Yonago Acta medica 1999;42:61–68

A 48-Hour Holter ECG Study in Migraineurs during Usual Daily Activities
Masako Tabata, Naoto Burioka* and Takao Takeshima
Division of Neurology, Institute of Neurological Sciences and *Third Department of Internal
Medicine, Faculty of Medicine, Tottori University, Yonago 683-0826, Japan
In order to clarify the condition of cardiac autonomic nervous activity in migraineurs,
48-h Holter electrocardiograms (ECGs) were carried out under free activity on 20 migraineurs during headache free periods and 20 healthy controls. We calculated hourly
standard deviation (SD), root mean square successive differences (RMSSD), the proportion fo cycles during which the RR difference is > 50 ms (%RR50), low frequency heart
rate fluctuation (LF), high frequency heart rate fluctuation (HF) and LF/HF ratio fromheart rate variability, and obtained serial 24 data of these parameters. SD, RMSSD,%RR50 and HF are parasympathetic parameters, and LF/HF is sympathetic. These
parameters were fit to cosines curve and analyzed circadian rhythms using the cosinor
method. By group mean cosinor analysis, the vectors of the amplitude-acrophases ofSD, RMSSD, %RR50, LF, HF and LF/HF significantly differed in the migraineurs
from those in the controls. The significant differences of vectors of SD, RMSSD, %RR50
and HF indicate cardiac parasympathetic dysfunction. Midline estimating statistic ofrhythms (MESORs) of those parameters did not significantly differ except in LF and
LF/HF between both groups. MESORs of LF and LF/HF were significantly decreasedin the migraineurs, which indicates cardiac sympathetic hypofunction. We concluded
that migraineurs might have cardiac parasympathetic dysfunction and sympathetic
hypofunction. By evaluating circadian rhythms using cosinor methods, the parametersof heart rate variability in migraineurs were significantly different from controls.
Migraineurs may have some disturbance in their rhythm generator.
Key words: autonomic nervous system; circadian rhythm; headache; parasympathetic nervous
system; sympathetic nervous system

Autonomic dysfunction in migraineurs is ofbroad interest. In a patient with migraine, symptoms of autonomic disturbance can be observed, associated with or without migraine attack,such as blood flow in the cranial artery, Horner’s
syndrome, etc. However, there is some controversy in the results of various studies on theautonomic nervous system. Abnormalities inthe sympathetic nervous system have been
fairly well documented in migraineurs during
the headache-free phase, such as pupillary sympathetic hypofunction (Fanciullacci, 1979;
Herman, 1983; Takeshima et al., 1987a), orthostatic hypotension (Gotoh et al., 1984; Havanka-

Kanniainen et al., 1986; Mikamo et al., 1989;
Pogacnik et al., 1993), a decrease in overshootin Valsalva’s maneuver (Gotoh et al., 1984;
Havanka-Kanniainen et al., 1986), a low levelof plasma norepinephrine (Gotoh et al., 1984;
Mikamo et al., 1989) and the cold pressor test
(Rubin et al., 1985; Takeshima et al. 1989).
However, Thomsen and colleagues (1995)
recently reported that there was no significant
sympathetic dysfunction in migraineurs. On
the other hand, dysfunction of the parasympathetic nervous system in migraineurs has not
yet been confirmed at all. Some reports showed
hyperfunction of parasympathetic activity in

Abbreviations: ABP, ambulatory blood pressure; ECG, electrocardiogram; HF, high frequency heart rate
fluctuation; LF, low frequency heart rate fluctuation; MESOR, midline estimating statistic of rhythm; MI,mean interval; RMSSD, root mean square successive differences; RR, between two QRS complexes in ECG;
%RR50, the proportion of cycles during which the RR difference is > 50 ms; SD, standard deviation

61

M. Tabata et al.

Table 1. Subjects

Number of subjects
Age
Sex (male:female)
Migraine with aura
Migraine without aura
Duration of illness
Frequency of migraine attack
Duration of migraine attack( ), range.
*Mean ± SD.

(year)(year)(times/month)(h)Controls

Migraine group20
29.6 ± 10.2*
3:17
–
–
–
–
–

20
29.2 ± 12.5*
4:16
2
18
10.6 ± 11.0* (0.5–35)
5.0 ± 4.0* (0.2–12)
17.0 ± 12.7* (2 –72)

migraineurs (Gotoh et al., 1984) and others
reported hypofunction (Havanka-Kanniainen etal., 1986a; Thomsen et al., 1995), in which
short period beat-to-beat variations and spectral
analysis in a supine position, standing and during free movement were examined (Appel etal., 1992; Pogacnik et al., 1993). The tone of
the sympathetic and parasympathetic autonomic nervous systems is influenced not only
by emotional, environmental and physical factors, but also by circadian rhythms. In earlier
works, many efforts were made to exclude thediurnal variation of autonomic nervous systems, by fixing the examination hour at a certain time of day. In general, sympathetic activities rise from morning to afternoon and parasympathetic activities rise during night time
(Furlan et al., 1990). Depending on the time
when the examinations are done, the results ofthe examinations on the autonomic nervous system may differ and these may be the reason why
reported results are contradictory. Recently, we
performed a 2-day measurement of ambulatory
blood pressure (ABP) in migraineurs and founda decrease in the circadian amplitude of ABP,
which suggests sympathetic hypofunction anddysfunction of the central circadian rhythm
generator (Takeshima et al., 1997). Measuring
serial data and applying rhythm analysis technology for a 2-day period can reveal a subject’s
state of autonomic function including diurnal
variations. Heart rate fluctuations are regulated
mainly by the activities of the parasympathetic
nervous system. In this study, we evaluatedheart rate variability in migraineurs under freedaily activity for 2 days, by means of Holter
electrocardiogram (ECG) recordings, time

domain statistical analysis and spectral analysisof heart rate fluctuations, and cosinor analysis
techniques. The aims of this study were: i) toevaluate cardiac parasympathetic tone on thebasis of circadian rhythm analysis; and ii) toreveal some specific circadian pattern, if present, of parameters of heart rate variability in migraineurs.

Materials and Methods

Subjects
Twenty subjects who were diagnosed as migraineurs according to the criteria developed by the
Headache Classification Committee of theInternational Headache Society (1988) had
Holter ECG recordings (Table 1) performed onthem. They were examined during headachefree periods. The mean period between the lastattack and the Holter recording was 18.8 ± 19.1
days (mean ± SD, range 1–65 days). During theexaminations, they were free from prophylactic
medication. Before starting this study, they
took anti-migraine drugs only when they had
attacks. Two of the migraineurs used a mixture of analgesics 1.0 g (Sedes G, Shionogi,
Tokushima, Japan) and metoclopramide 5 mg,
2 days before the examination. The others were
free from the abortive use of anti-migraine
drugs by at least 7 days prior to testing. The
control group consisted of 20 healthy volunteers (Table 1). All participants were neurologically normal, free from respiratory disease
and gave their consent after fully understanding
the procedure, nature and scope of the study.
62

Holter ECG study in migraineurs

60 min

R1

R2

t1

R3

t2

Rn

t3

tn

n

ti
MI = i = 1(ms)

RMSSD =

(ms)

n–1

n
SD =

(t i – t i–1 ) 2(MI – t i ) 2(ms)%RR50 =n

(Number of (t i – t i – 1 ) > 50)
n–1

(%)

Fig. 1. Definition of time domain analysis: MI, SD, RMSSD and %RR50. MI, mean interval; n, number ofbeats in 60 min; SD, standard deviation; RMSSD, root mean square successive differences; %RR50, theproportion of cycles during which the RR difference is > 50 ms; ti, RR interval in ms.

No examinees were admitted to the hospital.
All subjects were permitted normal daily activity during the 48-h Holter ECG recordings.
They were advised to spend their 48-h period as
usual, but were prohibited from hard exercise or
the intake of alcohol. They were also required
to take note of their activities.

which the RR difference is > 50 ms (%RR50)(Fig. 1). These parameters reflect mainly parasympathetic nervous system activity. Spectral
analysis of heart rate fluctuations was performed as follows. Spectral decomposition was
imposed on the heart rate time series by a Fast
Fourier transformer. The power spectrum ofheart rate fluctuations was calculated with acomputer-assisted analysis system, a subtrace
every 300 s, which was taken every 60 min
from the 48-h ECG signal. The analog signal
was sampled by an analog-to-digital converterwith a frequency of 128 Hz, and a moving window using a straight line was applied for digitalsmoothing. The heart rate power spectrum wascomputed in a frequency band from 0.02–0.40
Hz. Hourly low frequency heart rate fluctuation(LF) (0.02–0.15 Hz), high frequency heart rate
fluctuation (HF) (0.15–0.40 Hz) and LF/HF ratio(LF/HF) were calculated. The significance ofthe circadian rhythm of these parameters wastested using the single and the group-mean cosinor
methods (Nelson et al., 1979).

The 48-h Holter recordings
During the examination, the ECGs were recorded continuously using a Space Labs MedicalHolter recorder 90205. Five disposable Ag/AgCl electrodes were located so as to record ECG
signals corresponding to the V1 and V5 chest
leads. In this way, the 48-h sequential ECGs
were recorded. The 2 recorded ECG leads weretransferred from the Holter recorder to a Holter
ECG analysis system (FT2000A Medical
Analysis and Review Station, Space Labs
Medical, Inc., Redmond, WA).

Time domain analysis and spectral analysis

Single and group mean cosinor analyses
and comparison of heart rate related variables between groups

Following the removal of arrhythmia and noise,
we carried out, on an hourly basis, time domain
statistical analyses which consisted of the RR
mean interval (MI), standard deviation (SD),root mean square successive differences(RMSSD) and the proportion of cycles during

Hourly averaged values of MI, SD, RMSSD,%RR50, LF, HF and LF/HF were calculated ineach subject. As an example, RMSSD values
63

M. Tabata et al.

for Day 1 from 0900 to 0959, and for Day 2
from 0900 to 0959 were averaged and this value
was employed as the RMSSD for 0900. Thus
we obtained 24 hourly values of each parameterfor each examinee. The significance of theaverages of these hourly parameters was examined with the unpaired t-test among groups.
The significance of the circadian rhythm ofthese parameters was tested using the single andthe group-mean cosinor methods. We applied
cosinor analysis to the 24 serial data using
BASIC programming language. Following all
the single cosinor analyses, we carried out
group mean cosinor analyses and statisticalcomparisons between groups. Details of thecosinor analysis method have been described
elsewhere (Takeshima et al., 1997). In brief, wedetermined a fitted cosinor curve with a 24-hrhythm from measured values. The cosinor
curve is represented as y = M + A cos (ωt + φ),
where M = midline estimating statistic of rhythm(MESOR), A = amplitude, ω = 2π/24, φ = acrophase. According to cosinor analysis, the circadian rhythm of any ECG parameter is characterized by MESOR, amplitude and acrophase.
The significance of the circadian rhythm wastested by the zero-amplitude test. Single cosi-

nor analysis represents the circadian rhythm ofeach subject. With χ2-test, we examined thedifference between migraineurs and controls in
the number of subjects who had significant
circadian rhythms in each parameter. The otherside, group mean cosinor analysis represents
the circadian rhythm of a group. Inter-groupdifferences of MESORs were tested by the
MESOR test (Nelson et al., 1979). Amplitudes
and acrophases are given as a vector, so it wasnecessary to test differences in amplitude andacrophase between groups simultaneously.
Inter-group differences in the amplitudeacrophase vector were tested by the amplitudeacrophase test (Nelson et al., 1979). The 5%
possibility was regarded as statistically significant throughout the study.

Results

Time domain analysis, i.e., MI, SD, RMSSD
and %RR50, and spectral analysis, i.e., LF,
HF and LF/HF
MI, SD, RMSSD, %RR50, LF, HF and LF/HF
of 48-h data (mean ± SD), were 799 ± 72 ms,

LF/HF

0
+5

Amplitude
MESOR

–5

18

Bathyphase
066Acrophase
12

MESOR
Amplitude
Acrophase18

24 (h)

123.0

3.3 ± 0.6 (MESOR ± SE)
1.8(0.8 – 2.8)
14:03
(210˚, 177–243)

Fig. 2. An example of single cosinor analysis: Single cosinor analysis of LF/HF on a 22-year-old female
patient with migraine without aura. Left: The base line is MESOR (3.3) and the points of +5 and –5 indicate
MESOR ± 5. The hourly sequential data (J) are fitted to the cosinor curve. Right: Amplitude and acrophaseare shown on the cosinor display by a vector on the coordinates. The outside circle indicates a 24-h period.
Zero-amplitude test was performed. In a case where the 95% confidential circle, which is displayed by asmall circle, doesn’t include a zero-point, the circadian rhythm is regarded as significant. HF, high frequency
heart rate fluctuation; LF, low frequency heart rate fluctuation; MESOR, midline estimating statistic ofrhythm.

64

Holter ECG study in migraineurs

MI

0

RMSSD

0

Control

*
18

18

6

Migraine
6

MESOR
Control 44.5 ± 0.2
Migraine 40.4 ± 0.2

MESOR
Control 819.1 ± 1.6
Migraine 781.6 ± 1.5
1215 (ms)12150 (ms)*P < 0.05; amplitude-acrophase test

SD

0

%RR50

0

*
18

*
12

6

18

6

MESOR
Control 15.4 ± 0.2
Migraine 14.3 ± 0.1

MESOR
Control 87.5 ± 4.6
Migraine 79.7 ± 3.5
20 (ms)1212 (%)

Fig. 3. Group mean cosinor analysis of MI, SD, RMSSD and %RR50. The amplitude-acrophase vector and
MESOR of the MI showed no significant difference between groups. Amplitude-acrophase vectors of SD,
RMSSD and %RR50 in the migraine group were significantly different from those in controls (amplitudeacrophase test, P < 0.05, small circles represent the 95% confidence area). MESORs of these parameters
showed no significant difference between groups (MESOR test). MESOR, midline estimating statistic ofrhythm; MI, mean interval of heart rate; RMSSD, root mean square successive SD; %RR50, the proportion ofcycles during which the RR difference is > 50 ms.

65.8 ± 14.1 ms, 46.0 ± 16.3 ms, 14.2 ± 9.0%,2141 ± 1073 ms2, 495 ± 485 ms2 and 6.02 ±2.78 in the controls, and 776 ± 80 ms, 61.7 ±38.4 ms, 43.5 ± 18.3 ms, 15.2 ± 13.2%, 1683 ±808 ms2, 582 ± 524 ms2 and 4.21 ± 2.07 in the
migraine group, respectively. Averages of allparameters except for LF/HF were not significantly different between the migraine andthe control group. LF/HF in the migraineurs
was significantly smaller than that in the controls (unpaired t-test, P < 0.05).

LF/HF were 10, 13 and 8/20 in the controls and11, 9 and 11/20 in the migraineurs, respectively.
The incidence of significant rhythms of thesetime domain and spectral parameters showed nosignificant difference between the migrainegroup and the controls (χ2-test).

Group mean cosinor analysis of MI, SD,RMSSD and %RR50
With the group mean cosinor method, significant circadian rhythms were determined in MI,
SD, RMSSD and %RR50 in both the migrainegroup and the controls. In MI, there were no
significant differences in the MESOR or thevector of amplitude-acrophase between the 2groups. The amplitude-acrophase vectors of
SD, RMSSD and %RR50 in the migraine group
significantly differed from those in the controls(amplitude-acrophase test, P < 0.05). There
were no significant differences in MESORs of
SD, RMSSD and %RR50 between both groups(MESOR test, Fig. 3).

Single cosinor analysis of MI, SD, RMSSD,%RR50, LF, HF and LF/HF
A typical example of single cosinor analysis is
illustrated in Fig. 2. Nineteen out of 20 controls
and all 20 migraineurs showed significant MIrhythms. The incidence of significant circadianrhythms in SD, RMSSD and %RR50 were 9, 15
and 17/20 in the controls and 10, 14 and 18/20
in the migraineurs, respectively. The incidenceof significant circadian rhythms of LF, HF and65

M. Tabata et al.

LF

0

18

18

6

6

MESOR
Control 2152.1 ± 18.1
Migraine 1584.2 ± 10.8**
12

HF

0

LF/HF

MESOR
Control 9.3 ± 0.2
Migraine 5.6 ± 0.2***12700 (ms2)

15 (ms)0*
Control18

Migraine

6

MESOR
Control 503.9 ± 8.5
Migraine 524.4 ± 6.3
12*P < 0.05; amplitude-acrophase test**P < 0.05; MESOR test

400 (ms2)

Fig. 4. Group mean cosinor analysis of LF, HF and LF/HF. Amplitude-acrophase vectors of LF, HF and LF/
HF in the migraine group were significantly different from those in controls (amplitude-acrophase test, P <0.05, small circles represent the 95% confidence area). There were significant differences in the MESORs of
the LF and LF/HF ratio between the migraine group and the controls (MESOR test, P < 0.05). These results
suggest the dysfunction of the sympathetic nervous system and the possibility of circadian rhythm generators.
HF, high frequency heart rate fluctuation; LF, low frequency heart rate fluctuation; MESOR, midline
estimating statistic of rhythm.

and the examinations were performed at a certain time of day to exclude the influence of circadian variations. We carried out 48-h Holter
ECG recordings under free activity in order toobtain data during normal daily activity including circadian rhythms. Two-day recording andan hourly averaging method over a 2-day period
can minimize the influence of environmental,
physical and emotional incidental factors andenable an effective analysis of autonomic
nervous functions during normal daily activity(Takeshima et al., 1997). Other advantages ofthis method are: i) the procedures are noninvasive; ii) examination of circadian variations
in combination with cosinor analysis or otherrhythm analysis technologies is possible; andiii) comparison of groups utilizing group-mean
cosinor analysis can be performed.
The time domain analysis parameters, i.e.,
SD, RMSSD and %RR50, are thought to reflect
the activities of the parasympathetic nervous
system. LF (0.02–0.15 Hz), which is one typeGroup mean cosinor analysis of LF, HF
and LF/HF
With the group mean cosinor method, circadianrhythms existed in LF, HF and LF/HF in boththe migraine group and the controls. The
amplitude-acrophase vectors of LF, HF and LF/
HF were significantly different between bothgroups (amplitude-acrophase test, P < 0.05).
There were significant differences in the
MESORs of LF and LF/HF between the
migraine group and the controls (MESOR test,
P < 0.05, Fig. 4).

Discussion
In most earlier studies, the time domain statistical analysis and power spectral analysis ofheart rate variability were examined in a condition of rest, supine position for a short period,66Holter ECG study in migraineursof spectral analysis parameter, is mediated byboth sympathetic and parasympathetic contributions. Below 0.04 Hz relates to sympathetic
and parasympathetic function, and near 0.10 Hz
reflects sympathetic activity of the vasomotorreflex. HF is mediated by parasympathetic nervous control and is related to respiratory sinus
arrhythmia (Akselrod et al., 1981 and 1985;
Pomeranz et al., 1985). Therefore, the LF/HF
ratio reportedly represents sympathetic nervous
control. These parameters of spectral analysis
vary with respiratory frequency or posture. On
standing with eupnea, the LF component increases, which shows a relation to sympathetic
nervous activity, while the HF component
decreases in the same conditions, relating toparasympathetic nervous activity (Pomeranz etal., 1985; Zigelman et al., 1994). In the present
study, we did not record respiration, so we can
not tell how much influence it may have on
sympathetic function, and still more on LF and
HF. All of the subjects were free from any heartor respiratory disease, so we think respiration
may not have had muc effect on the data ofeither group.
In this study, only 2 patients had migrainewith aura. We also analyzed data excluding
migraine patients with aura (data not shown);
the overall results were essentially identical tothe presented data. Within 3 days before theexaminations, 3 migraineurs each had an attack.
One patient, who had an attack 24 h before theHolter ECG recording, did not take any medication. Regarding the possibility that migraine
pain by itself might influence their autonomic
function, we performed the recordings during aheadache free period and long enough after thelast attack, so that these influences were minimal even if they existed.
Using the rhythm analysis technique, we
found significant differences of time domain
and spectral analysis parameters of heart rate
fluctuation during normal daily activity between migraineurs and controls. The vectors of
amplitude-acrophases of SD, RMSSD, %RR50,
LF, HF and LF/HF in the migraineurs were significantly different from those in the controls.
There were no significant differences in the
MESORs of these parameters except for LF and

LF/HF between the migraine group and controls. The significant differences of vectors of
amplitude-acrophases for SD, RMSSD, %RR50
and HF indicate parasympathetic dysfunction in
migraineurs during headache free periods. The
MESORs of LF and LF/HF in migraineurs were
smaller, which suggests hypofunction of thesympathetic nervous system.
As for the coordinates, the time of acrophases in SD, RMSSD and %RR50 seemedalmost similar between both groups, while thelength of vectors of the migraine group wereshorter than those of controls (Fig. 3). The decrease in amplitudes might contribute mainly tosignificant differences in the amplitude-acrophase
test. The decrease in heart rate variability in migraineurs may be due to hypofunction of theparasympathetic nervous system.
In the case of a certain degree of disorder inthe effector organs, not only the amplitude but
also the MESOR should decrease (Takemiya,1994). The decreased MESOR of LF/HF suggests that sympathetic hypofunction might beassociated with a disorder at the level of theeffector organs. While only amplitudes of SD,
RMSSD and %RR50 were decreased, the oscillator of circadian rhythms may form weakrhythms in parasympathetic parameters.
In mammals, the circadian rhythm of theautonomic systems including heart rate fluctuations, blood pressure, body temperature andhormonal regulations are generated at the
suprachiasmatic nuclei, which have a rich innervation of serotonergic neurons (Moore et al.,
1978; Malmgren, 1990). Serotonergic abnormalities in migraineurs are well documented (Sicuteri
et al., 1961; Curran et al., 1965; Takeshima et al.,1987b). Recently, serotonin agonists have successfully been applied to the treatment of migraine. Dysfunction of serotonergic systems
may cause the change of the circadian rhythm ofheart rate fluctuations in migraineurs.
Considering the presented data, we concluded that migraineurs might have both cardiac
parasympathetic and sympathetic hypofunction
and might have some disorder in the rhythm
generator. Also, the cosinor method seems likea very useful tool in evaluating cardiac autonomic dysfunction in migraineurs.
67

M. Tabata et al.

Acknowledgments: We wish to thank Prof. Kenji
Nakashima, Div. of Neurology, Inst. of Neurological
Sciences, Prof. Takao Sasaki of the Third Dept. ofInternal Medicine, and Prof. Takayuki Nose of theDept. of Public Health, Faculty of Medicine, Tottori
University for their kind advice, useful suggestions
and critical readings of the manuscript.

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