-.06 -.04 -.02 0 .02 .04 .06
r＝0.01
ΔAT. kg-1
ΔHOMA-R
The change in ΔHOMA-R was not related to exercise tolerance,
but strongly correlated with the change in BMI (r = 0.61).
Discussion
One of the primary aims of cardiovascular rehabilitation is the secondary prevention of
risk factors. Modified diets and routine exercise programs effectively lower levels of LDL-C and
elevate levels of HDL-C. Exercise substantially reduces systolic and diastolic blood pressures
during and after the exercise period. Exercise also contributes to weight loss and improves
regulation of capillary blood glucose concentrations in patients with DM. Exercise training
programs result in physiologic changes, such as improved peripheral utilization of oxygen and
glycolytic-oxidative metabolic capacity, which improve functional capacity to decrease cardiac
effort. Blood flow increases during and after active exercise. Physical training elevates muscular
metabolic demand, and increased collateral circulation is the presumed mechanism of
symptomatic improvement. Coexisting cardiac limitations should be considered when an exercise
program is planned. Gradual improvement should be seen within 3-6 months of exercise is a
noninvasive and inexpensive activity with minimal complications and is an invaluable first-line
treatment for patients with AIM. Most patients with AIM, including those with concomitant
222
diabetes, can undertake exercise with a high level of safety. However, exercise is not without risk,
and the recommendation that people with diabetes participate in physical activity is made on the
basis that the benefits outweigh the risks. The American Diabetes Association developed a
position statement on exercise in the management of type 1 and type 2 diabetes (9). These
guidelines aim to minimize the possible risks of exercise for people with diabetes and
recommend that particular attention be paid to appropriate screening, program design, monitoring
and patient education when developing an exercise program. Nevertheless, people with AIM
complicated with diabetes have a poorer short- and long-term prognosis than people without
diabetes (10). Diabetic patients after AIM have 2x higher mortality than non-diabetics and
cardiovascular death accounts for 80% of the mortality in diabetics (11). If no contraindications
to exercise exist, the type of exercise that a person with diabetes performs is generally a matter of
personal preference. Most research documenting the benefits of physical activity for people with
diabetes incorporate aerobic activity such as walking, cycling, rowing, or swimming and circuit
type resistance exercise (12, 13, 14, 15). An area of ongoing concern is the possible adverse
effect of physical activity on existing complications of diabetes. It has been suggested that people
with complications of diabetes are often told to refrain from exercise for fear of deterioration of
the condition and development of further complications (16). This leads to further compromise of
physical and cardiovascular conditioning. It is important to develop exercise prescriptions for
individuals with diabetes complications that will result in improved participation in normal
activities and psychosocial well being while minimizing risk of further deterioration. In addition
to giving consideration to the varied physical characteristics related to exercise prescription for
people with AIM and diabetes, attention should also be paid to the different psychological
characteristics associated with exercise adherence. People with NIDDM report a higher
frequency of relapse from physical activity programs than the general population (17). They often
have a low self-efficacy for changing physical activity behavior and have little belief in the
beneficial effects of physical activity (18). Furthermore, the most frequently cited barriers to
physical activity generally relate to AIM and include physical discomfort from exercise, being
too overweight to exercise and having little or no support (19, 20). These factors, that may reduce
exercise adherence, need to be given due consideration when integrating such patients into
cardiac rehabilitation. The 2-WCR program is a new multidisciplinary program involving doctors,
nurses, cardiac technicians, dietitians, pharmacists and psychologists. As well as a structured
223
exercise program with cardiac monitoring aimed at optimizing exercise capability, this approach
enables the patient’s concerns to be dealt with and educated by the appropriate people in the early
post-infarction period.
Conclusion
The management of post-AMI patients presents many challenges and also many
opportunities to improve prognosis. The benefits of cardiovascular rehabilitation involve the
physical, emotional, and psychosocial aspects of a patient's life. With persistence, patients
achieve improvements in exercise tolerance and functional capacity. A reduction in cardiac
symptoms, as well as perceived stress and anxiety, occurs and lead to improved productivity and
psychological well-being. Patients learn to adapt and become self-reliant as they realize that they
can influence their hypertension, DM, weight, and smoking activity by means of behavioral and
lifestyle modifications. With comprehensive rehabilitation, the patient's QOL improves, they
return to work faster than they otherwise might, and their rates of hospital readmission are
reduced. It is vital to assess risk factors such as NIDDM and to deal with them appropriately. The
2-week hospitalized phase II cardiac rehabilitation program represents a new approach in
standard rehabilitation programs and patients can derive physical and psychological benefit from
it. This study suggests that 2-WCR program do not accelerate myocardial remodeling, could
provide beneficial effects on the patient's physical recovery phase and may also contribute to the
prevention of the onset of other cardiac risk factors.
This study was supported by the grant MSM 0021622402
References
1. Lehto S, Pyorala K, Miettinen H, et al. Myocardial infarct size and mortality in patients
with non-insulin-dependent diabetes mellitus. J Intern Med 1994; 236: 291-297.
2. Mak K, Moliterno D, Granger C, et al. Influence of diabetes mellitus on clinical outcomes
in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiology 1997; 30:
171-179.
224
3. Chun B, Dobson A, Heller R. The impact of diabetes on survival among patients with first
myocardial infarction. Diabetes Care 1997; 20: 704-708.
4. Haffner S, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects
with Type 2 diabetes and in non-diabetic subjects with and without prior myocardial
infarction. N Engl J Med 1998; 339: 229-234.
5. Ades PA, Waldmann ML, McCann WJ, Weaver SO. Predictors of cardiac rehabilitation
participation in older coronary patients. Arch Intern Med 1992; 152(5): 1033-5.
6. Wasserman K, Hansen JE, Sue DY et al. Principles of exercise testing and interpretation
(3rd
ed.), Lippincott Williams & Wilkins (eds.), Baltimore, MD 1999.
7. Takino T, Nakamura M, Hiramori K. Circulating levels of carboxyterminal propeptide of
type I procollagen and left ventricular remodeling after myocardial infarction. Cardiology
1999; 91(2): 81-6.
8. Zethelius B, Byberg L, Hales CN, Lithell H, Berne C. Proinsulin is an independent
predictor of coronary heart disease: Report from a 27-year follow-up study. Circulation
2002: 7; 105(18): 2153-8.
9. American Diabetes Association. Diabetes Mellitus and Exercise. Diabetes Care 2001; 24:
S51.
10. Malmberg K, Yusuf S, Gerstein H, et al. Impact of diabetes on long term prognosis in
patients with unstable angina and non Q wave myocardial infarction: Results from the
OASIS registry. Circulation 2000; 102: 1014-1019.
11. Yudkin JS. Managing the diabetic patient with acute myocardial infarction. Diabetic Med
1998; 15(4): 276-81.
225
12. Walker K, Piers L, Putt R, et al. Effects of regular walking on cardiovascular risk factors
and body composition in normoglycemic women and women with type 2 diabetes.
Diabetes Care 1999; 22: 555-561.
13. Brandenburg S, Reush J, Bauer T, et al. Effect of exercise training on oxygen uptake
kinetic responses in women with Type 2 diabetes. Diabetes Care 1999; 22: 1640-1646.
14. Trovati M, Carta Q, Cavalot F, et al. Influence of physical training on blood glucose
control, glucose tolerance, insulin secretion, and insulin action in non-insulin dependent
Diabetic patients. Diabetes Care 1984; 7: 416-420.
15. Honkola A, Forsen T, Eriksson J. Resistance training improves the metabolic profile in
individuals with type 2 diabetes. Acta Diabetol 1997; 34: 245-248.
16. Svacinová H, Nováková M, Placheta Z, Kohzuki M, Nagasaka M, Minami N, Dobsák P,
Siegelová J. Benefit of combined cardiac rehabilitation on exercise capacity and
cardiovascular parameters in patients with type 2 diabetes. Tohoku J Exp Med 2008;
215(1): 103-11.
17. Krug L, Haire-Joshu D, Heady S. Exercise habits and exercise relapse in persons with
non-insulin-dependent diabetes mellitus. The Diabetes Educator 1991; 17: 185-188.
18. Padgett D. Correlates of self-efficacy beliefs among patients with Non-Insulin Dependent
Diabetes Mellitus in Zagreb, Yugoslavia. Patient Education and Counseling 1991; 18:
139-147.
19. Swift C, Armstrong J, Beerman K, et al. Attitudes and beliefs about exercise among
persons with Non-Insulin-Dependent Diabetes. The Diabetes Educator 1995; 21: 533-
540.
226
20. Wilson W, Ary D, Bigard A, et al. Psychosocial predictors of self-care behaviors
(compliance) and glycemic control in Non-Insulin-Dependent Diabetes Mellitus. Diabetes
Care 1986; 9: 614-622.
* * *
227
ARTERIAL STIFFNESS DETERMINED BY PRESSURE WAVE VELOCITY,
AORTIC COMPLIANCE AND CARDIO-ANKLE VASCULAR INDEX
Fišer B., Siegelová J., Dobšák P., Dušek J.
Dept. of Physiology, Dept. of Physiotherapy end Rehabilitation, Dept. of Functional
Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University,
St. Anna Teaching Hospital, Brno, CZ
INTRODUCTION
Stiffness of large arteries has been related to cardiovascular mortality (1). Methods are used to
estimate this stiffness include cardiac ultrasound and pulse wave velocity (PWV)(2). The
arterial stiffness can be expressed by various indexes. Except PWV it is the aortic compliance
and the cardio-ankle vascular index (CAVI) (3). The relationship between these indexes is
determined by mathematical equations.
The aim of the present paper was to calculate PWV and CAVI in a group of normotensive and
hypertensive subjects where the aortic compliance was non-invasively measured and compare
the results with published data obtained from isolated aortas of human cadavers.
METHODS
The stiffness parameter beta is reported to be independent of blood pressure and is calculated
as:
BETA = ln(Ps/Pd)*D/dD..........................................................................................................(1)
where Ps and Pd are respectively the systolic and diastolic blood pressure in mmHg. D is the
diameter of the blood vessel and dD is the change of D. D/dD can be replaced by 2*V/dV
where V is the volume of the tube, the volume of aorta in our case.
BETA = ln(Ps/Pd)*2*V/dV......................................................................................................(2)
The relationship between volume elastic modulus V*dP/dV (index of the stiffness) and PWV
is expressed by formula
PWV2
= (V*dP/dV)/ .............................................................................................................(3)
where is blood density. Aortic compliance is dV/dP. Thus
V/dV= *PWV2
/dP.................................................................................................................(4)
If we substitute equation (4) for equation (2) we obtain the stiffness parameter
BETA = CAVI = ln(Ps/Pd)*2*( /dP)*PWV2
..................... ...................................................(5)
228
and volume measurement by ultrasound is superfluous. The last equation express the
relationship between CAVI and PWV. On the other hand direct comparison of these
parameters with compliance (dV/dP) is not possible because the value V (aortic volume) is
missing. The estimates of V from cadaver studies we used in our comparison.
The cadaver study includes 27 aortas from subjects 20 to 83 years old. The results after (4) are
published in Kenner Wetterer monograph (5).
The compliance data were obtained by noninvasive measurement from 8 healthy man 27+9
years old (from 21 to 49 years) with 24-hours blood pressure 121+10 / 75+8 mmHg, from 10
not-treated hypertensive man 48+8 years old (from 38 to 58 years) with 24 hours blood
pressure values 147+12 / 88+9 mmHg and from 6 hypertensive patients treated with
verapamil (slow release formula) 240 mg/24 h for 3 months. The mean age was 43+9 years
(from 32 to 53). Twenty four-hours blood pressure values were 143+7 / 88+4 mmHg before
treatment and 131+4 / 80+4 mmHg at the time of compliance investigation. The method and
the results of compliance measurement are described elsewhere (5).
RESULTS
The results of the cadaver study are seen in Fig.1. From the Fig. it 1 is clear that the slopes of
the curves (which corresponds to the compliance dV/dP are pressure dependent. The
parameters of the best fitted polynomal curves are seen in Table 1. together with compliance
values at 80 mmHg (value of diastolic pressure), the parameters of linear relationship between
compliance and pressure and calculated PWV at 90 mmHg (value of mean arterial pressure)
and CAVI (which is not pressure-dependent). PWV was calculated after equation (3).
Because PWV is aortic pulse wave velocity which is different from cardio-ankle pulse wave
velocity, we calculated at first aortic beta after equation (5) and then we calculated CAVI
using the regression equation CAVI = 7.5 + 0.15*aortic BETA (3). For CAVI we assume
Ps/Pd = 120/80 mmHg.
229
Aorta, pressure-volume diagram
0
50
100
150
200
250
300
0 50 100 150 200 250
mmHg
ml
20-39 years
40-59 years
60-69 years
70-83 years
Fig. 1 Pressure-volume diagram of cadavers´ aortas
The results of the analysis of our compliance data are seen in Table 2. The compliance values
were non-invasively measured as well as coefficients A and B, which we used for calculation
of compliance at 80 mmHg. The volume V was not measured in our study and thus we used
the values of V from cadavers’ aortas studies for the calculation of PWV estimate again for
mean pressure of 90 mmHg. Calculation of CAVI we performed identically as in cadavers’
aortas analysis.
Tab. 1 Cadavers´ aortas study
Ages (n) a b c A B dV/dp
(80mmHg)
PWV BETA
aortic
CAVI
years ml/mmHg m/s
20 – 39 (8) 40.54 1.897 -0.0051 1.897 -0.0102 1.081 11.71 21.08 10.66
40 – 59 (9) 76.77 1.778 -0.0050 1.778 -0.0100 0.978 13.20 26.78 11.51
60 – 69 (5) 105.10 1.849 -0.0054 1.849 -0.0108 0.985 14.20 31.00 12.15
70 -83 (6) 144.40 1.510 -0.0045 1.510 -0.0090 0.790 15.95 39.11 13.36
Legend: parameters a, b, c correspond to equation; volume = a + b* pressure +c* pressure2
;
parameters A, B: compliance = A + B* pressure; dV/dP (80mmHg): compliance at pressure
80 mmHg; PWV: pulse wave velocity; BETA: aortic stiffness; CAVI cardio-ankle vascular
index.
230
Tab. 2 Human noninvasive study
Group (n) dV/dp A B dV/dp
(80mmHg)
PWV BETA
aortic
CAVI
Ml/mmHg ml/mmHg m/s
Normotensives (6) 1.18±0.25 2.328 0.0154 0.969 11.77 21.29 10.69
Hypertensives (10) 0.96 ±0.21 2.219 0.0144 0.923 13.37 27.48 11.62
Treated hypertensives (6) 0.90 ±0.11 1.843 0.0122 0.745 13.86 29.50 11.92
Legend: dV/dp (±SD): measured compliance. Other parameters as in Table 1.
Despite completely different experimental situation the results of both analyses are similar.
Most interesting finding is similar regression coefficient B despite the fact that the smooth
muscle cells in cadavers’ aortas are dead.
DISCUSSION
Several studies determined the aortic compliance invasively and the values correspond to our
non-invasive methods. Also the regression coefficient between diastolic pressure and
compliance B (0.0157 ml*mmHg-2
) is similar in our study and in study of Lie at al. (x). They
found a value B = 0.0131 ml*mmHg-2
. In all compliance studies a big variation of compliance
among various subjects was observed.
From this point of view it is surprising the accord between cadavers’ aortas data and data of
living subjects.
Comparison of PWV calculated from our data and PWV measured in healthy subjects
revealed that our data corresponds to the high 2.5 centile of PWV variation in cadavers’ aortas
and in our healthy subjects in all age categories. On the other hand our data from hypertensive
and treated hypertensive patients. It is interesting that the stiffness is higher in treated
hypertensive patients than in non-treated. This finding can explain the fact, that blood
pressure in treated patients was initially higher and the treatment normalize blood pressure
relatively quickly but remodeling of arterial wall needs much more time.
Our analysis indicates that all parameters, aortic compliance, PWV and CAVI can be used for
estimation of arterial stiffness. It seems to be that stiffness data are more reliable for
determination of patient prognosis without treatment than blood pressure measurement. For
screening the method must be simple to perform. Here is the CAVI measurement advantage.
CAVI is only age dependent. PWV is pressure and age dependent. However CAVI and aortic
compliance measurement are not equal. CAVI take into account the atherosclerosis of arteries
of lower extremities. Thus aortic compliance and CAVI measurement are complementary.
231
Aortic compliance is pressure and age dependent but can be relatively simply normalized for
distinct value of diastolic pressure. The complicated methodical approach causes a limitation
of aortic compliance method for screening purposes.
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SUMMARY
Stiffness of large arteries has been related to cardiovascular mortality. It can be expressed by
pressure wave velocity (PWV), aortic compliance (C) and by the cardio-ankle vascular index
(CAVI). C was measured noninvasively in normotensive and hypertensive human subjects
and in human cadavers’ aortas, PWV and CAVI were calculated. Despite completely different
experimental situation the results of both analyses were similar. Also regression coefficients
between C and blood pressure were similar in both experimental conditions.
REFERENCES
1. BOUTOUYRIE P, TROPEANO AI, ASMAR R et al. Aortic stiffness is an indipendent
predictor of primary coronary events in hypertensive patients: A longitudinal study.
Hypertension 2002;39:10-15.
2. BAOYING LI, HAIQING GAO, XIAOLI LI et al. Correlation between brachial-ankle
pulse wave velocity and arterial compliance and cardiovascular risk factors in elderly
patients with arteriosclerosis. Hypertens Res 2006; 29:309-314.
3. TAKAKI A, OGAWA H, WAKEYAMA T et al. Cardio-ankle vascular index is a new
noninvasive parameter of arterial stiffness. Circ J 2007;71:1710-1714.
4. YAMBE T, YOSHIZAWA M, SAIJO Y et al. Brachio-ankle pulse wave velocity and
cardio-ankle vascular index (CAVI). Biomedicine and Pharmacotherapy 2004;58:95-98.
5. SHIRAI K, UTINO J, OTSUKA K et el. A novel blood pressure-independent arterial wall
stiffness parameters; Cardio-ankle vascular index (CAVI). J Atheroscler Thromb
2006;13:101-107.
6. KHOSHDEL AR, THAKKINSTIOAN A, CARNEY SL et al. Estimation of an agespecific
reference interval for pulse wave velocity: a meta analysis. J Hypertension
2006;24:1231-1237.
7. MIZUGUCHI Y, OISHI Y, TANAKA H et al. Arterial stiffness is associated with left
ventricular diastolic function in patients with cardiovascular risk factors: early detection
232
with the use of cardio-ankle vascular index and ultrasonic strain imaging. J Cardiac Fail
2007;13:744-751.
8. NAKAMURA K, TOMARU T, YAMAMURA S et al. Cardio-ankle vascular index is a
candidate predictor of coronary atherosclerosis. Circ J 2008;72:598-604.
9. SIMON E, MEYER WW. Das Volumen, die Volumendehnbarkeit und die Druck-LangenBeziehungen
des gesamten aortalen Windkessels in Abhangigkeit von Alter, Hochdruck
und Arteriosklerose. Klein Wschr 1958:36:424-432.
10. WETTERER E, KENNER TH. Grundlagern der Dynamik des Arterienpulses. SpringerVerlag
Berlin 1968:375p.
11. SAVIN E, SIEGELOVA J, FISER B et al. Detérmation non invasive de la compliance
aortique chez l’ homme. Arch Physiol Biochem 1996 ;104:257-264.
12. MESSERLI FH, FROHLICHE ED, NUTURA HO. Arterial compliance in essential
hypertension. J Cardiovasc 1985;7:33-35.
13. SIMON AC, SAFAR MF, LEVENSON JA et al. An evaluation of large arteries
compliance in man. Am J Physiol 1979;237:550-554.
14. LIU Z, BRIN KP, YIN FCP. Estimation of total arterial compliance: an improved method
and evaluation of current methods. Am J Physiol 1986;251:588-600.
15. LIU Z, TING CT, ZHU S, YIN FCP. Aortic compliance in human hypertension.
Hypertension 1989;14:129-136.
233
AMBULATORY ARTERIAL STIFFNESS INDEX IN PATIENTS MONITORED FOR
6 CONSECUTIVE DAYS
Siegelová J., Fišer B., Havelková A., Dobšák P., Dušek J.,Pohanka M., Cornélissen G.*
,
Halberg F.*
Dept. of Physiotherapy and Rehabilitation, Dept. of Functional Diagnostics and Rehabilitation,
Dept. of Physiology, Faculty of Medicine, Masaryk University,
St. Anna Teaching Hospital, Brno, CZ, *
Halberg Chronobiology Center, University of
Minnesota, Minneapolis, MN, USA
INTRODUCTION
Stiffening of large arteries predicts adverse cardiovascular outcomes (1-3). Measurements of
arterial stiffness require ultrasound equipment to measure peripheral arteries in the subject in
the supine or sitting position (4). The ambulatory arterial stiffness index (AASI) is defined as
one minus the regression slope of diastolic on systolic pressure during 24 h ambulatory blood
pressure monitoring and might be a measure of arterial stiffness (5, 6). The stiffer arterial tree
the closer the regression slope and AASI are ranging from 0 to 1, respectively (7, 8).
In the present paper we attempted to estimate the reliability of AASI determination in
individual patients. Studying the infradian rhythms in chronobiology of blood pressure we
perform ambulatory blood pressure monitoring for 7 consecutive days (9, 10, 11). This
enables us to obtain 6 values of AASI in 6 full consecutive days. The preliminary results from
our laboratory were published (12).
METHODS
The set being monitored consisted of fourteen patients after myocardial infarction in the
past history more than 6 months before, of mean age 63 ± 6.5 and mean ejection fraction of
the left ventricle 43 ± 12.3 %.
The patients underwent phase II of cardiovascular rehabilitation (controlled ambulatory
rehabilitation program) lasting two to three months with the frequency of three times in a
week at the Department of Functional Diagnostics and Rehabilitation of St. Anna Teaching
Hospital.
234
In the course of rehabilitation they went through 7-day ambulatory monitoring of blood
pressure. During blood pressure recording they did not interrupt their pharmacotherapy.
The seven-day blood pressure monitoring was made by using the instrument TM – 2421 of
the Japanese firm AD on the principle of oscillometric methods of blood pressure
measurement. The regime of measurement of blood pressure was done for 7 days repeatedly
every 30 minutes from 5 to 22 h during the day time and once in an hour from 22 to 5 h at
night (Siegelová et al. 2004).
The measured blood pressure values for every patient from the monitored set were statistically
processed in the form of arithmetic means for systolic and diastolic blood pressure value
during each hour for every measured day. The average SBP and DBP and their standard
deviations (SD) in the given days were determined by the calculation of arithmetic mean of
these values.
These data were used for every consecutive day of seven day monitoring to calculate the slope
of diastolic on systolic pressure and to calculate the ambulatory arterial stiffness index (AASI)
as one minus regression slope of diastolic on systolic blood pressure.
The study was approved by local ethic committee and the patients signed the informed
consent.
RESULTS
Results of AASI values together with 24-hour mean values of systolic (SBP) and diastolic
blood pressure (DBP) of 14 patients are seen in Table 1.
235
Tab. 1 Variability of 24-hour blood pressure values and AASI in 14 patients calculated for 6
consecutive days
SBP (mmHg) DBP (mmHg) AASI RAGE
(Y) 6 d ±SD MIN MAX 6 d ±SD MIN MAX 6 d ±SD MIN MAX MIN MAX
1 74 113 3 110 117 57 2 55 62 0,72 0,13 0,56 0,83 0,14 0,49
2 68 134 3 131 139 86 2 84 89 0,56 0,15 0,32 0,77 0,36 0,77
3 66 128 4 124 134 75 3 73 81 0,70 0,17 0,50 0,99 0,02 0,72
4 56 106 4 102 113 67 4 62 73 0,61 0,22 0,20 0,86 0,19 0,89
5 60 118 3 115 123 63 2 60 66 0,84 0,16 0,59 1,10 -0,20 0,68
6 58 124 7 115 134 66 3 60 70 0,68 0,12 0,51 0,87 0,22 0,71
7 58 126 7 114 137 72 4 64 78 0,61 0,10 0,50 0,79 0,40 0,73
8 60 107 4 103 113 65 4 60 69 0,69 0,12 0,50 0,90 0,13 0,90
9 72 128 4 123 132 63 1 62 65 0,74 0,12 0,54 0,89 0,38 0,69
10 61 113 5 108 119 71 2 68 73 0,69 0,11 0,48 0,83 0,45 0,72
11 54 117 2 112 120 76 1 73 77 0,39 0,09 0,20 0,49 0,59 0,82
12 66 133 6 126 144 87 4 82 91 0,23 0,17 0,02 0,58 0,61 0,94
13 53 141 6 129 147 90 5 80 93 0,22 0,16 0,00 0,44 0,68 0,9
14 70 119 3 115 123 67 5 60 75 0,51 0,2 0,28 0,76 0,34 0,64
SBP, mean systolic blood pressure; DBP, mean diastolic blood pressure; AASI, ambulatory
arterial stiffness index; r, correlation coefficient between DBP and SBP; 6d, mean of 6 days
values; SD, standard deviation; min, max, minimum and maximum 24-hours values.
The mean systolic and diastolic blood pressure variations are seen in Tab 1 as well as the
inter-individual variations of AASI and there are large.
DISCUSSION
The simplest explanation for the variation in AASI is that it reflects spontaneous variability in
arterial stiffness from one session to another. However, it should be considered that AASI is
under the influence of other sources of variability, which are necessarily related to arterial
functional properties (13).
Due to mathematical reasons AASI obtained form standard regression analysis depends on
day-night blood pressure change (14), and hence variation in the latter may be expected to
induce variation in the former. The reproducibility of day-night blood pressure changes and of
the dipper-nondipper classification is far from being optimal. In a recent study (15) in which
150 hypertensive patients underwent 24-hour blood pressure monitoring twice, between
session agreement for the dipping-nondipping classification was found to vary from fair-to-
236
moderate and the coefficient of repeatability of day-night blood pressure change was as high
as 42-49 %. Such a large variation can be expected to influence variability of AASI as well.
The strong relation between AASI and day-night blood pressure changes is further confirmed
by the paradoxical finding that daytime and night-time AASI are both much higher (0.48
±0.26 and 0.40 ± 0.21) than the corresponding 24-h values (0.31 ± 0.17), emphasizing its
limited ability to specifically reflect arterial wall properties (16).
A further source of variation in AASI values is represented by the night/day ratio of blood
pressure measurements number. In our study we calculated the AASI from the blood pressure
values, given in regiment one per hour. In the literature it was demonstrated that the
dependency of AASI of the number of daytime and nocturnal readings is a phenomenon
related to the above relationship between day-night blood pressure reduction and AASI (17).
The is a need for more substantial data on AASI repeatability in larger cohorts of hypertensive
patients and in the normal individuals in any case, due attention should be paid to the
influence of day-night blood pressure changes and to that of daytime and night-time betweenreading
time intervals on AASI and its variability (18).
The inter-individual variation of AASI is large. It doesn’t mean that the determination of
AASI as a risk factor of individual patient is useless, but that the determination of AASI from
24-hour blood pressure monitoring should be supplemented by blood pressure self-monitoring
lasting several days irrespective of the method of AASI calculation.
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REFERENCES
1. Benetos A, Safar M, Rudnichi A et al. Pulse pressure: a predictor of long-term
cardiovascular mortality in French male population. Hypertension 1997;30:1410-1415.
2. Hayashi T, Nakayama Y, Tsumura K et al. Reflection in the arterial system and the risk of
coronary heart disease. Am J Hypertens 2002;15:405-409.
3. Weber T, Auer J, O´Rourke MF, et al. Arterial stiffness, wave reflections, and the risk of
coronary artery disease. Circulation 2004;20:184-189.
4. Van Bortel LM, Duprez D, Starmans-Kool MJ et al. Clinical applications of arterial
stiffness, task force III: recommendations for user procedures. Am J Hypertens
2002;15:445-452.
5. Li Y, Wang LJ, Dolan E et al. Ambulatory arterial stiffness index derived form 24-hour
ambulatory blood pressure monitoring. Hypertension 2006;47:359-364.
237
6. Dolan E, Thijs L, Li Y et al. Ambulatory arterial stiffness index as a predictor of
cardiovascular mortality in the Dublin outcome study. Hypertension 2006;47:365-370.
7. Meaume S, Benetos A, Henry OF et al. aortic pulse wave velocity predicts cardiovascular
mortality in subjects > 70 years of age. Arterioscler Thromb Vasc Biol 2001;21:2046-
2050
8. Schillaci G, Parati G. Ambulatory arterial stiffness index: merits and limitations of a
simple surrogate measure of arterial compliance. J Hypertension 2008;26:182-185.
9. Siegelová J, Dusek J, Fiser B, Homolka P, Vank P, Kohzuki M, Cornellisen G, Halberg F.
Relationship between circadian blood pressure variation and age analyzed from 7-day
ambulatory monitoring. J Hypertension 2006;24:Suppl.6:122.
10. Halberg, F., Cornélissen, G. & Schwartzkopff, O.. Seven day blood pressure
measurement: Contraversion in single 24-h profiles of blood pressure and heart rate. In
Halberg, F., Kenner, T., Fišer, B., Siegelová, J. Noninvasive Methods in Cardiology, 2006,
s. 10 – 26.
11. Halberg, F. - Cornélissen, G. - Otsuka, K. - Sánchez de la Pe a, S. - Schwartzkopff, O. Watanabe,
Y. - Pati, A. K. - Wall, D. G. - Delmore, P. - Borer, K. - Beaty, L. A. - Nolley,
E. S. - Adams, C. - Siegelová, Jarmila - Homolka, Pavel - Dušek, Ji í - Fišer, Bohumil P
ikryl, P. Why and how to implement 7-day/24 hour blood pressure monitoring? Geronto
Geriatrics, 2007, 8,. 1-31.
12. Siegelová J, Fiser B. Variability of ambulatory arterial stiffness index and of 24-h blood
pressure values in patients monitored for 6 consecutive days. J Hypertension
2008;26:1501-1502.
13. Schillaci G, Parati G. Reply to variability of ambulatory arterial stiffness index and of 24h
blood pressure values in patients monitored for 6 consecutive days. J Hypertension
2008;26:1502-1503.
14. Schillaci G, Parati G, Pirro M et al. Ambulatory arterial stiffness index is not a specific
marker of reduced arterial compliance. Hypertension 2007;49:986-991.
15. Henskens LH, Kroon AA, Van Oostenbruge RJ et al. Different classification of nocturnal
blood pressure dipping affect the prevalence of dippers and nondippers and the relation
with target-organ damage. J Hypertension 2008;26:691-698.
16. Schillaci G, Parati G, Pirro M et al. Dipping safely into the ambulatory arterial stiffness
index. Hypertension 2007;50:e61.
17. Schillaci G, Parati G, Pirro M et al. Response to: interstudy to variability in the
ambulatory arterial stiffness index. Hypertension 2007;50:e66.
18. Dechering DG, Adiyaman A, van der Steen M et al. Interstudy to variability in the
ambulatory arterial stiffness index. Hypertension 2007;50:e65.
238
PHYSICAL ACTIVITY AND 24-HOUR PROFILE OF BLOOD PRESSURE
ALENA HAVELKOVÁ, JARMILA SIEGELOVÁ, BOHUMIL FIŠER, LEONA MÍFKOVÁ,
PAVEL HOMOLKA, PAVEL VANK, MICHAL POHANKA, GERMAINE
CORNÉLISSEN*, FRANZ HALBERG*
Dept. of physiotherapy and rehabilitation, Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital,
Brno, CZ, *Halberg Chronobiology Center, University in Minnesota, USA
INTRODUCTION
Sedentary life and excessive body mass contribute to the risk of hypertension development (1-
8). It has been demonstrated that physical exercises decrease the risk of hypertension
development. In our clinic we carry out 7-day ambulatory monitoring of blood pressure (9-12).
It enables us to monitor blood pressure changes induced by exercises in the course of the
following 24 hours if we compare them with the values in subsequent next 24 hours. This
approach takes fully into consideration circadian fluctuation of blood pressure.
The aim of the study was to compare 24-hour course of blood pressure immediately after the
exercises with the values from the following day when the patient did no exercises.
METHODOLOGY
The set being monitored consisted of 10 patients after myocardial infarction of the age (63 ±
6,3) years and ejection fraction (43 ± 12,3) %.
The patients were subjected to phase II of cardiovascular rehabilitation (controlled ambulatory
rehabilitation program) lasting two to three months with the frequency of three times a week
at the Department of Functional Diagnostics and Rehabilitation of St. Anna Teaching
Hospital. The duration of the training unit was 60 min and it consisted of warm-up phase (10
min), aerobic phase (25 min), toning phase (15 min) and relaxation phase (10 min).
In the course of rehabilitation they underwent 7-day ambulatory monitoring of blood pressure.
During TK recording they did not interrupt pharmacotherapy.
7-day monitoring of blood pressure was made by means of the instrument TM – 2421 of
Japanese firm AD operating on the principle of oscillometric analysis. The instrument
measured blood pressure for 7 days repeatedly every 30 min from 5 to 22 o'clock and once an
hour from 22 to 5 o'clock. If a value not much probable from the point of view of the
instrument setting was recorded, another check measurement was made (Siegelová et al.
2004).
239
The results were processed by using Halberg cosinor analysis. The data were smoothed by a
sinusoidal curve. The mean value of the sinusoid, designated MESOR, and amplitude of
circadian fluctuation were determined. The measured TK values of each patient from the
monitored set were statistically processed in the form of arithmetic means for every hour after
the completion of exercises for the time of 48 hours. This enabled us to compare the means in
individual hours after the exercises with the hour means obtained 24 hours later, i.e. in the day
when the patient did no exercises. We calculated therefore for every patient differences in
individual hours between the day immediately after the exercises and the subsequent day
without exercises. Statistical significance was tested by Wilcoxon test.
The study was accepted by ethical commission and the patients signed their informed
approval.
RESULTS
The result was comparison of two 24-hour profiles of blood pressure, the first one beginning
immediately after the exercises, the second one shifted by 24 hours. In the second case the
patient did no exercises. Halberg cosinor analysis demonstrated that there are no differences
in 24-hour MESOR and circadian amplitude between both profiles both in systolic and in
diastolic blood pressure (Fig. 1, 2).
Comparison of hour differences indicated that only in the first hour after the exercises systolic
pressure is lower than in the check course (p<0,01). Also in the second hour after the
exercises the value is lower, the difference, however, is not statistically significant any more.
In the other hours both profiles were not different (Fig. 3, 4). We have found no differences in
diastolic pressure. The analysis of differences is in accordance with the finding of the same
MESOR quantities and amplitudes.
The analysis shows that the exercises do not change profiles of 24-hour blood pressure
immediately after the exercises. Positive effect of the exercises must be explained by other
mechanisms than by means of blood pressure changes in the day following after the exercises.
240
0
20
40
60
80
100
120
140
STK DTK STK DTK
mmHg
day with exercises day without exercises
Fig. 1 MESOR of circadian fluctuation of systolic blood pressure and diastolic blood
pressure in the day with exercises and in the day without exercises
AMPLITUDA
0
2
4
6
8
10
12
14
16
18
20
STK DTK STK DTK
den se cvi ením den bez cvi ení
mmHg
Fig. 2 Amplitude of circadian fluctuation of systolic blood pressure and diastolic blood
pressure in the day with exercises and in the day without exercises
241
STK
-60
-40
-20
0
20
40
60
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
as (h)
DIF(mmHg)
Fig. 3 Difference of systolic blood pressure between the day with exercises and the day
without exercises in individual hours of the day
DTK
-40
-30
-20
-10
0
10
20
30
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
as (h)
DIF(mmHg)
Fig. 4 Difference of diastolic blood pressure between the day with exercises and the day
without exercises in individual hours of the day
242
DISCUSSION
Meta-analysis of controlled studies demonstrated convincingly that aerobic exercises decrease
systolic and diastolic blood pressure (13). We have shown that the exercises themselves do
not decrease blood pressure in the subsequent hours. Other mechanisms must be therefore
taken in consideration. The information found in literature indicate that one of possible
explanations can be related to the decrease of body mass. A number of published data and a
logical explanation exist. Adipose tissue produces leptin that increases sympathetic activity
and thus blood pressure.
It seems, however, that physical activity is positive also when body mass is not decreased.
One of possible explanations can be in affecting of psychological stress. Psychological stress
increases blood pressure even in young people (14). Physical activity and feeling of a better
fitness in patients with cardiovascular diseases reduces their fear of further progression of the
disease and stress connected with it, and exercising can therefore be beneficial even due to
this mechanism.
Supported by grant MSM 0021622402.
LITERATURE
1. Williams P.T. A Cohort study of incident hypertension in relation to changes in vigorous
physical activity in men and women. J Hypertension, 2008, 26: 1068-1093.
2. Stamler R., Stamler J., Riedlinger W.F., Alegra G., Roberts R.H. Weight and blood
pressure. Findings in hypertension screening of 1 million Americans. JAMA, 1978, 204,
1607-1610.
3. Canoy D., Luben R., Welch A., Bingham S., Warenham N., Day N., Khaw K.T. Fat
distribution, body mass index and blood pressure in 22.090 men and women in the
Norfolk cohort of the European prospective investigation in to cancer and nutrition (EPIC
– Norfolk study). J Hypertension, 2004, 22: 2067-2074.
4. Huang Z., Wilett W., Manson J., Rosner B., Stampfer M., Speizer F., Colditz G. Body
weight, weight change an risk of hypertension of women. Ann Intern Med, 1998, 1287,
81-88.
5. Williems P.T., Hoffman K., La I. Weight-related increases in hypertension,
hypercholesterolemia, and diabetes risk in normal weight male and female runners.
Arterioscler Tromb Vasc Biol, 2007, 27, 1811-1819.
6. Paffenbarger R.J., Wing A.L., Hyde R.T., Jung D.L. Physical activity and incidence of
hypertension in college alumni. Am J Epidemiol, 1983, 117, 245-257.
7. US Department of Health and Human Services. Physical activity and health: a report of
the Surgeon general. Atlanta, GA: US Department of Health and Human Services, Centers
243
for disease control and prevention, national center for chronic disease prevention and
health promotion, 1996.
8. Williems P.T., Franklin B. Vigorous exercise and diabetic, hypertensive, and
hypercholesterolemia medication use. Med Sci Spors Exer, 2007, 39 1939-1941.
9. Siegelová, J. & Fišer, B.. Diagnostika hypertenze – sou asnost a budoucnost. Vnit ní
léka ství, 2005, 51 (S 3), s. 50 – 53.
10. Siegelová, J., Fišer, B. & Dušek, J.. 24-hodinové monitorování krevního tlaku u
nemocných s esenciální hypertenzí. Vnit ní léka ství, 1993, 39 (2), s. 183 – 190.
11. Siegelová, J., Fišer, B. & Dušek, J.. Nové trendy v monitorování krevního tlaku.
Postgraduální medicína, 2004, 6 (5), s. 474 – 477.
12. Halberg, F., Cornélissen, G. & Schwartzkopff, O.. Seven day blood pressure
measurement: Contraversion in single 24-h profiles of blood pressure and heart rate. In
Halberg, F., Kenner, T., Fišer, B., Siegelová, J. Noninvasive Methods in Cardiology, 2006,
s. 10 – 26.
13. Whelton S.P., Chin A., Xin X., He J. Effect of aerobic exercise on blood pressure: a metaanalysis
of randomized, controlled trials. Ann Intern Med, 2002, 136, 493-503.
14. Al-Kubati M., Fišer B., Siegelová J.: Baroreflex sensitivity during psychological stress.
Physiol. Res., 1997, 46, 27-33.
SUMMARY
The aim of the study was to compare 24-hour course of blood pressure immediately after the
exercises with the values from the following day when the patient did no exercises. The set
being monitored consisted of 10 patients after myocardial infarction of the age (63 ± 6,3)
years and ejection fraction (43 ± 12,3) %. In the course of rehabilitation the patients were
subjected to 7-day ambulatory blood pressure monitoring. During the blood pressure
recording their pharmacotherapy was not interrupted.
The analysis shows that the exercises do not change 24-hour blood pressure profiles
immediately after the exercises. Positive effect of the exercises must be explained by other
mechanisms than by means of blood pressure changes in the day following after the exercises.
KEY WORDS: circadian fluctuation of blood pressure, physical activity, 7-day ambulatory
blood pressure monitoring
244
INTERVAL AND CONTINUOUS TRAINING IN CARDIOVASCULAR
REHABILITATION IN MEN AFTER ACUTE MYOCARDIAL
INFARCTION: INFLUENCE ON AEROBIC CAPACITY AND
PERFORMANCE ON THE LEVEL OF ANAEROBIC THRESHOLD
VERONIKA CHLUDILOVÁ, LEONA MÍFKOVÁ, ALENA HAVELKOVÁ, JAROSLAVA
POCHMONOVÁ, NABIL ABDULAH IBRAHIM AL-MAHMODI, BOHUMIL FIŠER,
FRANTIŠEK VÁRNAY, JARMILA SIEGELOVÁ
Dept. of physiotherapy and rehabilitation and Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital, Brno,
CZ
INTRODUCTION
Cardiovascular rehabilitation is a universally accepted part of the complex care of patients
with cardiovascular disease. It starts already during hospitalization and after the discharge to
home care it continues in the form of controlled out-patient rehabilitation program individual
training at home (1). It increases physical fitness, improves quality of life (2-4) and decreases
cardiovascular mortality (5,6). Dynamical endurance aerobic activities are the basis of each
training unit (7-9,13,14). The best known and most widespread type of aerobic training is the
training with continuous work load. Interval training (1,10) can be an alternative training
method for persons with a low tolerance of load, with a lower contractility of left ventricle, or
for elderly people.
AIM OF THE STUDY
To evaluate the effect of 12-week controlled out-patient rehabilitation program with
continuous and interval work load on aerobic capacity and performance on the level of
anaerobic threshold in men after acute myocardial infarction (AIM) treated by percutaneous
thoracoplasty of coronary artery (PTCI with stent implantation).
SET OF PATIENTS
36 men patients after AIM were included into the study. According to ejection fraction of left
ventricle (EF) they were divided into two groups. The group with a higher EF (54 ±7,7 %,
group K, n=18) went in aerobic phase through the training with continuous work load, the
245
second group with a lower EF (47 ±12,7 %, group I, n=18) went in aerobic phase through the
interval training.
Controlled out-patient rehabilitation was started within 12 weeks after AIM. AIM diagnosis
was identified at 1st
internal cardioangiological clinic of Faculty of Medicine, Masaryk
University, St. Anna Teaching Hospital in Brno (treated by PTCI with stent implantation).
During rehabilitation all patients were symptomatically stable and their medication was not
changed.
The groups did not differ in age, their characteristic is given in Table 1.
Table 1 Characteristic of the set
Group K Group I
Number (n) 18 18
Age (years) 57 ± 12 60 ± 7
Ejection fraction (%) 54 ± 7.7 47 ± 12.7
Starting RHB (weeks after AIM) 6 ± 2.5 5 ± 3.4
METHODOLOGY
Methods of examination
Before the beginning of rehabilitation (RHB) program and after its completion we made
spiroergometric examination to symptom-limited maximum (Pulmonary Function System
1070, MedGraphics, USA). The examination was started by monitoring resting EKG in lying
and sitting position (Schiller CS 100), followed by 3-minute adaptation in sitting position on
ergometer. The work load was increased every 2 minutes by 20 W to symptom-limited
maximum. Anaerobic threshold was determined from the course of changes of ventilatoryrespiratory
parameters. For the use of RHB it was expressed in watts, heart rate and degrees
of RPE (Borg scale).
Before the beginning of resistance training (i.e. in the 3rd
week of RHB program) we made
isometric test („handgrip“, DHG-SY3, Recens) to verify blood pressure response to isometric
load. In the case of a normal response the entrance 1-RM test (one repetition maximum test)
was made in three exercises of resistance training. The test was repeated in the 6th
week and in
the 12th
week of RHB program.
246
Rehabilitation program
The controlled out-patient RHB program lasted 12 weeks altogether with frequency three
times a week. The training unit lasted 60 minutes and consisted of warm-up phase (10 min),
aerobic phase (1st
to 2nd
week 40 min; 3rd
to 12th
week 25 min), toning phase (3rd
to 12th
week
15 min) and relaxation phase (10 min). The patients in „K“ group went in aerobic phase
through continuous training, in „I“ group they went through interval training. For the interval
training the following modification was chosen: 30 s of working phase with intensity on the
level of anaerobic threshold and 60 s of relaxation phase with the minimum work load 5
watts.
The interval training was indicated by residual ischemia, low ejection fraction of left
ventricle, generally low tolerance of work load.
The warm-up phase was aimed at preparing cardiovascular and motoric system to further
load, prevention of muscular-skeletal lesion. It consisted of dynamical endurance exercises
(simple floor gymnastic exercises, exercises with gymnastic apparatus) and stretching of
muscle groups with a tendency to shortening.
The aerobic phase was effected on a bicycle ergometer (Ergoline REHA E900) controlled by
the program ErgoSoft+ for Windows. The aerobic training intensity was determined on the
anaerobic threshold level.
The resistance training was realized on multifunctional muscle conditioning machines TKHC
COMPACT. Four exercises were done (bench press, pull down, leg extension on the
machine and sitting-lying positions). The resistance training intensity was determined by the
method 1-RM and training loads were determined in percents of maximum: 30-60 % 1-RM
each week increase by 10 %). The number of sequences was 3 - 5 with ten repetitions. Before
starting the resistance training, the patients were thoroughly informed about proper breathing
and technique of doing exercises.
Modified Schultz autogenic training was used for relaxation.
In the course of the whole training monitoring of heart rate, blood pressure and degree of
RPE, during the aerobic phase also EKG was carried out.
Statistical processing
Statistical processing was made in the programs Microsoft Excel and Statistica, version 8.
Distribution was tested by Lillefors modification of Kolmogorov-Smirnov test of normality.
According to the result either paired t-test or Wilcoxon test for dependent specimens were
used. The significance level was determined to 0,05, at the statistical significance on this level
247
the testing was made on the level 0,01 (0,001). The results are presented as means with
standard deviations.
RESULTS
After the completion of the program a statistically significant increase of the oxygen intake
on the level of anaerobic threshold in both groups was recorded (table 2). VO2ANP increased
in „K“ group by 13 %, VO2ANP/kg by 11 %. VO2ANP increased in „I“ group by 20 %,
VO2ANP/kg also by 20 %.
Table 2 Parameters of aerobic capacity on the level of anaerobic threshold
Group K Group I
Before RHB After RHB
p
Before RHB After RHB
p
VO2ANP (ml.min-1
) 1086±190,6 1225±291.5 0.001 995±209,9 1194±242,6 0.05
VO2ANP/kg(ml.min-1
.kg-1
) 12.9 ± 1.7 14.3 ± 2.5 0.01 11.6 ± 3.30 13.9 ± 3.71 0.05
VO2ANP = oxygen intake on the level of anaerobic threshold
Tolerance of work load on the level of anaerobic threshold also improved statistically
significantly in both groups (table 3). WANP in „K“ group increased by 15 % and WANP/kg
by 17 %. In „I“ group WANP increased by 35 % and WANP/kg by 37 %.
Table 3 Performance parameters on the level of anaerobic threshold
Group K Group I
Before RHB After RHB
p
Before RHB After RHB
p
WANP (W) 62 ± 14.2 71 ± 19.4 0.01 52 ± 10.2 70 ± 16.1 0.001
WANP/kg(W.kg-1
) 0.7 ± 0.17 0.8 ± 0.19 0.05 0.6±0.17 0.8 ± 0.26 0.001
WANP = performance on the level of anaerobic threshold
DISCUSSION
The training with continuous work load and the interval training are used widely not only
in sports activities, but also in rehabilitation. The interval training in cardiovascular
rehabilitation is often recommended and conducted individually with regard to the health and
functional state, to the age and gender of the patient. Work load intensity, duration of working
and relaxation phases in interval training and the total number of exercise intervals differ
according to the orientation of the training (10-12). Mífková et al. (11) used in her study the
following modification of interval training: 30 s of working phase on the level of anaerobic
threshold and 60 s of relaxation phase on the level of 5 watts. 38 men with ischemic heart
disease were monitored in the study. Both groups differed in age and ejection fraction. The
248
total work done by the patients in this interval training modification was 2,5 to 3 times lower
than in the group of patients for which the continuous training was prescribed. In the final
spiroergometric examination there was no statistically significant difference between the
groups with interval and continuous training either in performance parameters or in
parameters of aerobic capacity (evaluated on the level of the highest values achieved). Both in
interval and continuous type of the training similar results were obtained at the same training
work load intensity.
In our study we used the same modification of interval training: (30 s of working phase
with intensity on the level of anaerobic threshold and 60 s on the level of 5 W). We evaluated
selected parameters on the level of anaerobic threshold. The patients in our group did not
differ in age, but they differed in ejection fraction. Ejection fraction in the group with interval
training was considerably lower than in the group with continuous training (low ejection
fraction is one of indications for interval training). The benefit of interval training lies in the
possibility of obtaining improvement even in risk patients (11). In our study we verified the
method in patients with decreased ejection fraction of left ventricle and in patients with
residual ischemia and generally low tolerance of work load. In these patients preference
should be given to interval training before continuous one, also for safety reasons (11).
CONCLUSION
The group with interval training (I) had already before the starting of the program a lower
oxygen intake and a lower tolerance of work load than the group with continuous training (K).
After the completion of the program the oxygen intake on the level of anaerobic threshold
increased statistically significantly in both groups (VO2ANP increased in „K“ group by 13 %,
VO2ANP/kg by 11 % . VO2ANP increased in „I“ group by 20 %, VO2ANP/kg also by 20 %).
The tolerance of work load increased statistically significantly on the level of anaerobic
threshold in both groups. (WANP increased in „K“ group by 15 % and WANP/kg by 17 %. In
„I“ group WANP increased by 35 % and WANP/kg by 37 %.) In both groups we recorded
statistically significant improvement of the monitored parameters after 12-week rehabilitation
program. Both types of the training were well tolerated.
Supported by grant MSM 0021622402
249
LITERATURE
1. Chaloupka V, Siegelová J, Špinarová L. a kol. Rehabilitace u nemocných
s kardiovaskulárním onemocn ním. Cor Vasa 2006; 48: K 127-45.
2. Izawa K, et al. Improvement in physiological outcomes and health-related quality of life
following cardiac rehabilitation in patients with acute myocardial infarction. Circ J. 2004;
68(4):315-320.
3. McKelvie RS, Teo KK, Roberts RM. et al. Effects of exercise training in patients with
heart failure: the Exercise Rehabilitation Trial (EXERT). Am Heart J.2002; 144(1):23-30.
4. Pollock ML, Franklin BA, Balady GJ et al. Resistance exercise in individuals with and
without cardiovascular disease: benefits, rationale, safety, and prescription.
Circulation.2000;101:828-833.
5. Špa ek R, Widimský P. Infarkt myokardu.1. vyd.Praha: Galén, 2003.
6. Špinar J, Vítovec J. a kol. Ischemická choroba srde ní.1. vyd.Praha:Grada Publishing,
2003.
7. Clausen JP.Circulatory adjustments to dynamic exercise and effect of physical training in
normal subjects and in patients with coronary artery disease. Prog Cardiovasc Dis
1976;18:456-495.
8. Thompson PD.The benefits and risks of exercise training in patients with chronic coronary
artery disease.JAMA.1988; 259:1537-1540.
9. Balady GJ, et al.Cardiac rehabilitation programs. Circulation.1994;90:1602-1610.
10. Siegelová J., Mifková L., Novák M. a kol. Interval and continuous training in
cardiovascular rehabilitation. Eur.J. Cardiovascular Prev.Rehabilitation 2006, 13,
Suppl.1., 85.
11. Mífková L, Siegelová J, Vymazalová L. a kol. Intervalový a kontinuální trénink
v kardiovaskulární rehabilitaci. Vnit lék 2006; 52 (1): 44-50.
12. Mookerjee S. The Application of interval training for exercise prescription in cardiac
rehabilitation. J Cardiopulm Rehabil 1998; 18: 233-235.
13. Mífková L, Kožantová L, Siegelová J. a kol. Kombinovaný trénink u pacient po akutním
infarktu myokardu. Med Sport Boh Slov 2005; 14(3): 115-123.
14. Chludilová V, Várnay F, Mífková L. a kol. Zm ny transportního systému kyslíku vlivem
kombinovaného tréninku u muž s akutní a chronickou ischemickou chorobou srde ní.
XV. sjezd Spole nosti rehabilita ní a fyzikální medicíny,Luha ovice, ISBN 978-80-254-
1238-1, Spole nost rehabilita ní a fyzikální medicíny, 2008, 77.
SUMMARY
The purpose of the study was to examine the effect of two modifications of aerobic training
(interval and continuous) during 12 weeks of controlled out-patient cardiovascular
rehabilitation program on aerobic capacity and performance on the level of ventilatory
anaerobic threshold. 36 males were included in our study. They were divided into two
subgroups. Group K (EF 54±7.7 %, n=18) passed aerobic phase of the program with
continuous work load, in group I (EF 47±12.7 %, n=18) interval training was prescribed.
250
Intensity of the training was on the level of ventilatory anaerobic threshold in both groups.
The groups did not differ in age. Symptom-limited spiroergometry was provided before and
after rehabilitation program. The rehabilitation program was carried out three times a week
for 60 min. Oxygen intake was increased in both studied groups (VO2ANP was increased in
„K“ by 13 %, VO2ANP/kg by about 11 %. VO2ANP was increased in „I“ by 20 %, VO2ANP/kg
by 20 %). The work load on the level of anaerobic threshold improved significantly (WANP
was increased by 15 % in „K“ and WANP/kg by about 17 % in „K“. WANP was increased by
about 35 % and WANP/kg by about 37 % in “I”). Statistically significant improvement in
aerobic capacity and performance on the level of anaerobic threshold was observed in both
groups. Both modifications of aerobic training were well tolerated.
KEY WORDS
Cardiovascular rehabilitation, continuous training, interval training, infarctus myocardium.
251
BAROREFLEX SENSITIVITY IN MULTIPLE SCLEROSIS
LUMÍR KONE NÝ, PETR POSPÍŠIL, FARAG HASSAN ANBAIS,
BOHUMIL FIŠER, JARMILA SIEGELOVÁ, PETR DOBŠÁK
Dept. of physiotherapy and rehabilitation and Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk UniveSMity, St. Anna Teaching Hospital,
Brno, CZ
INTRODUCTION
Disseminated multiple sclerosis (SM) is a chronic system autoimmunity disease
causing, on the basis of dissemination of demyelinisation focuses in CNS region,
functional neurological deficit. The course is typically episodical, with acute attacks of
demyelinisation occurring in irregular intervals and bringing about often increasing
motor deficit and loss of sensoric functions (1).
Dysfunctions of autonomic nervous system (ANS) are quite a frequent
phenomenon in SM. They are characterized particularly by dysfunctions of urinary
bladder, disorder SM of sexual and sudomotoric functions (2-4). Autonomic
dysfunctions affecting the cardiovascular system regulation, however, are also
documented more and more frequently (5-11). Incidence of these dysfunctions varies as
to frequency, importance of abnormities and autonomic reflex tests being used
(5,6,10,12,13). Alterations of cardiovascular system parameters SM were demonstrated
in SM patients both at rest and during physical load when ANS is responsible for
compensation of hemodynamic cardiovascular response to physical stress. Autonomic
dysfunctions can lead therefore to limitation of physical load capacity and can
contribute to the fatigue of SM patients that has not yet been explained (14-19).
Cardiovascular autonomic functions in SM are most frequently followed-up by
means of conventional reflex tests (5,6,20,21). These methods are limited mainly by
difficult interpretation and differentiation of the sympathetic or parasympathetic
component of cardiovascular regulation by autonomic nervous system.
A contemporary trend in testing of autonomic nervous system is based on
examination of heart rate variability (HRV) the results of which we have published
already (22,23). Monitoring of baroreflex sensitivity (BRS) is another possibility of
evaluation of cardiovascular regulation.
252
AIM
Our study is aimed at finding out whether disturbed regulation of blood
circulation is connected with the degree of clinical disability in the set of patients with
disseminated cerebrospinal sclerosis. We evaluated the regulation of blood circulation
by means of determination of baroreflex sensitivity (BRS), clinical disability of patients
with SM was evaluated according to Kurtzke’s Expanded Disability Status Scale,
EDSS.
METHODOLOGY
The examined set of patients consisted of patients with diagnoses from
neurological outpatients' department for SM of 1st
neurological clinic of Faculty of
Medicine, Masaryk University, St. Anna Teaching Hospital, and from the team of Unie
ROSKA Brno-m sto. The patients with internal, metabolic and other diseases which
could influence validity of the results of autonomic testing, were excluded from the
study. The patients were tested in clinically stabilized state of the disease. They
confirmed their participation in the study by signing „Informed approval of the patient“;
the study was accepted by the relevant ethical commission of St. Anna Teaching
Hospital in Brno. Clinical evaluation of disability by EDSS scale was performed before
the examination of autonomic nervous system.
EDSS (Kurtzke’s Expanded Disability Status Scale) (26) is a standard scale for
evaluation of disability of SM patients. It is a neurological examination with evaluation
by 0.5 point, in the interval from 0 (no functional disorder or impairment) to 10 (death
because of SM), impact of SM disease on 8 basic functional systems.
BRS (baroreflex heart rate sensitivity) characterizes the function of
baroreceptors participating in maintaining blood pressure and heart rate and expresses
the level of activity of autonomic nervous system. Extension of heartbeat interval R - R
(CI) in milliseconds at increasing of SBP by 1 mm Hg is an indicator of BRS. BRS
value (ms. mmHg-1
) is the function expressing the relation between spontaneous
fluctuation of SBP and R - R intervals.
The examination was carried out by means of non-invasive continuous recording
of heart rate and blood pressure made by TASK FORCE MONITOR (CNS System,
Graz, Austria) (25), by beat-by-beat measurement method. 5-minute record was made in
253
supine position with controlled breathing rate according to the metronome 0.33 Hz, for
comparison of the results between the patients. By software processing of continuous
recording of heart rate and blood pressure (BP) by sequential analysis there are found
events of at least three or more consecutive monotonous changes of SBP with a minimal
deviation 1 mmHg/1 heartbeat and, at the same time, at least three consecutive
monotonous changes of RR intervals with a minimal change 4 ms/1 heart beat. The
events of SBP changes can thus have BP up-events or BP down-events. Then regression
terms for all up-events and all down-events and mean values for both types of events are
calculated. The results are given separately for up- and down-events and further as the
total BRS for all events in ms/mmHg. The values are given as mean ± SD. Impossibility
of a reliable measurement of BRS because of low number of events (less than 8) we
considered to be a disturbed cardiovascular regulation.
Heart rate variability (HRV) was also examined by the instrument TASK
FORCE MONITOR (CNS System, Graz, Austria) (25). We evaluated, by means of
spectral analysis, very low-frequency component of HRV (0.02 - 0.05Hz, VLF-RRI),
low-frequency component of HRV (0.05 - 0.15Hz, LF-RRI), high-frequency component
of HRV (0.15 - 0.50Hz, HF-RRI), total spectral power (HRV TP), index of sympathovagal
balance (LF/HF), length of cardiac interval (RRI), heart rate SF.
Statistical analysis of the data (program STATISTICA for Windows – version
7.7) was made by means of t-test for independent specimens and Wilcoxon test.
RESULTS
27 patients with verified SM disease, in the remission stage (mean age 43.4
years, duration of SM disease 6.4 let, EDSS 3.25) were examined.
On the basis of evaluation of BRS examination we divided the set into two
groups according to the number of down- or up-events of blood pressure. The group A
with disturbed cardiovascular regulation consists of patients with BP up-events or BPdown
events 8. The group B consists of patients with the number of events 8.
Characteristic of anthropometric data and characteristic of SM disease in both
groups are in Table 1.
254
Table 1 Basic anthropometric data and data characterizing SM disease in
examined groups (the values are expressed as mean ± SD)
Totally 27 SM patients Group A (BRS 8 events) Group B (BRS 8 events)
n= 13 N=14
Gender 2M/11F 3M/11F
Age 46.3 ± 8.7 40.5 ± 6.2
Height [m] 1.7 ± 0.1 1.7 ± 0.1
Mass [Kg] 67.7 ± 12.6 69.0 ± 12.6
BMI 23.8 ± 4.3 23.8 ± 4.1
Body surface area [m2
] 1.80 ± 0.13 1.81 ± 0.14
EDSS 4.2 ± 1.2 2.1 ± 0.5 *
Duration of SM 6.3 ± 7.6 6.5 ± 5.7
RR form 8 9
SP form 4 3
PP form 1 2
RR form- relabs-remittent form of SM disease, SP - form secondary progression, PP - form primary
progression, BMI - body mass index, * p < 0.05
Examined indicators of baroreflex sensitivity are in Table 2.
Table 2 Results of baroreflex sensitivity (BRS) in monitored groups
Controlled breathing 0.33Hz Group A Group B
R-R Interval [ms] 826.3 ± 102.0 837.0 ± 115.9
HR [heartbeat/min] 74.0 ± 9.0 73.4 ± 10.3
SBP [mmHg] 115.0 ± 13.7 114.2 ± 5.4
DBP [mmHg] 78.2 ± 9.8 74.9 ± 4.3
n (number of up-events) Not evaluated * 12.9 ± 5.3
BRS up-events [ms/mmHg] Not evaluated * 13.7 ± 6.4
N (number of down-events) Not evaluated * 15.4 ± 8.8
BRS down-events [ms/mmHg] Not evaluated * 12.5 ± 4.6
n (number of all events) Not evaluated * 28.3 ± 13.3
BRS all events [ms/mmHg] Not evaluated * 13.2 ± 5.4
HR – heart rate, SBP, DBP - systolic, diastolic BP, BRS up-events - absolute value of baroreflex
sensitivity for up-events, BRS down-events - absolute value of BRS for down-events, BRS all events absolute
value BRS all events, n – number of recorded events, * not evaluated by sequential analysis of
BRS because of insufficient number of recorded events
Additional examined values of heart rate variability (HRV) are given in Table 3
with statistical significance of comparison between the groups.
255
Table 3 Results of heart rate variability (HRV)
HRV controlled breathing 0,33Hz Group A Group B P
VLF-RRI [ms²] 357.8 ± 878.5 112.3 ± 93.1 NS
LF-RRI [ms²] 178.7 ± 312.2 475.4 ± 1070.5 NS
HF-RRI [ms²] 298.6 ± 551.3 551.1 ± 1356.8 NS
TP-RRI [ms²] 835.0 ± 1205.3 1138.8 ± 2440.5 NS
LF/HF [1] 1.4 ± 1.5 1.6 ± 1.3 NS
R-R Interval [ms] 826.3 ± 102.0 837.0 ± 115.9 NS
SF [bpm] 74.0 ± 9.0 73.4 ± 10.3 NS
VLF-RRI - very low-frequency component of HRV (0.02 - 0.05Hz), LF-RRI - low-frequency component
of HRV (0.05 - 0.15Hz), HF-RRI - high-frequency component of HRV (0.15 - 0.50Hz), TP – total power
of HRV, LF/HF - index of sympatho-vagal balance, RRI - interval of RR, SF- heart rate, NS - low
statistical significance
DISCUSSION
Disorder of regulation of cardiovascular functions in SM is clinically less
frequent, but potentially dangerous (35). These abnormalities were studied in the past
on the basis of a number of examination of cardiovascular reflexes with a different
measure of informative value. That is why the results and interpretation of disorders of
cardiovascular functions often diverge in the published papers. Abnormalities of
cardiovascular reflexes were proved controversially in both branches of sympathetic and
parasympathetic nervous supply (3,5,6,9-11,29). Saari et al. (2004) (27) documented
that the measure of disability in SM correlates with reduction of cardiovascular
response and also with the volume of lesions of central nervous system, verified by
means of magnetic resonance examination. According to the authors it can be supposed
that particularly lesions of midbrain, ale also, even if with a lesser impact, lesions of
hemispheres are responsible for most of cardiovascular abnormalities. This hypothesis
was indicated already by the results of Acevedo et al. (5) who established connection of
cardiovascular dysfunctions in SM with affection of reflex paths in the brain-stem. A
partial response to the question whether autonomic cardiovascular regulation in SM is
affected by direct mechanism, was given by the study of authors Sanya et al. (28) that
investigated carotid baroreflexes in patients with SM separately for parasympathetic and
sympathetic cardiovascular regulation. Baroreflex function was not reduced only in
256
cardiac regulation of baroreflex, also sympathetic regulation of tonus of arterial bed was
affected. The authors think that indirect impairment of sympathetic vasomotor
regulation can be responsible for postural disorders and vertigo that are described in as
many as 49 % of SM patients (29). The finding of sympathetic vasomotor disorder of
the function and its correlation with general fatigue in SM was established also in the
study of authors Flachenecker et al. (31).
The results of our study indicate that mechanisms of baroreflex control in the
group B with EDSS 2.9 with a clearly expressed BRS in the values corresponding to the
average age of healthy population seem to be in the range of reference standard values
(36, 37,38). In this group there were measured values of BRS of BP up-events 13.7 ±
6.4 ms/mmHg, BP down-events 12.5 ± 4.6 ms/mmHg and mean BRS for BP totalevents
13.2 ± 5.4 ms/mmHg.
On the other hand, in the second group of SM patients (group A) for BRS
determination by sequential method in 13 patients was not found a sufficient number of
BP up-events or BP down-events. This difference between the groups A and B can be
hypothetically explained by dissimilarity of autonomic regulation of BRS and increase
of sympathetic tonus in the group A can be supposed. The group A does not differ
statistically significantly from the group B either in anthropometric values or in duration
of the disease (6.3 ± 7.6 vs. 6.5 ± 5.7 let). The groups do not differ either in proportional
representation of the forms of SM disease. It can be explained by the significant
difference of the extent of clinical disability of autonomic nervous system. In the group
A there is a larger measure of disability according to EDSS (3,6 ± 1,4) than in the group
B (2.9 ± 1.4). We have not found, however, correlation between the indicators of BRS
and EDSS. HRV indicators show a generally lower total power (TP) in the group A
(835.0 ± 1205.3 ms2
) than in the group B (1138.8 ± 2440.5 ms2
) and decrease of LF and
HF of HRV component as against the group B (178.7 ± 312.2 vs. 475.4 ± 1070.5ms2
;
298.6 ± 551.3 vs. 551.1 ± 1356.8 ms2
); it was not statistically significant, however.
On the basis of our results we can conclude that a lower degree of clinical
disability need not be connected with cardiovascular regulation impairment and a higher
degree can mean its impairment at the level of baroreceptors. Question arises whether
reduced baroreflex sensitivity of heart rate will increase the risk of occurrence of
cardiovascular diseases in SM patients. Fleming et al. (34) found out that elderly SM
257
patients have a lower probability of falling ill with such diseases as acute IM, heart
failure, hypertension, angina pectoris and cerebrovascular diseases than their
contemporaries of the same age. Slawta et al. (33) documented on the group of 123
women with SM that the risk of heart diseases is approximately the same as in normal
population. Even if we meet serious cardiovascular diseases in connection with SM
relatively rarely in our clinic, there exists a possibility of lesion of cardiovascular
functions in SM patients. Verification of our results requires, however, further
examination of SM patients.
CONCLUSION
Sequential analysis of baroreflex sensitivity of heart rate established in 14
patients (group B – mean age 40.5 ± 6.2, duration of the disease 6.5 ± 5.7, EDSS 2.9 ±
1.4) baroreflex regulation to be in compliance with the reference values. This method
could not be evaluated in 13 patients (group A - mean age 46.3 ± 8.7, duration of the
disease 6.3 ± 7.6, EDSS 3.6 ± 1.4) because of a low number of recorded up- or downevents.
We regard the difference between the groups A and B as dissimilarity of
autonomic regulation of BRS. The results indicate that a lower degree of clinical
disability need not be connected with cardiovascular regulation impairment and a higher
degree can mean its impairment at the level of baroreceptors.
Supported by grant MSM 0021622402.
LITERATURE:
1. HAVRDOVÁ, E. Roztroušená skleróza. PRAHA: TRITON, 2002, 3.vyd. 110 s., ISBN 80-7254-
280-X
2. BETTS CD, JONES SJ, FOWLER CG, FOWLER CJ. Erectile dysfunction in multiple sclerosis.
Associated neurological and neurophysiological deficits, and treatment of the condition. Brain
1994;117:1303–10.
3. DRORY VE, NISIPEANU PF, KROCZYN AD. Tests of autonomic dysfunction in patients with
multiple sclerosis. Acta Neurol Scand 1995;92: 356–60.
4. ELIE B, LOUBOUTIN JP. Sympathetic skin response (SSR) is abnormal in multiple sclerosis.
Muscle Nerve 1995;18:185–9.
5. ACEVEDO, A.R., NAVA, C., ARMADA, N., VIOLATE, A., CORONA, T. Cardiovascular
dysfunction in multiple sclerosis. Acta neurol Scand 2000; 101:85-88 Acevedo et al. (2000)
6. ANEMA, J.R.,HEIJENBROK, M.W., FAES, TJ., HEIMANS, J.J., LANTING, P., POLMAN,
C.H. Cardiovascular autonomic function in multiple sclerosis. J Neurol Sci 1991; 104:129–134
258
7. FLACHENECKER P, WOLF A, KRAUSER M, HARTUNG HP, REINESM K. Cardiovascular
autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance. J Neurol.
1999 Jul; 246(7):578-86.
8. FRONTONI M, FIORINI M, STRANO S, CERUTTI S, GIUBILEI F,URANI C,
BASTIANELLO S, POZZILLI C (1996) Power spectrum analysis contribution to the detection
of cardiovascular dysautonomia in multiple sclerosis.Acta Neurol Scand 93:241–245
9. GUNAL, D.I., AFSAR, N., TANRIDAG, T., AKTAN, S. Autonomic dysfunction in Multiple
Sclerosis: correlation with disease-related parameteSM, European Neurology, 2002;48:1-5
10. NORDENBO, A.M., BOESEN, F.,ANDESMEN, E.B. Cardiovascular autonomic function in
multiple sclerosis. J Auton Nerv Syst 1989; 26:77–84
11. SENARATNE MP, CARROLL D,WARREN KG, KAPPAGODA T (1984) Evidence for
cardiovascular autonomic nerve dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry
47: 947–952
12. CARTLIGE NEF: Autonomic function in multiple sclerosis, Brain, 1972; 95:661-664 Cartilage
(1972)
13. PENTLAND, B., EWING, D.J. Cardiovascular reflexes in multiple sclerosis. Eur Neurol 1987;
26:46–50
14. KONE NÝ, L., POSPÍŠIL, P., DUFEK, M., DRLÍKOVÁ, L., DOBŠÁK, P., VANK, P.,
SIEGELOVÁ, J.: Fitness in Multiple Sclerosis. In NONINVASIVE METHODS IN
CARDIOLOGY. 1. vyd. Brno: LF MU, 2007. od s. 121 - 130, 162 s. ISBN 9784634.
15. KONE NÝ, L., POSPÍŠIL, P., DUFEK, M., DRLÍKOVÁ, L, FARAG HASAN, E., ASHREF,
A., DOBŠÁKP.: Functional impairment in multiple sclerosis. Scripta medica, Brno: Léa ská
fakulta MU Brno, 80/2007, 5, od s. 225 - 232, 8 s. ISSN 1211-3395.
16. KONE NÝ, L., POSPÍŠIL, P., DUFEK, M., DRLÍKOVÁ, L., DOBŠÁK, P., VANK, P.,
SIEGELOVÁ, J.: T lesná zdatnost, únava a sob sta nost u roztroušené sklerózy mozkomíšní. In
Optimální p sobení t lesné zát že a výživy. Hradec Kráové: Univerzita Hradec Kráové, 2007.
od s. 152 -158, 7 s. PdF, UHK. ISBN 978-80-7041-513-9.
17. KONE NÝ, L., POSPÍŠIL, P., MIFKOVÁ, L., ANBAIS FARAG HASSAN, ASHEF, A.,
VOHLÍDALOVÁ, I., SIEGELOVÁ, J.: Kombinovaný trénink u sclerosis multiplex. Cor et
Vasa, eská republika: eská kardiologická spole nost, 48, 4, od s. 53 - 53, 1 s. ISSN 010-8650.
2006
18. OLINDO S, GUILLON B, HELIAS J, PHILIBERT B, MAGNE C, FEVÈ JR: Decrease in heart
ventricular ejection fraction during multiple sclerosis. European J of Neurology 2002; 9: 287-
291.
19. ZIABER J, CHMIELEWSKI H, DRYJANSKI T, GOCH JH: Evaluation of myocardial muscle
parameteSM in patients with multiple sclerosis. Acta Neurol Scand 1997; 95: 335-337.
20. NASSERI, K.,TEN VOORDE, B.J., ADER, H.J., UITDEHAAG, B.M., POLMAN, C.H.
Longitudinal follow-up of cardiovascular reflex tests in multiple sclerosis. J. Neurol Sci 1998;
155:50-54
21. THOMAIDES, T.T., ZOUKOS, Y., CHAUDHURI, K.R., MATHIAS, C.J. Physiological
assessment of aspects of autonomic function in patients with secondary progressive multiple
sclerosis. J. Neurol. 1993; 240:139-143
22. KONE NÝ, L., POSPÍŠIL, P., ANBAIS FARAG HASSAN, ASHREF, A., VANK, P.,
SIEGELOVÁ, J.: ízené dýchaní u nemocných s roztroušenou sklerózou. Sborník abstrakt
Luha ovice 2007, 1/2007, 1s. 27 - 27. ISSN 9788023987447.
23. POSPÍŠIL, P., KONE NÝ, L., VOHLÍDALOVÁ, I., SIEGELOVÁ, J., SVA INOVÁ, H.,
FIŠER, B., DUŠEK, J., JAN ÍK, J., SVOBODA, L. Heart rate variability in patients with
multiple sclerosis. In: Noninvasive methods in cardiology [Congress MEFA - Book of
abstracts]. Brno: Kongresové centrum Brno, 2004., s. 20. ISBN 80-86607-14-3
24. KAUTZNER, J., MALIK, M.: Variabilita srde ního rytmu a její klinická použitelnost. II. ást.
Cor Vasa, 1998, 40, s. 244 - 251.
25. TASK FORCE: The European Society of Cardiology and The North American Sociaty of Pacing
and Electrophysilogy. Heart rate variability – Standards of Measurement, Physiological
Interpretation, and Clinical Use. European Heart Journal 1996, 17, 354 – 381.
26. KURTZKE, J. (1983). Rating neurologic impairment in multiple sclerosis: an expanded
disability status scale (EDSS). Neurology, , . 33, s. 1444 – 1452.
259
27. SAARI, A., TOLONEN, U., PAAKKO, E., SUOMINEN, K., PYHTINEN, J., SOTANIEMI, K.,
MYLLYLA, V. Cardiovascular autonomic dysfunction correlates with brain MRI lesion load in
MS. Clin Neurophysiol 2004; 115: 1473-1478
28. SANYA, E.O., TUTAJ, M., BROWN, C.M., GOEL, N., NEUNDORFER, B., HILZ, M.J,
Abnormal heart rate and blood pressure response to baroreflex stimulation in multiple sclerosis
patiens. Clin Auton Res 2005; 15: 213-218
29. VITA, G., FAZIO, M.C, MILONE, S., BLANDINO, A., SALVI, L., MESSINA, C.,
Cardiovascular autonomic dysfunction in multiple sclerosis likely related to brainstem lesions. J
Neurol Sci 1993; 120(1):82-86
30. NASSERI, K., UITDEHAAG, B.M., VAN WALDERVEEN, M.A., ADER, H.J.,
Cardiovascular autonomic function in patients with relapsing remitting multiple sclerosis. A new
surrogate marker of disease evolution. Eur J Neurol 1999;6:29–33.
31. FLACHENECKER, P., RUFER, A., BIHLER, I., HIPPEL, C., REINESM, K., TOKYKA, KV.,
KESSELRING, J. Fatigue in MS is related to sympathetic vasomotor dysfunction. Neurology
2003; 61:851-853
32. THOMAS, P., LEIST, S.G., HARNETT, K., KALMAN, B. Monitoring of Cardiac function
during Mitoxantrone Therapy. In: 57th Annual Meeting AAN. Miami, 2005
33. SLAWTA JN, WILCOX AR, MCCUBBIN JA, NALLE DJ, FOX SD, ANDESMON G. Health
behavioSM, body composition, and coronary heart disease risk in women with multiple
sclerosis. Arch Phys Med Rehabil 2003;84:1823-30.
34. FLEMING ST, BLAKE JR. RL. Patterns of comorbidity in elderly patients with multiple
sclerosis. J Clin Epidemiol 1994;47:1127–32.
35. FRONTONI, M., STRANO, S., CERUTTI, S., FIORINI, M., URANI, C., GIUBILEI, F.,
CALCAGNINI, G., FIESCHI, C. Spectral analysis of heart rate variability in patients with
Multiple sclerosis. Journal of the Autonomic Nervous System 1993; 43,suppl 1: 77
36. SIEGELOVÁ J., FIŠER B., DUŠEK J., AL-KUBATI M. Die Baroreflexsensitivitátsmessung
bei Patienten mit essentieller Hypertonie: Einfluss von Enalapril. Nieren und
Hochdruckkrankheiten 24(1), 1995:20-22
37. FIŠER B. SIEGELOVÁ J., DUŠEK J., CORNELISSEN G., HALBERG F.: Determination of
heart rate baroreflex sensitivity in man by spectral analysis during 24 houSM period. Scripta
medica 66, 1993:11-14
38. SIEGELOVÁ J., FIŠER B., DUŠEK J., AL-KUBATI M., MAYER P.: The effect of Isoptin
SR240 therapy on baroreflex heart rate sensitivity in essential hypertension. Scripta medica
67(Suppl 1), 1994:13-16
260
SUMMARY
Our study is aimed at finding out whether disturbed regulation of blood circulation is
connected with the degree of clinical disability in the set of patients with disseminated
cerebrospinal sclerosis. We evaluated the regulation of blood circulation by means of
determination of baroreflex sensitivity (BSM), clinical disability of patients with SM
was evaluated according to Kurtzke’s Expanded Disability Status Scale, EDSS.
Patients and methodology: We examined 27 patients with clinically defined
disseminated sclerosis in the remission stage (mean age 43,4 yeaSM, duration of SM
6,4 yeaSM, EDSS 3,25). The examination was carried out by means of non-invasive
continuous recording of heart rate and blood pressure made by TASK FORCE
MONITOR (CNS System, Graz, Austria), by beat-by-beat measurement method. 5minute
record was made in supine position with controlled breathing rate according to
the metronome 0,33 Hz. By software processing of continuous recording of heart rate
and blood pressure by means of sequential BSM analysis there were evaluated upevents,
down-events and total BSM for all events. On the basis of evaluation of BSM
examination we divided the set into two groups. The group A (13 patients, mean age
46,3 ± 8,7, duration of the disease 6,3 ± 7,6, EDSS 4,2 ± 1,2) consisted of patients with
the number of up- or down-events 8. The group B (14 patients, mean age 40,5 ± 6,2,
duration of the disease 6,5 ± 5,7, EDSS 2,1 ± 0,5) consisted of patients with the number
of events 8.
Results: Sequential analysis of BSM in the group B: up-events 13,7 ± 6,4 ms/mmHg,
down-events 12,5 ± 4,6 ms/mmHg, all events 13,2 ± 5,4 ms/mmHg. In the group A
BSM could not be evaluated by sequential analysis because of a low number of
recorded up- or down-events, which we regard as disturbed cardiovascular regulation.
Conclusion: Sequential analysis of baroreflex sensitivity of heart rate established in
14 patients (group B – mean age 40,5 ± 6,2 yeaSM, duration of the disease 6,5 ± 5,7
yeaSM, EDSS 2,1 ± 0,5) baroreflex regulation to be in compliance with the reference
values. This method could not be evaluated in 13 SM patients (group A – mean age 46,3
± 8,7 yeaSM, duration of the disease 6,3 ± 7,6 yeaSM, EDSS 4,2 ± 1,2) because of a
261
low number of recorded up- or down-events indicating disturbed cardiovascular
regulation of blood circulation.
262
EFFECTIVITY OF PHYSIOTHERAPY IN STROKE IN ACUTE PHASE
MARTINA TARASOVÁ, BARBORA BÁRTLOVÁ, EVA NOSAVCOVOVÁ, ABDUL
KARIM AL FADHLI, PETR POSPÍŠIL, LUMÍR KONE NÝ, BOHUMIL FIŠER,
PETR DOBŠÁK, JARMILA SIEGELOVÁ
Dept. of Physiotherapy and Rehabilitation, Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital, Brno,
CZ
INTRODUCTION
Optimal rehabilitation of stroke (CMP) is based on analysis of factors influencing the
rehabilitation potential of the patient. These factors include: measure of disablement, other
diseases, level of cognitive functions, limitation of daily life activities, barriers in the
neighbourhood and social integration. Several tests are used for quantification of the
monitored parameters (1, 2, 3, 4, 5).
Testing of condition of the patients before and after the treatment is a necessary part of
determination of medical treatment and evaluation of effect of physiotherapy. It enables to
compare successfulness of various medical treatments and quality of clinical workplaces by
means of an objective evaluation. Testing by means of special scales and tests made or
suitable for the given group of patients gives evidence of the measure of functional
disablement and enables to determine:
- functional potential of the patient
- functional prognosis
- treatment efficacy
It objectifies condition of the patient and enables statistical evaluation and comparison of
effect of therapy and shows the actual range of disablement in comparison with the stated
diagnose.
CMP is a serious disease. Quality of life in stroke is given not only by local neurological
symptoms, such as motor and sensory deficits of neurological functions and aphasia, but also
by the presence of negativity, depression, fatigue, vascular dementia and frequent falls with
injuries and bone fractures (2). Testing of condition of the patients after stroke in acute
rehabilitation is necessary for evaluation of the process of the whole disease and for
verification of both medication therapy and complete rehabilitation.
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AIM
The aim of the study was analysis of affecting functional state of the patients after stroke
(CMP) with moderate and light disablement with intensive rehabilitation treatment.
METHODOLOGY
The group consisted of 96 patients of average age 62,1 ± 12,0 years (range 30 -91 years) with
the diagnose I 60 – I 69 (generally impairment of CNS with motor disorder) with moderate
and light affection of motor and cognitive functions, evaluated according to the measure of
functional disablement (Functional Independence Measure, FIM, 6, 7, 8), who were
hospitalized after acute attack of CMP in Ist
neurological clinic of St. Anna Teaching Hospital
in Brno. In the group there were 36 women of average age 61.6 ± 13.4 years (range 30-83
years) a 60 men of average age 62,5 ± 11,3 years (range 34-91 years). Age distribution of the
monitored group is in Table 1.
Table 1. Age distribution of patients with stroke
0
5
10
15
20
25
30
44 a mén 45 - 54 55 - 64 65 -74 75 a více
age (years)
The average duration of hospitalization was 14,2 ± 7,5 days (minimum 3 days and maximum
42 days) and 78 patients were discharged from hospital for home care, 18 patients to a longterm
care hospital. Arteria carotis interna sinistra was the most often affected arterial territory
in this group. Lateralization of the disease is in Table 2.
264
Table 2. Lateralization of the disease
Lateralization of the disease
Symptoms number
right-hand side hemiparesis 39
left-hand side hemiparesis 35
VB territory (CVS, cerebelum sy) 22
VB territory – vertebrobasilar territory, CVS – central vestibular syndrome
The following test scales were used for evaluation of the disablement measure and
possibilities of monitoring (9, 10, 11, 12):
For evaluation of activity (disability):
Functional independence measure (FIM)
Barthel test (BI) – assessing independence
For measurement of impairment:
Mini-mental state examination according to Folstein (MMSE) – evaluation of cognitive
functions and mental conditions.
Evaluation of the general condition and walking according to Chedok McMaster rehabilitation
centre, Canada (CH)
For evaluation of quality of life:
Index of quality of life - short version of SF 36- Index of quality of life Short Form (SF 36)
The tests ware carried out on the first day of rehabilitation (entry) and then at discharging
from neurological clinic (exit).
Methods of rehabilitation
Rehabilitation treatment in our clinic was made on the basis of the prescription and the
contents of exercise unit, choice of exercises and methodologies was based on kinesiologic
analysis, functional examination of independence and current condition of the patient.
Intensity was, as necessary, 1-2x daily of individual exercises at least 5 days in a week with
application of facilitation elements and methods, the patients were provided also with
logopaedic and psychological care.
The study was accepted by local ethical commission and the patients signed their informed
approval. The results are presented as average ± standard deviation. For statistical evaluation
Wilcoxon test for paired values was used.
265
RESULTS
We give the results of functional state of CMP patients at neurophysiotherapeutic treatments
acquired by means of test scales. Examinations were made at the beginning of rehabilitation
and at discharging from neurological clinic. The results are presented in the form of tables.
Evaluation of activity (disability):
Table 3 Evaluation of functional state by means of FIM in patients with stroke in acute phase
characteristic of
the group
FIM entry
x ± SD
FIM exit
x ± SD
difference
exit-entry
statistical
significance
whole group
(n = 96)
98.2 ± 15.7 110.9 ± 13.5 12.7 p 0.01
group of women
(n = 36)
99.8 ± 16.8 112.8 ± 11.8 13 p 0.01
group of men
(n=60)
98.0 ± 15.0 109.8 ± 11.7 11.8 p 0.01
n – number of patients, SD – standard deviation, x – average, p 0,001-level of statistical significance; FIM functional
independence measure
Table 4 Evaluation of functional state by means of BI in patients with stroke in acute phase
characteristic of
the group
BI entry
x ± SD
BI exit
x ± SD
difference
exit-entry
statistical
significance
whole group
(n = 96)
78.2 ± 16.7 94.5 ± 8.6 16.3 p 0.001
group of women
(n = 36)
76.9 ± 17.5 93.5 ± 9.5 16.6 p 0.001
group of men
(n=60)
78.9 ± 16.4 95.0 ± 7.9 16.1 p 0.001
n – number of patients, SD – standard deviation, x – average, p 0,001- level of statistical significance; BIBarthel
index
266
Evaluation of impairment:
Table 5 Evaluation of functional state by means of MMSE in patients with stroke in acute
phase
characteristic of
the group
MMSE entry
x ± SD
MMSE exit
x ± SD
difference
exit-entry
statistical
significance
whole group
(n = 96)
25.2 ± 4.7 28.0 ± 2.6 2.8 p 0.001
group of women
(n = 36)
25.3 ± 4.8 28.2 ± 2.5 2.9 p 0.001
group of men
(n=60)
25.1 ± 4.7 27.8 ± 3.0 2.7 p 0.001
n – number of patients, SD – standard deviation, x – average, p 0,001- level of statistical significance; MMSEMini
mental State Examination
Table 6 Evaluation of functional state by means of CH in patients with stroke in acute phase
characteristic of
the group
CH entry
x ± SD
CH exit
x ± SD
difference
exit-entry
statistical
significance
whole group
(n = 96)
79.8 ± 16.2 92.0 ± 11.6 12.2 p 0.001
group of women
(n = 36)
79.1 ± 17.5 91.5 ± 12.4 12.4 p 0.001
group of men
(n=60)
80.2 ± 15.5 92.4 ± 11.1 12.2 p 0.001
n – number of patients, SD – standard deviation, x – average, p 0,001- level of statistical significance; CH test:
Chedock Mc Master Rehabilitation center
Evaluation of quality of life:
Numerical formulation of dimensions of life quality – individual dimensions influencing
quality of life are based on the questionnaire SF-36 and are calculated as mean values of
specific questions from the questionnaire structured in a particular way. These dimensions
attain the values from 0 to 100. A lower value means generally worse value of the given
dimension and decreases total quality of life, a higher value means generally better value of
the given dimension and increases total quality of life.
267
The patients in all monitored groups evaluated Physical role, i.e. limitation of physical
activity because of health state, as the worst part of quality of life. Mental health was
evaluated as the best one.
Elderly patients (70 years of age and older) assessed their general physical health to be the
worst. The biggest differences are apparent in perceiving Emotional role in the group of men
and women, namely 21,8, with better subjective perception of women. Then quite a big
difference was recorded in the categories Physical role, evaluated better by women with the
difference 11,2, and Pain, tolerated better by men with the difference 9,3.
Table 7 Dependence of final functional state according to FIM on index of quality of life –
general mental and physical health SF 36 in patients with stroke in acute phase
FIM x PCS
FIM x MCS PCS x MCS
correlation
coefficient
correlation
coefficient
correlation coefficient
whole group 0.175 NS 0.053 NS 0.485**
group of women 0.123 NS 0.096 NS 0.557*
group of men 0.237 NS -0.015 NS 0.469*
group under 70
years of age
0.197 NS 0.067 NS 0.685**
group of 70 years
of age and older
0.074 NS -0.355 NS 0.112 NS
n – – number of patients, SD – standard deviation, x – average, p 0,001- level of statistical significance; FIM functional
independence measure, MCS – total motoric score, PCS – mental total score
DISCUSSION
Rehabilitation in patients after CMP is aimed at achieving maximal functional independence.
Rehabilitation treatments were based on the recommended medical treatments of CMP (13,
14, 15, 16, 17). In these patients so called 24-hour therapy program proved to be suitable
requiring cooperation of doctors, attending staff, physiotherapists, occupational therapists,
speech therapists, psychologists and family members. Successful therapy lies not only in
isolated muscle exercising, however, it is important to practice meaningful, goal-directed
activities with the patient, e.g. movements on the bed, shifting from supine to sitting position
and then to standing position, training of self-attendance, etc. The patient learns to feel better
268
his body and to control it in space, to involve the affected parts of his body in routine daily
activities, and he is more motivated as well.
Motor disablement of a half of the body is the most typical affection of patients after ictus, for
most of them, however, the consequences are much more complex. Moving abilities and
cooperation of the patient can be complicated, in addition to the loss of locomotion, from the
following reasons:
- disorders of muscle tonus, presented either as hypertonia (spasticity) or hypotonia
- disorders of sensitivity and sensorial functions (neglect, pusher syndrome, hemianopsia)
- psychic troubles, affection of autonomic functions
- disorder of proprioception, disorder of body perception, loss of balance and equilibrium
reactions
- disorder of stereognosis, dyspraxie, gnostic troubles
- phatic, communication troubles
The given perception problems result in disturbing the image of one´s own body in space, so
called body image. The goal-directed stimulation of senso-motor functions has, in this case, a
considerable therapeutic effect. It must be emphasized that in one-sided affection of brain,
including also ictus, significant troubles at both sides of body occur.
From acute phase of the disease therapeutic rehabilitation is important for further life of the
patient. Several facilitation methods are used for affection of voluntary locomotion disorder,
muscular unbalance and pathological reflection changes. A number of individual methods
were developed, being often named after the authors (NDT = neuro-developmental treatmentBobath
concept, proprioceptive neuromuscular facilitation-PNF, Brunnström, Rood, Perfetti,
Johnstone, Brunkowov, Vojta, Forced use, Method of sensomotoric stimulation, Biofeedback,
Templ Fay, Mi atský, Affolter, 17). Their common feature is a reflection action leading to
facilitation of voluntary locomotion, at the same time, however, to inhibition of pathological
reflection activity (spasticity). In the states after CMP they can be used in acute phase already,
when they influence recurring voluntary locomotion and simultaneously carrying out of
purposeful movements in walking and self-attendance activities.
Even if evaluation of the measure of disablement is fundamentally important for assessment
of seriousness of stroke, it cannot encompass all main factors influencing quality of life. They
include not only health state, but also social and economic conditions, mental state,
fulfillment of aims in life, culture and value system in various geographical conditions.
269
Quality of life is a subjectively perceived level of living by means of which people evaluate
their physical, emotional and social abilities (1, 2).
Evaluation of quality of life becomes an integral part of studies in which health state of
patients in different branches of medicine is followed for a long time and the conception of
quality of life covers a wide scale of perceiving life (2).
Our results show that patients after stroke achieve a lower number of points in subjective
evaluation of quality of life, and in all aspects, as it had been expected in generic disorders
causing disability (7, 8).
As the questionnaire SF-36 is a simple and cheap means for determination of quality of life,
the information provided by this questionnaire could be used both before and after specific
therapies for determination of changes in quality of life by means of the changes in points of
patients, concurrently with clinical measurements of seriousness of the disease (12).
We asked a question whether there is a dependence of functional state of patients with CMP
(tested by FIM) in the time of their discharging from the clinic and quality of life evaluated
according to SF 36. According to our results there is no statistically significant correlation of
both states.
CONCLUSION
The results proved that a complex therapy along with intensive rehabilitation led in patients
after CPM in acute phase to improvement of their functional state and reduction of the
measure of impairment of motor and cognitive functions; the differences were statistically
significant.
The results show that the patients after CMP assessed their physical health to be worse than
mental health.
We have found no relation between FIM and SF 36 in the group of patients after CMP by
means of correlation analysis. There is correlation between the index General physical health
and the index Mental Health and it is apparent that in younger patients physical health
influences significantly mental health. We have not found this significant correlation in the
patients older than 70 years of age.
Supported by VZV MSM0021622402
270
LITERATURE
1. Amber, Z. Cévní p íhody mozkové a význam randomizovaných klinických studií. es.
Slov.Neurol. Neurochir., 59, 1996, s.18-20.
2. Astrom M, Asplund K. Handicap and quality of life after stroke. In Bogousslavsky J (ed)
Long term effects of stroke. New York : Marcel Dekker; 2002: 25-50.
3. Bobathová, B. Hemiplégia dospelých. Bratislava: Lie reh Gúth, 1997. 175 s. ISBN 80-
967383-4-8.
4. Granger, CV., Brownscheidle, CM. Outcome measurement in medical rehabilitation. Int.
J. Technik. Health Care, 11, 1995, s. 262-268.
5. Hook, O. Priorities in health and welfare in Sweden. The importnant role of rehabilitation
of persons with disabilities. Scand. J. Reagan. Med., 1995, Suppl. 33, s. 25-34
6. Chlumský, J. Diagnostika a lé ba cévních mozkových p íhod. Prakt. Lék. 2000, 6, s. 314-
316.
7. Iwanenko, W., Fiedler, RC., Granger, CV., Lee, MK. Uniform data system for medical
Rehabilitation:report of first admission to subacute rehabilitation for 1998. Am. J. Phys.
Med. Rehabil.., 80, 2001, s. 65-61.
8. Pazdírek, J. a kol. Functional Independence Measure in Patients with Stroke.
Chronogiology in Medicine. NCO NZO Brno: LF MU Brno, 2004, s. 129-133.
9. Zittoun, R. et.all.:Assessement of quality of life during intensive chemotherapy bone
marrow transplantation. Psychooncology, 1999,vol. 8, no. 1, p. 64 73.
10. Quality of Life for Patients with Chronic Illness
http://www.nih.gov/ninr/about/legislation/chronic_illnesss.htm
11. Curtis, J.R., et al.: Measure of the Quality of Dying and Death: Initial Validation Using
After-Death Interviews with Family Members. J. Pain Sympt. Management, 2002, vol. 24,
no.1, p. 17 31
12. SF-36® Health Survey Scoring Demonstration, http://www.sf-36.org/ SF-36® Health
Survey Scoring Demonstration.htm
13. Janda, V.-Kraus, J. Neurológia pre rehabilita ných pracovníkov. Martin: Osveta, 1988.
233 s.
14. Va ásková, E. a kol. Hodnocení nemocných po cévní mozkové p íhod testy sob sta nosti
na l žkovém rehabilita ním pracovišti. Rehabilitace a fyzikální léka ství. 2003, 2, s. 60-64
15. Va ásková, E. a kol. Náhlé cévní p íhody mozkové – testování v rehabilita ní pé i.
Rehabilitace a fyzikální léka ství, 1994, 1, s. 28-31.
16. Va ásková, E. Testování v rehabilita ní praxi-cévní mozkové p íhody. NCONZO Brno,
2004.65 s. ISBN 80-7013-398-8.
17. WHO.Rehabilitace po cévní mozkové p íhod . Praha: Grada Publishing, 2004, 200 s.
ISBN 80-247-0592-3.
SUMMARY
The aim of the study was analysis of functional state of patients by means of test scales in the
set of patients after acute stroke (CPM) with moderate and light disablement in the course of
hospitalization in I neurological clinic LF MU with intensive rehabilitation treatment.
271
96 patients were examined before and after complete rehabilitation and the measure of
functional disablement, functional disorder and quality of life were tested. The results proved
that a complex therapy along with intensive rehabilitation led in patients after CPM in acute
phase to improvement of their functional state and reduction of the measure of impairment of
motor and cognitive functions; the differences were statistically significant.
Key words: stroke, impairment of function, rehabilitation
272
MUSCLE STRENGTH EXAMINATION OF HAND AND MOTOR
SKILLS OF HAND IN PATIENTS WITH CEREBRAL PALSY
LENKA DRLÍKOVÁ1
, ALENA HAVELKOVÁ, MOHSIN KAID ALI HASHIM2
,
FARAG HASSAN ANBAIS2
, ASHREF ALI ERAJHI2
, MICHAL MAŠEK2
, LUMÍR
KONE NÝ2
, HELENA ZEMANOVÁ1
, BOHUMIL FIŠER,
JARMILA SIEGELOVÁ2
1
Home for handicapped children and youth, Kociánka, CZ,
2
Dept. of physiotherapy and rehabilitation, Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital, Brno,
CZ
INTRODUCTION
International Classification of Functioning is the document of WHO directing our attention in
assessment of patients mainly to functional abilities and possibilities of participation in
society (1).
Gross Motor Function Classification System (GMFCS) is an important instrument for
evaluation of gross motor skills in children with cerebral palsy (DMO) within the framework
of their common functions. Recently, The Manual Ability Classification System (MACS) has
been developed as a relevant method of classification for evaluation of fine motor skills of
hand in DMO (2,3). The test evaluates fine motor skills by the technique used in GMFCS
already. In another aspect, both classification systems are also important for Evidence Based
Practice because easy scoring and quick realization enable the common language to be
established both for professionals and for parents of children included in a very heterogeneous
group of DMO (4). Childhood cerebral palsy involves a diversified group of patients with
long-time demands on rehabilitation. Characteristics of DMO are different in individual
papers. The group for the research of DMO in Europe Surveillance of Cerebral Palsy in
Europe recommends the DMO syndrome to be characterized as follows: It is the category of
permanent, but not unchangeable disorders of motion and/or posture and motor functions,
evolving on the basis of non-progressive disturbance, lesion or abnormality of the developing
immature brain (5).
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AIM
The aim of this study is evaluation of the results of The Manual Ability Classification System
(MACS), Gross Motor Function Classification System (GMFCS), and muscle strength
examination measured by dynamometer in children with cerebral palsy.
METHODS
Set of patients
We examined 51 patients with DMO in the age ranging from 8 years to 26 years 8 months
(average age 17,3 ± 4,2). 8 patients were at the age of 8 - 12 years, 20 patients were at the age
of 12 - 18 years, 23 patients were older than 18 years. The set consisted of 28 girls and 23
boys. The subtypes of DMO were determined according to the classification of Mr. and Mrs.
Bobath.
The patients with DMO suffered from spastic form in 47 cases, in 10 patients it was
hemiplegia, in 18 patients diplegia, in 3 patients triplegia, in 16 patients quadruplegia, in 1
patient ataxic form, in 3 patients dyskinetic form. All patients are in charge of Home for
handicapped children and youth Kociánka in Brno.
Tests GMFCS and MACS
Functional test for evaluation of fine motor skills in DMO: The patients were included,
according to functional skills of hand, on the basis of observation of a physiotherapist in one
of 5 levels of MACS (5th
level means the most serious disablement). This classification is
focused on skills performed by the patient in usual daily situations, it should not serve for
evaluation of the maximum potential. It evaluates the common work of both hands.
In the scale of the test of gross motor functions GMFCS the examined patients were included
in one of five levels characterizing in the best way their gross motor skills in usual
environment on the basis of observation of a physiotherapist (5 means the most serious
disablement). This system evaluates gross motor functions on the basis of initiation of motion
stressing the sitting position, movements and mobility. The differences between the groups
are given by limitations, by necessity of using aids or wheelchair and by reduced quality of
motion (2).
The maximum handgrip was measured by hand dynamometer, first on the upper extremity
with a lesser motor disablement, and then on the second upper extremity. The examined
patients were sitting on a chair or a wheelchair during the measurement. The upper extremity
was not supported, the arm was in adduction close to the body, flexion in elbow 90o
, central
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position of forearm and wrist. The position of some patients was modified because of
contractures.
RESULTS
Tests GMFCS and MACS
All 51 patients with DMO were included in functional levels 1- 5 according to the test of
gross motor functions GMFCS. We assessed the score of the functional test for evaluation of
fine motor skills of hand MACS and muscle strength of dominant and non-dominant upper
extremities in patients with DMO.
Tab. 1 Correlations distribution of the fine motor skills test (MACS) and of the gross motor
skills test (GMFCS) in patients with DMO
MACS levels
GMFCS levels I II III IV V TOTAL
I 8 5 - - - 13
II 2 2 2 - - 6
III 2 4 2 - - 8
IV - 1 2 - - 3
V - - 11 8 2 21
TOTAL 12 12 17 8 2 51
Distribution of the group into individual categories of gross motor skills (according to
GMFCS) and fine motor skills (according to MACS) is in Table 1 and graph 1.
14 patients with DMO (27%) had better results in MACS, conformity in both tests was in 30
patients (59%), 7 patients (14%) had better results in GMFCS. It means that GMFCS does not
correlate with MACS in 73% of patients.
275
0
2
4
6
8
10
12
14
16
1 2 3 4 5
kategorie
poetproband
GMFCS MACS
Graph 1 – Results of the test of gross motor skills (GMFCS) and of the test of fine motor
skills (MACS) in patients with DMO
Muscle strength in patients with DMO
Muscle strength of the hand with a lesser disablement in the whole set was in the range from
34 to 442 N (average 235.8± 85.9), muscle strength of the second hand was in the range from
5 to 376 N (average 66.7± 66.2). Relationship between muscle strength of the hand with a
lesser disablement and functional ability of the hand according to MACS can be seen on
graph 3 and relationship between muscle strength and GMFCS is represented on graph 4.
Correlation between muscle strength of the hand and MACS is low, but statistically
significant (R= 0.342; p < 0.05); between muscle strength and GMFCS there is no correlation.
276
y = -0,0046x + 3,1596
R2
= 0,1169
0
1
2
3
4
5
6
0 50 100 150 200 250 300 350 400 450 500
Maximální sílá kon etiny (N)
MACS
Graph 3 - Relationship between muscle strength of the hand with a lesser disablement and
functional ability of the hand according to MACS
y = -0,0039x + 3,7955
R2
= 0,0393
0
1
2
3
4
5
6
0 50 100 150 200 250 300 350 400 450 500
Maximální síla kon etiny
GMFCS
Graph 4 - Relationship between muscle strength of the hand with a lesser disablement and
functional ability of the hand according to GMFCS
277
DISCUSSION
The test MACS serving for elimination of influence of gross motor skill disorders places
emphasis on handling things in personal space of the examined patient. Eliasson et al. gives
intrinsic coefficient of correlation in the group of observers physiotherapists 0.97, in the
group parents - physiotherapists 0.96 (3).
We expected that correlation between handgrip and motor tests would be low. We confirmed
thus the assumption that measurement of strength cannot serve even for a rough estimate of
the level of disablement.
Beckung and Hagberg in their study also dealt with the function of hand in DMO, they used,
however, for evaluation the test Bimanual Fine Motor Function (BFMF), that cannot be
compared either with the score of functional test for evaluation of fine motor skills of hand
MACS in patients with DMO or with examination of muscle strength measured by
dynamometer, and its reliability has not yet been tested. BFMF is directed more at the
disorder, while MACS more at the activity (6).
In evaluation of GMFM and MACS in individual patients with DMO we arrived at similar
results as Carnahan et al. in the study of relation of GMFCS and MACS. These authors found
conformity between MACS and GMFCS in 53% of patients, better MACS than GMFCS in
20% of patients and better GMFCS than MACS in 27% of patients (7). This leads to the same
conclusions as our study.
The score of functional test for evaluation of fine motor skills of hand in DMO MACS
describes very well the functional state of the child with DMO. This evaluation can be used
for improving the quality of communication between professionals and parents of these
children. It is also evident, however, that the function arises from the organ, but the mere
description of the state of the organ, e.g. muscle strength measured by dynamometer, does not
give a clear picture of the patient in such a varied group as DMO.
Supported by grant MSM 0021622402.
LITERATURE
1. World Health Organisation (2001): International Classification of Functioning, Disability
and Health. Geneva: World Health Organisation
2. Palisano, R.: GMFCS-E&R, CanChild Centre for Childhood Disability Research,
McMaster University
278
3. Eliasson A.C., Krumlinde- Sundholm L., Rosbland B., Beckung E., Arner M., Ohrwall
AM, Rosenbaum P, (2006): The Manual Ability Classification system for children with
cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child
Neurol. 48:549-554
4. Steenbergen B. (2006): Using the MACS to facilitate communication about manual
abilities of children with cerebral palsy- commentary. Dev Med Child Neurol 48:948-948
5. SCPE. http://www-rheop.ujf-grenoble.fr/scpe2/site_scpe/index.php Cit. 10.6.2008
6. Beckung E., Hagberg G. (2002): Neuroimpairment, activity limitations, and participation
restrictions in children with cerebral palsy. Dev Med Child Neurol. 44:309-316
7. Carnahan K.D., Arner M., Hägglund G. (2007): Association between gross motor function
(GMFCS) and manual ability (MACS) in children with cerebral palsy. A population-based
study of 359 children. BMC Musculoskelet Disord. 8:50.
SUMMARY
The aim of this study is evaluation of the results of The Manual Ability Classification System
(MACS), Gross Motor Function Classification System (GMFCS), and muscle strength
examination measured by dynamometer in children with cerebral palsy. We examined 51
patients with cerebral palsy in the age ranging from 8 years to 26 years (average age 17.3±
4.2) living in the Home for handicapped children and youth Kociánka Brno. The group
consisted of 28 girls and 23 boys.
Maximum handgrip was measured by hand dynamometer in both upper extremities. After the
examination by a physiotherapist the patients were categorized according to their gross motor
skills using Gross Motor Function Classification System (GMFCS) and fine motor skills
using The Manual Ability Classification System (MACS). Muscle strength in the better hand
in the whole group ranged from 34 to 442 N (average 235.8± 85.9), in the second hand from 5
to 376 N (average 66.7± 66.2). The results show a weak correlation between muscle strength
of handgrip and MACS, but it is statistically significant (R= 0.342; p < 0.05), correlation
between muscle strength of handgrip and GMFCS does not exist.
Key words: cerebral palsy, dynamometry, Gross Motor Function Classification System, The
Manual Ability Classification System
279
QUALITY OF LIFE AFTER CARDIOVASCULAR
REHABILITATION IN CHRONIC ISCHEMIC HEART DISEASE
JAROSLAVA POCHMONOVÁ, LEONA MÍFKOVÁ, LUCIE VYMAZALOVÁ,
ALENA HAVELKOVÁ, ASHREF ALI ERAJHI, PAVEL HOMOLKA, PAVEL
VANK, JARMILA SIEGELOVÁ
Dept. of Physiotherapy and Rehabilitation and Department of Functional Diagnostics
and Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching
Hospital, Brno, CZ
INTRODUCTION
Rehabilitation of cardiac patients plays a significant clinical and psychological role. It
helps the patients in the process of decondition and physiological changes appearing
after acute myocardial infarction. Cardiovascular rehabilitation induces the feeling of
security and helps the patient to return to normal life activities. Cardiovascular
rehabilitation turns out to be important for a better physical performance and a feeling
of health (1, 2). It leads to the increase of performance and capacity of the transport
system for oxygen. Subjective perceiving of quality of life is also related to it.
Quality of life (QOL) reflects how a person takes his position in the world in the
context of culture and value systems in which he lives, and in relation to his aims,
expectations, life style and interests (3).
Even if correlation between increased performance and improved quality of life can
be expected, this relation is not obvious.
The function of cardiovascular system in patients with heart arrhytmias being at risk
of a sudden cardiac death improves in the case of pacemaker implantation. In some
cases, however, nervous patients can experience psychological disorders after
pacemaker implantation that can be accompanied by anxiety and depressions.
In clinical practice we meet very often with a discrepancy between the opinion of the
doctor and the patient.
AIMS OF THE STUDY
The aim of the study was to compare influence of 12-week combined training on
subjectively perceived quality of life and on objectively measured indicators of
performance (expressed as maximal achieved performance and performance converted
280
to 1 kg of the body mass) and on capacity of the transport system (expressed as
maximal oxygen intake and maximal oxygen intake converted to 1 kg of the body mass)
in patients with ischemic heart disease determined by coronarography with regard to
their gender.
METHODOLOGY
The group of examined patients included 84 men (62±9 years) with
coronarography determined ischemic heart disease (with means ejection fraction EF
48±10 %) and 19 women (64±7 years, mean EF 46±8 %) who participated in 12-week
rehabilitation program.
Graph 1
Basic characteristic of the group of patients
Legend: age (years), EF (%), BMI (body mass index), women – yellow, men – dark
The patients included in cardiac rehabilitation had to comply with the following
criteria: they did not suffer acute myocardial infarction or attack of unstable angina
pectoris in the period of three months before the beginning of exercises, no patient had
valvular defect or insufficiently compensated hypertension.
0
10
20
30
40
50
60
70
80
age EF BMI
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The patients with serious rhythm disorders, with symptoms of haemodynamic
instability, with substantial marks of ischemia at rest or at load were excluded. Also the
patients with uncontrolled hypertension and other conditions and diseases making
rehabilitation exercises impossible were not included into the group.
Before starting rehabilitation all patients were subjected to basic clinical examination
and Doppler echocardiography by the instrument SONOS 5500 (Hewlett Packard).
Before the starting and after the finishing of the rehabilitation program a
spiroergometric exercise test on a bicycle ergometer was made. 12-lead
electrocardiogram was recorded by the instrument Cardiovit CS 100 – Schiller.
Ventilatory-respiratory values were determined by means of the analyzer of gases
Pulmonary Function System 1 070 – MedGraphics CPX/D, USA, fitted with software
for their analysis and evaluation.
The examination was made in morning hours and the patients were advised
beforehand to take the morning dose of their usual medication. The reason of the
examination and its expected results were explained to all patients. 12-lead
electrocardiogram at rest was monitored from the beginning of the exercise test. Within
the adaptation phase lasting 2 – 5 minutes in the sitting position on ergometer for
stabilization of parameters the resting values of heart rate (HR) and blood pressure (BP)
were read.
The protocol with graded load without interruptions up to the symptom-limited
maximum was determined for the examination. The patient kept the speed rate in the
range of 50 – 55/min. In the course of examination SF was read from ECG record each
two minutes, the examined patient assessed the rating of perceived exertion (RPE) and
his BP was measured by auscultation method with a mercury manometer. Respiratory
parameters in breath were determined by means of an analyzer of breath gases in real
time breath-by-breath. In addition to achieving the symptom-limited maximum
generally valid criteria were used for finishing the test, so called end points (4, 5).
Seattle Angina Questionnaire. To find out subjective perception of health state and
affecting quality of life, the patients were given Seattle Angina Questionnaire (SAQ) to
be filled out in the beginning of the rehabilitation program and after its termination.
Questionnaire is divided into five parts (hereafter and in the results SAQ 1-5) and it
contains nineteen items altogether.
282
Part 1 (SAQ 1) The patient indicates how chest pain or anginous pain restricted him
during the last four weeks in performing the given activities. The activities are arranged
according to physical severity.
Part 2 (SAQ 2) It deals with comparison of the current health state with the period
four weeks ago as to the frequency of occurrence of anginous difficulties in performing
usual daily activities.
Part 3 (SAQ 3) The patient indicates how many times a day or a week in the past
month, in comparison with the same period four weeks ago, he had anginous difficulties
and how many times he had to take nitroglycerin because of them.
Part 4 (SAQ 4) The patient indicates subjective feeling of the therapy and his
satisfaction with it.
Part 5 (SAQ 5) The last part should describe how the patients feel quality of their
life with the present illness and its potential fatal termination.
Rehabilitation program
The ambulatory controlled exercise training program lasted 12 weeks with the
frequency three times a week. The training unit lasted 60 min and consisted of four
phases (6, 7).
The warm-up phase was aimed at preparing the cardiovascular and locomotive
system for additional load, prevention of musculoskeletal lesion. The exercise training
was composed of dynamic endurance exercises (simple floor exercises, exercises with
gymnastic apparatus) and stretching of muscle groups tending to be shortened.
The aerobic phase took place on a bicycle ergometer (Ergoline REHA E900)
controlled by the program ErgoSoft+ for Windows. Intensity of aerobic training was set
at the aerobic threshold level.
The strength training was performed on multifunctional toning machines TK-HC
COMPACT. Four exercises were done (benchpress, pull down, leg extension on the
apparatus and sitting-lying positions). Intensity of strength training was set by the
method 1-RM and training loads were determined in per cents of maximum: 30-60 % 1RM
(every week increasing by 10 %). The number of series was 3 - 5 with ten
repetitions. Before starting the strength training the patients were thoroughly informed
about proper breathing and performing of exercises.
Relaxation phase: modified Schultz autogenic training was used.
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Heart rate, blood pressure and RPE degree were monitored in the course of the whole
training, during the aerobic phase and in 1-RM test also ECG.
The examination protocol of the study was accepted by local ethical commission and
the patients signed their informed approval.
The results are given as average ± standard deviations, for statistical evaluation
Wilcoxon test for paired values was used.
RESULTS
After going through the rehabilitation program the body mass and BMI neither in
men nor in women were changed and also the initial systolic and diastolic pressure,
maximal achieved diastolic pressure, maximal heart rate and both resting and maximal
product heart rate-pressure (product of systolic blood pressure and heart rate /100) have
not been statistically significantly changed in both cases.
Our results indicated in the group of men (before versus after) a significant change of
systolic blood pressure at maximum load (196.9±28.2 mmHg v. 203.4±27.1 mmHg;
p<0.05), heart rate (HR) initial (64.7±10.9 cpm v. 61.9±10.4 cpm; p<0.05). The increase
of performance occurred, it is statistically significant only in men, however (graph 2, 3).
Maximal muscle strength increased in the group of men: WmaxSL 113.35±33.14 W v.
123.0±35.6 W; p<0.01; WmaxSL.kg-1
1.3±0.4 W v. 1.45±0.45 W; p<0.01.
The transport system for oxygen at achieving the symptom-limited maximum
(VO2SL) was improved: 1691.±411.8 ml/min v. 1833.8±45.2 ml/min, p<0.01; VO2SL.kg-
1
19.9±4.8 ml/min/kg v. 21.6±5.7 ml/min/kg, p<0.01; MET 5.7±1.4 v. 6.2±1.7, p<0.01.
Quality of life measured by means of the questionnaire in the group of men improved
after rehabilitation considerably in all aspects: SAQ1 80.7±18.8 v. 84.9±15.8, p<0.01;
SAQ2 79.6±21.6 v. 86.4±16.1, p<0.01; SAQ3 83.5±16.1 v. 88.5±14.4, p<0.01; SAQ4
88,4±16,1 v. 93.0±10.4, p<0.01; SAQ5 66.6±17.5 v. 73.6±17.6, p<0.01.
In the group of women we recorded a significant increase of the transport system
capacity: VO2SL 1134.8±155.4 ml/min v. 1215.0±184.6 ml/min, p<0.05; VO2SL.kg-1
15.1±2.4 ml/min/kg v. 16.3±2.4 ml/min/kg, p<0.05; MET 4.4±0.7 v. 4.70±0.67, p<0.05.
The questionnaire for quality of life in women indicated increased quality of life in all
aspects: SAQ1 69.0±20.5 v. 75.7±16.2, p<0.01; SAQ2 78.0±18.2 v. 88.0±16.4, p<0.05;
284
SAQ3 77,5±20,8 v. 84,2±17,1, p<0,01; SAQ4 89,9±12,7 v. 93,9±9,0, p<0,05; SAQ5
62,82±20,6 v. 72,15±17,27, p<0,01.
Graph 2 Increase of maximal performance after cardiovascular rehabilitation in men
Legend: Wmax (W), before and after, women – yellow, men – dark;
Graph 3 Increase of maximal performance (to 1 kg of the body mass) after
cardiovascular rehabilitation in men
Legend: Wmax per kg, before and after, women – yellow, men – dark
W max (W)
ženy muži
0
20
40
60
80
100
120
140
160
180
**
W maximální/kg (W.kg
-1
)
ženy muži
0,0
0,5
1,0
1,5
2,0
**
285
DISCUSSION
The relation between quality of life and results of functional examination by load
was studied in a number of the papers (8, 9, 10). The definition of quality of life given
in the introduction to our study. The quality of life is influenced by the particular culture
in the given population. That is why it is useful to study the relations separately in all
cultural backgrounds. We have proved in our study a positive influence of
cardiovascular rehabilitation on quality of life in patients with chronic ischemic heart
disease in men and women in the Czech Republic.
CONCLUSION
12-week combined training in men with ischemic heart disease resulted in increase
of their performance and capacity of the transport system. They attained a lower heart
rate at rest and at the same time increased values of maximal systolic pressure at the
achieved higher performance.
As a result of 12-week combined training male patients had fewer anginous
difficulties in performing normal daily activities and they did not have to take
nitroglycerin because of these difficulties. The men included into the training were also
evidently more satisfied with the course and quality of therapy after the training. The
most important improvement, however, was achieved, as assumed, in subjective
perception of quality of life.
In women with ischemic heart disease 12-week combined training led to increased
capacity of the transport system, neither performance nor the other monitored
parameters changed significantly, but occurrence of anginous difficulties in performing
normal daily activities and necessity of taking nitroglycerin decreased.
Supported by grant MSM0021622402
LITERATURE
1. Dafoe W., Huston P., Current trends in cardiac rehabilitation: Can. Med. Assoc.
J. 1997, 156, 27-32.
286
2. Giannuzi P., Temporelli P.L., Corra U., et al. Attenuation of unfavorable
remodeling by exercise training in postinfarction patients with left ventricular
disfunction: results of the exercise in left ventricular disfunction trial.
Circulation 1997, 96, 1790-1797.
3. DRAGOMIRECKÁ, E. – ŠKODA, C. 1997. Kvalita života. Vymezení, definice
a historický vývoj pojmu v sociální psychiatrii. . S. Psychiatrie, ro . 93, .2, s.
102-108. 1.
4. CHALOUPKA, V. Siegelová J, Špinarová L. a kol. Rehabilitace u nemocných
s kardiovaskulárním onemocn ním. Cor Vasa 2006; 48: K 127-45.
5. PLACHETA, Z. – SIEGELOVÁ, J. – ŠTEJFA. et al. 1999. Zát žová
diagnostika v ambulantní a klinické praxi. Grada Publishing, s. 51-178, ISBN
80-7169-271-9
6. JAN ÍK, J. – DOBŠÁK, P. – SVA INOVÁ, H. – SIEGELOVÁ, J. –
PLACHETA, Z. 2002. Zát žová vyšet ení u nemocných s chronickým srde ním
selháním. Kardiol. Revue, ro . 3., s. 175-179.
7. JAN ÍK, J. – VANK, P. – MÍFKOVÁ, L. – CHLUDILOVÁ, V. – FIŠER, B. –
SIEGELOVÁ, J. – EICHER, J. CH. 2004. Aerobní trénink kombinovaný se
silovými prvky u nemocných s chronickou ischemickou chorobou srde ní: vliv
na variabilitu srde ní frekvence. In Optimální p sobení t lesné zát že a výživy.
Hradec Králové: Gaudeamus, s. 213-216, ISBN 80-7041-666-1.
8. Arena R, Humphrey R, Peberdy MA. Relationship between the Minnesota living
with heart failure questionnaire and key ventilatory expired gas measures during
exercise testing in patients with heart failure. J Cardiopulmonary Rehab, 2002,
22,273-277.
9. Gottlieb SS, Fisher ML, Freudenberger R et al. Effect of exercise training on
peak performance and quality of life in congestive heart failure patients. J Card
Fail, 1999, 5,188-194.
10. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial
of long-term moderate exercise training in chronic heart failure: effect on
functional capacity quality of life, and clinical outcome (see comments).
Circulation, 1999,99,11731182.
SUMMARY
The aim of the study was to compare influence of 12-week combined training on
subjectively perceived quality of life and on objectively measured indicators of
performance (expressed as maximal achieved performance and performance converted
to 1 kg of the body mass) and on capacity of the transport system (expressed as
maximal oxygen intake and maximal oxygen intake converted to 1 kg of the body mass)
in patients with ischemic heart disease determined coronographically with regard to
their gender.
287
12-week combined training in men with ischemic heart disease resulted in increase
of their performance and capacity of the transport system. They attained a lower heart
rate at rest and at the same time increased values of maximal systolic pressure at the
achieved higher performance.
As a result of 12-week combined training male patients had fewer anginous
difficulties in performing normal daily activities and they did not have to take
nitroglycerin because of these difficulties as frequently as before the training. The men
included into the training were also evidently more satisfied with the course and quality
of therapy after the training. The most important improvement, however, was achieved,
as assumed, in subjective perception of quality of life.
In women with ischemic heart disease 12-week combined training led to increased
capacity of the transport system, neither performance nor the other monitored
parameters changed significantly, but occurrence of anginous difficulties in performing
normal daily activities and necessity of taking nitroglycerin decreased.
Key words: Quality of life, combined training, chronic ischemic heart disease, gender
difference
288
AUTONOMIC NERVOUS SYSTEM IN PARKINSON’S DISEASE
PETR POSPÍŠIL, LUMÍR KONE NÝ, PAVEL VANK, HANA SROVNALOVÁ*
,
IRENA REKTOROVÁ*
, JARMILA SIEGELOVÁ
Department of Physiotherapy and Rehabilitation,
Department of Functional Diagnostics and Rehabilitation,
*
I Department of Neurology,
Faculty of Medicine, Masaryk University, St. Anna Faculty Hospital in Brno, Brno, CZ
INTRODUCTION:
Autonomic nervous system dysfunction is an integral part of symptomatology of
idiopathic Parkinson’s disease (PD) from its early outset (3, 19, 21, 24, 29, 36, 37).
Clinical studies examine the function of autonomic nervous system by means of
standard autonomic tests – orthostatic test (32), Valsalva´s maneuver (5, 40), isometric
exercise test (40), ratio of heart rate increase to 15th
heartbeat after standing up from
supine position to its decrease to 30th
heartbeat (30:15 ratio; 4), ratio of the longest RR
interval in expiration to the shortest RR interval in inspiration (E:I ratio; 4), evaluation
of reaction of heart rhythm and blood pressure to deep breathing test (5, 40) and tilt
table test (4, 25), sympathetic skin response (4, 43) etc.
A number of studies document, according to the applied method of examination, that
the progression of autonomic dysfunction is proportional to the course of development
of other PD symptoms (5, 23, 25, 28, 32, 40).
Measurement of heart rate variability (HRV) and its analysis is a non-invasive
examination revealing autonomic dysfunction in mild stage of PD already (6). Decrease
of spectral power in mild stage of PD disablement was documented in short-term HRV
examination by Rodriguez (35), Haapaniemi (11) gives consistent results in 24-hour
HRV analysis.
Even if spectral power of HRV decreases naturally with increasing age, influence of
age as a unique factor inducing this decrease was not confirmed in PD patients.
Dysfunction of autonomic nervous system in PD patients demonstrates a marked
dependence mainly on the disease progression evaluated according to motor scale
UPDRS III or H&Y score (H&Y) UPDRS V (40).
Influence of anti-parkinsonian medication as the only factor influencing the
development of symptomatology of autonomic dysfunction was disproved as well.
Presence of autonomic dysregulation was described and well documented also in the
289
studies evaluating spectral power of HRV in patients with idiopatic PD even before
starting this medication (9, 20, 26).
Evaluation of the measure of dysfunctions of autonomic nervous system is a
permanent subject of the research (1, 4, 5, 7, 23, 30, 41). Most of preceding studies,
however, have not yet been dealing adequately with important factors of day time of
short-term HRV examination, differences in the extent of disablement by PD, type of
dopaminergic or other pharmacotherapy, changes of breathing rate during examination
etc. (5).
AIM OF THE STUDY:
Evaluation of disorder of autonomic cardiovascular regulation in PD patients in mild
and advanced stage according to H&Y score by means of spectral analysis of short-term
HRV examination.
DESIGN AND METHODS:
25 PD patients whose diagnosis was established at the Ist
Neurological Clinic of St.
Anna Faculty Hospital in Brno were included into the study (8). Absence of other
diseases and anti-parkinsonian or other pharmacological therapy influencing results of
HRV examination was the condition of inclusion into the study (2, 3, 12, 14, 16, 22, 27,
33, 40). The patients included into the study also met criteria of stable medication
without any changeat least in the last 4 weeks before the examination, compliance of
usual daily schedule including medication, in the day before the examination without
excessive physical activity, in the night before the examination at least 6 hours of good
sleep, in the morning before the examination only light breakfast without coffee, tea,
alcohol, with regard to the age of patients, at least 2 hours before the examination.
The patients were divided into two groups according to the measure of clinical
disablement. H&Y score in the range of 1-1.5 was a criterion for inclusion into the
group “SI”; H&Y score in the range of 2-3 was a criterion for inclusion into the group
„SII“.
290
Basic anthropometric characteristics of the groups are given below in Table l as
mean ± SD:
Table 1: Basic anthropometric characteristic of evaluated groups of PD patients
H&Y
AGE
(years)
BMI
PD DURATION
(years)
Group SI 1.3±0.3 65.7±11.0 24.7±2.5 7.6±3.9
Group SII 2.3±0.4 68.2±7.1 26.7±2.1 5.7±3.0
Examined patients underwent short-term measurement and spectral analysis of heart
rate variability in supine position (15, 20). The methodology of metronome-paced
breathing rate f = 0.33 Hz (18, 34, 38, 39, 42) was used for reducing the effect of
different rate of spontaneous breathing on spectral power in the groups of patients
subjected to examination (5, 13, 28, 31, 40). Graphic representation of the effect of
controlled breathing on spectral power is given below in Graph 1.
Graph 1: Example of graphic representation of the results of spectral analysis of heart
rate variability by the system Task Force Monitor, CNSystems Medizintechnic GmbH.
All HRV tests were accomplished always in morning hours between 9 and 11 a.m.
The measure of autonomic dysfunction evaluated by means of spectral analysis of
HRV was compared between the groups of patients with a different degree of clinical
disablement according to H&Y.
The differences of values of selected parameters of spectral analysis of HRV
between the groups SI and SII were statistically evaluated by Kolmogorov-Smirnov test
(test of distribution) and T test (Statistica, StatSoft Inc., version 7, 2004).
The study was accepted by ethical commission of Masaryk University in Brno and
all participants of the study signed their informed consent.
291
RESULTS:
The results of selected parameters of spectral analysis of short-term examination of
HRV are given below in Table 2 (mean ± SD): total power (TP, ms2
), power in lowfrequency
band (0.04-0.14 Hz; Power LF; ms2
), power in high-frequency band (0.15-
0.4 Hz; Power HF; ms2
) and ratio Power LF / Power HF (LF/HF).
Table 2: Results of HRV spectral analysis, metronome-paced breathing (f = 0,33 Hz)
TP
(ms2
)
Power LF
(ms2
)
Power HF
(ms2
)
LF/HF
Group SI 438 ± 411 132 ± 95 251 ± 315 1.0 ± 0.6
Group SII 123 ± 108 40 ± 37 47 ± 62 1.9 ± 2.3
P *0.018 **0.005 *0.038 N.S.
Graphic representation of the difference of selected parameters of spectral analysis of
short-term HRV examination during metronome-paced breathing (f = 0.33 Hz) is given
below (Graph 2).
Graph 2: Comparison of selected parameters of spectral analysis of HRV
0
50
100
150
200
250
300
350
400
450
500
Power LF SII.Power LF SI. Power HF SI. Power HF SII. TP SI. TP SII.
ms
2
**
*
*
p 0.01
p 0.05
p 0.05
In statistical comparison of selected parameters of spectral analysis of HRV,
a significant difference was found between the group SI with a milder degree of
disablement and the group SII with a more advanced degree of disablement according to
H&Y. In the group SII a statistically significant decrease of total power (TP) and of
power in low-frequency (Power LF) and high-frequency (Power HF) spectral band
292
occurred. The change of ratio of low-frequency power and high-frequency power
(LF/HF) was not statistically significant.
DISCUSSION:
Autonomic dysfunctions in PD patients progress in accordance with progression of
the disease (25, 32, 40). Their exact examination and scoring in the present clinical
practice are still more important.
Examination of short-term heart rate variability meets demanding criteria of a noninvasive
and objective, reproducible, reliable and valid test of autonomic regulation (10,
15, 35). Kallio (20) recommends, because of a higher sensitivity, application of spectral
analysis (frequency domain) of HRV before time analysis (time domain). It was proved
that the measure of disorder of autonomic control of heart function is identical with the
nigrostriatal dopaminerg system disorder (1, 4).
We have demonstrated statistically at two examined groups, SI with a mild degree of
disablement (H&Y = 1.3) and SII with a more advanced degree of disablement (H&Y =
2.3), with the difference in the measure of clinical disablement of 1 degree, a significant
difference of the total power and the power in low-frequency and high-frequency
spectral component in the short-term examination of HRV. We consider the short-term
examination and its spectral analysis also to be sufficiently sensitive for evaluation of
autonomic dysfunctions progression in PD.
Our results are in accordance with the testing of other authors using similar methods
of HRV examination. Linden (25) made a comparative study with two groups of
average age 67.6 years with a higher H&Y (2.1 vs. 3.3) and found out also significant
decrease of low-frequency and high-frequency spectral power in the group with a higher
H&Y in comparison with the group with a lower H&Y.
Rodriguez (35) presents decrease of power in all spectral bands in the group of
examined patients with PD of average age 30.8 years in comparison with the group of
examined patients with PD of average age 61.9 years and a higher H&Y.
The same results found out by means of spectral analysis of HRV, ie. autonomic
dysfunction progression in connection with the disease development, are given also by
Deiseroth (5) in his study made on 30 patients in the age of 39-84 years.
293
Van Dijk (40) determined dependence of a reduced autonomic response in the shortterm
examination of HRV on age, duration of anti-parkinsonian medication and higher
H&Y and, on the contrary, excluded a direct relation with duration of the disease.
Devos (6), unlike the preceding authors, takes in the methodology of examination
into consideration also the day time of examination, pharmacotherapy, breathing rate
and previous physical load. He compares the results of the short-term examination of
HRV of three groups of examined PD patients with a different degree of motor
dysfunction according to the motor scale UPDRS III. (7.0 vs. 8.9 vs. 19.0) and of the
control group, average age being always 61 years. In all groups of examined PD
patients he finds significant differences in all spectral bands of HRV.
The results of Hisayoshi study (17) prove in the mild stage of PD in comparison with
the corresponding control group of healthy subjects only decrease of spectral power in
the low-frequency band.
The difference in spectral power in the short-term examination of HRV between the
group of healthy population and age corresponding to examined PD patients in the mild
stage is denied only by Krygowska-Wajs (23). Her methodology of examination does
not take into consideration, however, all factors influencing the results of the short-term
examination of HRV and does not use methodology of controlled breathing. In another
study (24), where she evaluates the changes of heart rate in mild stage of PD by means
of the tilt table test (30:15 ratio), a statistically significant difference between the
examined patients in mild stage of PD and the check group of healthy population of the
corresponding age and sex is already confirmed.
Piha (32) attained the same conclusions on the basis of testing orthostatic
hypotension.
Statistically significant changes of spectral power in mild grade PD patients (H&Y =
1.5) in comparison with the control group of healthy subjects are given also by
Haapaniemi in his study (11) based on the results of 24-hour HRV examination.
CONCLUSION:
We established a greater disorder of autonomic regulation of heart rate in the group
of patients in advanced stage of PD (H&Y = 2.3) in comparison with the group in mild
stage of PD (H&Y = 1.3). On the basis of our results demonstrating statistically
significant difference between the groups with average H&Y score differing by one
294
degree (1.3 vs. 2.3) in the spectral power values (TP 438 vs. 123 ms2
, Power LF 132 vs.
40 ms2
, Power HF 251 vs. 47 ms2
) we consider spectral analysis of short-term
examination of HRV to be a suitable method of evaluation of autonomic dysfunction in
PD patients.
Supported by grant MSM0021622402
LITERATURE:
1. Amino, T. et al. (2005) Proufound cardiac sympathetic denervation occurs in
Parkinson’s disease. Brain Pathology, 15/1, s. 29-34.
2. Bhattacharya, K. F. et al. (2003) Selegiline in the treatment of Parkinson’s
disease: its impact on orthostatic hypotension. Parkinsonism and Related Disorders, 9,
s. 221–224.
3. Bouhaddi, M. et al. (2004) Impaired cardiovascular autonomic control in newly
and long-term-treated patients with Parkinson’s disease: involvement of L-dopa
therapy. Autonomic Neuroscience-Basic and Clinical, 116/1-2, s. 30-38.
4. Byung, O. C. et al. (1998) Sympathetic skin response and cardiovascular
autonomic function tests in Parkinson’s disease. Yonsei Medical Journal, 39/5, s. 439-
445.
5. Deiseroth, Th., Greulich, W., Gehlen, W. (1997) Changes of heart rate
variability in the assessment of autonomic dysfunction in Parkinson’s disease. EEG and
Clinical Neurophysiology, 102/4, s. P41.
6. Devos, D. et al. (2003) Heart rate variability and Parkinson’s disease severity.
Journal of Neural Transmission, 110, s. 997-1011.
7. Djaldetti, R., Melamed, E., Gadoth, N. Abnormal skin wrinkling in the less
affected side in hemiparkinsonism – a possible test for sympathetic dysfunction in
Parkinson’s disease. (2001) Biomedicine and Pharmacotherapy, 55/8, s. 475-478.
8. Gelb, D. J., Oliver, E., Gilman, S. (1999) Diagnostic criteria for Parkinson‘s
disease. Archives of Neurology, 56/1, s. 33-39.
9. Goldstein, G. S. (2003) Dysautonomia in Parkinson’s disease:
neurocardiological abnormalities. The Lancet Neurology, 2, s. 669-676.
10. Gurevich, T. Y. et al. (2004) R-R interval variation in Parkinson’s disease and
multiple system atrophy. Acta Neurologica Scandinavica, 109, s. 276-279.
11. Haapaniemi, T. H. et al. (2001) Ambulatory ECG and analysis of heart rate
variability in Parkinson’s disease. Journal of Neurology, Neurosurgery and Psychiatry,
70, s. 305-310.
12. Haapaniemi, T.H. et al. (2000) Levodopa, bromocriptine and selegiline modify
cardiovascular responses in Parkinson’s disease. Journal of Neurology, 247/11, s. 868-
874.
13. Haas, B. M., Trew, M., Castle, P. C. (2004) Effects of respiratory muscle
weakness on daily living function, quality of life, activity levels and exercise capacity in
mild to moderate Parkinson’s disease. American Journal of Physiology, Medicine and
Rehabilitation, 83/8, s. 601-607.
14. Harnod, T. et al. (2005) Acute effects of bilateral subthalamic stimulator
implantation on heart rate variability of patients with Parkinson’s disease. Tzu Chi
Medical Journal, 2005, 17/1, s. 21-26.
295
15. Hartikainen, J. E. K., Tahvanainen, K. U. O., Kuusela, T. A. Short-term
measurement of heart rate variability. In: Malik, M. (ed.) Clinical guide to cardiac
autonomic tests. Kluwer Academic Publishers, 1998, s. 149-176.
16. Havránková, P., Roth, J. (2006) Sou asná terapie Parkinsonovy choroby.
Medical Tribune, 2/3, s. 6.
17. Hisayoshi, O., Soichiro, M., Kenji, O. et al. (2006) Cardiovascular
dysautonomia in de novo Parkinson‘s disease. Journal of the Neurological Sciences,
241, s. 59-65.
18. Hsieh, C. W. et al. (2003) Respiratory effect on the pulse spectrum. Journal of
Medical Engineering and Technology, 27/2, s. 77-84.
19. Chaudburi, K. R. (2001) Autonomic dysfunction in movement disorders.
Current Opinion in Neurology, 14/4, s. 505-511.
20. Kallio, M. et al. (1997) Comparison of simple pulse rate change, power spectral
analysis and fractal dimension as indicators of autonomic dysfunction in Parkinson’s
disease. EEG and Clinical Neurophysiology, 1997, 103/1, s. 184-185.
21. Kaufmann, H. et al. (2004) Autonomic failure as the initial presentation of
Parkinsonism and dementia with Lewy bodies. Neurology, 63/6, s. 1093-1095.
22. Korchounov, A., Kessler, K. R., Schipper, H. I. (2004) Differential effects of
various treatment combinations on cardiovascular dysfunction in patients with
Parkinson’s disease. Acta Neurologica Scandinavica, 109/1, s. 45-51.
23. Krygowska-Wajs et al. (1997) Autonomic nervous system dysfunction in
Parkinson’s disease evaluated by the heart rhytm variability test. Folia Medica
Cracoviensia, 38/3-4, s. 47-52.
24. Krygowska-Wajs et al. (2002) Early diagnosis of orthostatic hypotension in
idiopathic Parkinson’s disease. Folia Medica Cracoviensia, 43/1-2, s. 59-67.
25. Linden, D., Diehl, R. R., Berlit, P. (1997) Sympathetic cardiovascular
dysfunction in long-standing idiopathic Parkinson’s disease. Clinical Autonomic
Research, 7/6,
s. 311-314.
26. Lucetti, C. et al. (2006) Long-term clinical evaluation in patients with
Parkinson’s disease and early autonomic involvement. Parkinsonism and Related
Disorders, 12,
s. 279-283.
27. Meco, G. et al. (2000) Heart rate variability in Parkinson’s disease patients
treated with tolcapone. Parkinsonism and Related Disorders, 2000, 6/4, s. 223-227.
28. Médigue, C. et al. (2001) Relation between pulse interval and respiratory sinus
arrhytmia: a time and frequency domain analysis of the effects of atropine. European
Journal of Physiology, 441, s. 650-655.
29. Micielli, G. et al. (2003) Autonomic dysfunction in Parkinson’s disease.
Neurology, Science, 24, s. 32-34.
30. Oka, H. et al. (2006) Cardiovascular dysautonomia in Parkinson’s disease and
multiple system atrophy. Acta Neurologica Scandinavica, 113, s. 221-227.
31. Penttilä, J. et al. (2001) Time domain, geometrical and frequency domain
analysis of cardiac vagal outflow: effects of various respiratory patterns. Clinical
Physiology, 21/3, s. 365-376.
32. Piha, S. J. et al. (1988) Autonomic dysfunction in recent onset and advanced
Parkinson’s disease. Clinical Neurology and Neurosurgery, 1988, 90/3, s. 221-226.
296
33. Pospíšil, P. et al. (2006) Variabilita srde ní frekvence u Parkinsonovy choroby s
kardovaskulárním onemocn ním. In: Optimální p sobení t lesné zát že a výživy,
Univerzita Hradec Králové, Pedagogická fakulta, 2006, s. 162-165.
34. Pospíšil, P. et al. (2007) Zm ny variability srde ní frekvence u pacient s
Parkinsonovou nemocí vyvolané ízeným dýcháním. Sborník abstrakt Luha ovice,
1/2007, s. 29.
35. Rodriguez, M., Sabate, M., Troncoso, E. (1996) Time and frequency domain
analysis for the assessment of heart autonomic control in Parkinson’s disease. Journal of
Neural Transmission, 103/4, s. 447-454.
36. Siddiqui, M. F. et al. (2002) Autonomic dysfunction in Parkinson’s disease:
a comprihensive symptom survey. Parkinsonism and related Disorders, 8/4, s. 277-284.
37. Singer, C. et al. (1992) Autonomic dysfunction in men with Parkinson’s disease.
European Neurology, 32/3, s. 134-140.
38. Stark, R. et al. (2000) Effects of paced respiration on heart period and heart
period variability. Psychophysiology, 37, s. 302-309.
39. Strauss-Blasche, G. et al. (2001) Relative timing of inspiration and expiration
affects respiratory sinus arrhytmia. Clinical and Experimental Pharmacology and
Physiology, 27, s. 601-606.
40. Van Dijk, J. G. et al. (1993) Autonomic nervous system dysfunction in
Parkinson’s disease: relation with age, medication, duration and severity. Journal of
Neurology, Neurosurgery and Psychiatry, 56, s. 1090-1095.
41. Visser, M. et al. (2004) Assessment of autonomic dysfunction in Parkinson’s
disease: the SCOPA AUT. Movement Disorders, 19/11, s. 1306-1311.
42. Yasuma, F., Hayano, J. (2004) Respiratory sinus arrhytmia. Why does the
heartbeat synchronize with respiratory rhytm? Chest, 125/2, s. 683-690.
43. Zakrzewska-Pniewska, B. Jamrozik, Z. (2003) Are electrophysiological
autonomic tests useful in the assessment of dysautonomia in Parkinson’s disease?
Parkinsonism and Related Disorders, 9, s. 179-183.
297
SUMMARY:
Exact quantitative evaluation method of autonomic dysfunction in Parkinson’s
disease (PD) for everyday clinical use has not been developed yet.
The aim of this study was to evaluate autonomic cardiovascular regulation in mild
and advanced stages of PD with the use of heart rate variability (HRV) examination.
25 patients entered the study and passed short-term HRV examination in supine
position with metronome-controlled breathing f = 0.33 Hz.
Following parameters of power spectral analysis were evaluated: Total Power (TP;
ms2
), Low Frequency Power (0.04-0.14 Hz; Power LF; ms2
), High Frequency Power
(0.15-0.4 Hz; Power HF; ms2
) and Ratio Power LF / Power HF (LF/HF).
The results show statistically significant decrease of TP (438 vs. 123 ms2
), Power LF
(132 vs. 40 ms2
) and Power HF (251 vs. 47 ms2
) in the group of patients with a higher
mean H&Y (1.3 vs. 2.3; T test). The change of LF/HF was not statistically significant.
The short-term examination of heart rate variability fulfils the criteria for test
objectivity, reproducibility, reliability and validity. We proved a higher impairment of
autonomic cardiovascular regulation in the group of PD patients with advanced PD
(H&Y = 2.3) than in mild PD (H&Y = 1.3). Short-term HRV examination is also
sensitive enough to be used for comparison of the difference of autonomic dysfunction
corresponding to the change of impairment by 1 grade in H&Y score.
KEYWORDS: Parkinson’s disease; autonomic dysfunction; heart rate variability;
UPDRS; Hoehn & Yahr score; metronome-controlled breathing; rehabilitation
298
PATIENTS WITH STROKE: RESULTS OF PHYSIOTHERAPY
AND OCCUPATIONAL THERAPY
BARBORA BÁRTLOVÁ, EVA NOSAVCOVOVÁ, MARCELA NOVÁKOVÁ,
LENKA DRLÍKOVÁ, ABDUL KARIM AL FADHLI, FARAG HASSAN ANBAIS,
ASHREF ALI ERAJHI, JARMILA SIEGELOVÁ
Dept. of physiotherapy and rehabilitation and Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital,
Brno, CZ
INTRODUCTION
Stroke is the third most frequent cause of death. Improved quality of medical care in
acute phase of stroke reduced mortality and extended life of disabled persons, many
surviving patients, however, are afflicted with serious residual functional deficit in the
field of motor and cognitive functions. These patients require then considerable
economic cost for further treatment and subsequent long-term care.
After CMP a differential movement ability of hand can be lost and overlooked and
uncorrected disorders can be then the cause of the resulting ineptitude of the patient in
usual handling activities. A lot of people after stroke live with a substantial sensomotor
disability of the upper limb worsening considerably the level of their functional
independence. This disability can be frustrating for them, it can increase the risks of
their impairment and can bring about worse social contacts.
That is why the early starting of comprehensive rehabilitation that should be able to
prevent the origin or at least reduce the measure of various types of disabilities is very
important. Occupational therapy (ET) that is dominant in helping to restore personal
independence in daily life activities is an integral part of comprehensive rehabilitation.
The results of various studies show that the patients who went through ET have a higher
degree of independence in daily life activities than the patients without ET (1, 7, 8, 14).
AIM OF THE STUDY
The aim of our study was to evaluate the results of subsequent rehabilitation in 148
patients with diagnosis I60 – I69, general affection of central nervous system on the
basis of vascular disease with motor activity and cognitive functions disorder, divided
into the group attending only physiotherapy, and into the group going through the
combination of physiotherapy and occupational therapy, and evaluation of
299
independence measure in basic daily activities by means of the test of functional
examination (Functional Independence Measure, FIM test) and Barthel test (BT).
GROUP OF EXAMINED PATIENTS
In 2007 174 patients with diagnosis I 60 – 69, CNS affection on the basis of vascular
disease with motor activity disorder, were hospitalized in After-treatment and
rehabilitation ward in our hospital.
89 of them were discharged to home care …………………………………. 51 %
59 of them were discharged to social service institutions ………………….. 34 %
12 of them were moved back to emergency ward …………………………… 7 %
14 of them died ……………………………………………………………… 8 %
FIM test and BT were evaluated in the group of 148 patients from the total number
of 174, who completed the rehabilitation and occupational therapy program and were
discharged to home care or to institutions for social services, separately in the group of
94 patients for whom only physiotherapy was prescribed, and in 54 patients who went
through both physiotherapy and occupational therapy.
The average age of the patients for whom only physiotherapy was prescribed was 79
years and the average age of the patients, who went also through occupational therapy
was 72 years. The age distribution of the patients in both groups can be seen in graph 1.
5 4 5
14
28
25
49
10
7
1
0
5
10
15
20
25
30
35
40
45
50
< 60 60-69 70-79 80-89 90-99
PHYSIOTHERAPY
PHYSIOTHERAPY
+ ERGOTHERAPY
P
Graph 1 Age distribution of all 148 patients with CMP
300
Duration of rehabilitation in our ward on average was 49 days; in the group of
patients for whom only physiotherapy was prescribed it was on average 47 days and in
the patients for whom also occupational therapy was prescribed it was on average 54
days. Intensity of rehabilitation was 1 hour of individual physiotherapy and half an hour
of occupational therapy 5 days in a week.
4 4
26
11
16
12
20
7
18
8
7
5
1
2
1
2
1
3
0
5
10
15
20
25
30
< 15 16-30 31-45 46-60 61-75 76-90 91-105 106-120 > 121
PHYSIOTHERAPY
FYZIOTERAPIE +
ERGOTHERAPY
Graph 2 Duration of hospitalization in patients with stroke
METHODOLOGY
For evaluation of functional fitness of the patients we used the test of Functional
Independence Measure (FIM test) and Barthel test, evaluating independence in basic
everyday activities and thus suitable for monitoring progress of the treatment.
FIM test – or measurement of functional independence, evaluates 18 activities in 6
categories: 1. Self attendance, 2. Control of sphincters, 3. Displacements, 4. Mobility, 5.
Communication, 6. Social abilities. Each item has a scale consisting of seven points,
301
when 1 means full assistance and 7 full independence. The total score can be 18 – 126
points (2, 5, 6, 9, 11, 14).
Barthel test – test of basic everyday activities evaluates 10 activities: 1. Eating,
drinking, 2. Dressing, 3. Taking a bath, 4. Personal hygiene, 5. Continence of
defecation, 6. Continence of urination, 7. Using WC, 8. Displacement from the bed to
the chair, 9. Walking on even ground, 10. Climbing stair. Individual items are evaluated
mainly in three degrees of dependence – does not accomplish (0), accomplishes with
assistance (5) and accomplishes independently without assistance (10). The total score
can be therefore 0 – 100 points (2, 3, 4, 6, 13, 15).
As Barthel test does not contain evaluation of cognitive components, we used only
the corresponding items of evaluation of motor score of FIM test to compare the results
with FIM test.
RESULTS
We compared the results of motor score of FIM test and the results of Barthel test at
the beginning of rehabilitation and at discharge in the group of 94 patients for whom
only physiotherapy was prescribed, and in the group of 54 patients who went through
both physiotherapy and occupational therapy (ET).
Groups FIM input FIM output Barthel input Barthel output
Patients with physiotherapy 28 16 34 19** 37 30 47 33**
Patients with physiotherapy
and ET
35 16 49 15** 49 27 74 24**
** p < 0,0001
For evaluation of functional state of input and output parameters of both tests we
used Wilcoxon paired test and the results showed statistically significant improvement
of the function at the level p < 0.001 in both functional tests in all groups.
302
Fyzioterapie + Ergoterapie
0
20
40
60
80
100
0 20 40 60 80
Pouze fyzioterapie
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
Graph 3. Results of functional independent measure (FIM test) before and after 3month
rehabilitation in both groups of patients with CMP
Fyzioterapie + Ergoterapie
0
20
40
60
80
100
120
0 20 40 60 80 100 120
Pouze fyzioterapie
0
20
40
60
80
100
120
0 20 40 60 80 100 120
Graph 4 Results of functional Barthel test (BT) before and after 3-month rehabilitation
in both groups of patients with stroke
DISCUSSION
Functional disorders accompanying stroke are often a serious complication for senior
patients. Conclusions of our tests, however, confirm the assumption that age is not a
factor excluding in advance senior patients from the rehabilitation program and that also
elderly people are able to improve their physical functions, which leads to improvement
of their quality of life and reduces social and economic impacts on the society.
The measured results show that a long-term rehabilitation of patients with stroke
connected with occupational therapy brings about a substantial improvement of their
independence in basic daily activities. With regard to increasing number of elderly
people in the population, connected with a high number of disabilities and
polymorbidities, the utmost necessity of prevention and rehabilitation programs directed
at this very segment of our population is more and more noticeable (7, 10, 12, 15).
303
On the basis of functional tests (BT and FIM test) we have proved effectiveness of
rehabilitation in the patients after stroke. Rehabilitation and occupational therapy are
indicated in all patients, regardless their age and a measure of functional impairment.
CONCLUSION
The results of the test of functional examination after the subsequent rehabilitation of
148 patients with the diagnosis of general affection of central nervous system on the
basis of vascular disease with motor activity and cognitive functions disorder, divided
into the group attending only physiotherapy and into the group going through the
combination of physiotherapy and occupational therapy, showed improvement of both
groups of patients in basic daily activities.
Supported by grant MSM0021622402
LITERATURE
1. Desrosiers, J., Bourbonnais, D., Corriveau, H., Gosselin, S., Bravo, G.(2005).
Effectiveness of unilateral and symmetrical bilateral task training for arm during the
subacute phase after stroke: a randomized controlled trial, Clinical Rehabilitation
2005; 19: 581-593.
2. Grünerová, M. (2005). Neurorehabilitace. Praha: Galén.
3. Guth, A. (1995). Vyšetrovacie a lie ebné metodiky pre fyzioterapeutov. Bratislava:
LIE REH
4. Kalvach, P. (1997). Mozkové ischemie a hemoragie. Praha: Grada.
5. Kelly, P.J., Stein, J., Shafqat, S., Eskey, C., Doherty, D., Chang, Y., Kurina, A., and
Furie, K.L. (2001). Functional recovery after rehabilitation for cerebral stroke,
Stroke, 2001; 32: 530 - 534.
6. Kwon, S., Hartzema, A.G., Duncan, P.W., Min-Lai, S. (2004). Disability measures
in stroke: Relationship among the Barthel Index, the Functional Independence
Measure, and the Modified Rankin Scale. Stroke, 2004; 35: 918 - 923.
7. Landi, F., Cesari, M., Onder, G., Tafani, A., Zamboni,V., Cocchi, A.(2006). Effects
of an occupational therapy program on Functional Outcomes in older stroke
patients. Gerontology 2006; 52: 85-91.
8. Machá ková, K., Vyskotová, J., Opavský, J., Sochorová, H.(2007). Diagnostika
poruch senzomotorických funkcí ruky pacient po ischemické cévní mozkové
p íhod (P ípadové studie), Rehabil.fyz. Lék., 14, 2007, 3: 114-121.
9. Malý, M. (2001). Testovanie funk nej sebesta nosti. Rehabilitácia, 34,2001 Med J
Aust; 177(8):452 – 456.
10. Országh, J., Káš, Sv. (1995). Cévní p íhody mozkové. Praha: Brána.
11. Švestková, O. (2004). Možnosti posouzení funk ních schopností, aktivit
a participací. Autoreferát doktoranské práce. Praha: Univerzita Karlova.
12. Tarasová, M., Ošmerová, J., Svoboda, L., Vohlídalová, I., Vank, P., Frajhi, F.A.,
Karim, A.F.A., Sosíková, M., Siegelová, J. (2005). Testování funk ního stavu
304
pacient po cévní mozkové p íhod . Hradec Králové: Univerzita Hradec Králové,
s. 212-225.
13. Va ásková, E. (2004). Testování v rehabilita ní praxi – cévní mozkové p íhody.
Brno: NCONZO.
14. Va ásková, E., Tošnerová, V., Buka , J.(2004). M ení a hodnocení v rehabilitaci
cévní mozkové p íhody, Rehabilitácia 2004; 41: 3-9.
15. Weber, P. (2000). Minimum z klinické gerontologie. Brno: IDVPZ.
SUMMARY
The aim of this study was to evaluate the questionnaire Functional Independence
Measure (FIM) and Barthel test (BT) in 148 patients with stroke with impairment of
motor and cognitive functions before and after three months of physiotherapy and
combination of physiotherapy and occupational therapy.
Methods: We examined 148 patients with stroke by means of FIM questionnaire and
Barthel test.
Results and conclusion: We have found an improvement of functional state in our
patients after physiotherapy and combination of physiotherapy and occupational
therapy.
Key words: stroke, physiotherapy, occupational therapy, functional independence
measure