DOI: 10.

1093/brain/awh236 Brain (2004), 127, 2099–2108

Autonomic asymmetry in migraine: augmented

parasympathetic activation in left unilateral
migraineurs
Yudith Avnon,1,2 Meir Nitzan,3 Elliot Sprecher,1 Zeev Rogowski2 and David Yarnitsky1,2
1
Department of Neurology, Rambam Medical Center, Correspondence to: David Yarnitsky, MD, Department of
2
Faculty of Medicine, Technion, Haifa and 3Department of Neurology, Rambam Medical Center, Haifa, Israel
Applied Physics/Electro-optics, Jerusalem College of E-mail: davidy@tx.technion.ac.il
Technology, Jerusalem, Israel

Summary

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Brain autonomic control is asymmetrical, the left hemi-
sphere affecting predominantly parasympathetic func-
tion and the right hemisphere affecting predominantly
sympathetic function. It is not known whether the extent
of autonomic activation is altered in migraine, although
the fact that some migraineurs express parasympathetic
features such as facial flushing, lacrimation and rhinor-
rhoea might suggest increased parasympathetic activa-
tion. We instilled diluted soapy eyedrops and measured
(i) the trigemino-parasympathetic reflex by the vasodila-
tor response of forehead skin bilaterally using photo-
plethysmography; (ii) the somato-sympathetic reflex by
vasoconstriction in the index finger; and (iii) heart rate
response. We studied 14 left-sided and 15 right-sided
unilateral migraineurs outside attacks. We found that
left-side migraineurs had significantly higher bilateral
parasympathetic vasodilatation, regardless of the stimu-
lation or measurement side ( þ 60.1 6 6.4%) compared
with right-side migraineurs ( þ 41.9 6 6.4%, P < 0.05).
Sympathetic vasoconstriction, however, was similar for
the two groups (left,
15.9 6 4.2%; right,
17.7 6 4.1%,
NS). Bradycardia was significantly more pronounced for
the left-side migraineurs (interbeat, RR interval increase
of þ 6.2 6 1.1% versus þ 3.1 6 1.1%, P < 0.04). We
conclude that unilateral left-side migraineurs have
increased parasympathetic activation in response to
pain compared with right-side migraineurs. Sympathetic
responses were similar in the two groups and seemed not
to be affected by migraine side. Since cranial parasym-
pathetic activity induces cerebral vasodilatation, this
augmentation might be an inherent part of the migraine
pathophysiology in these patients.

Keywords: migraine; parasympathetic; brain asymmetry; photoplethysmography; trigemino-parasympathetic reflex

Abbreviations: AM = amplitude; BL = baseline; BP = blood pressure; HF = high frequency; HR = heart rate;

PPG = photoplethysmography
Received February 15, 2004. Revised April 20, 2004. Accepted May 9, 2004. Advanced Access publication July 28, 2004

Introduction
Almost two centuries have passed since the first discovery
of asymmetrical functions of the brain hemispheres by Dax
(1836), who apparently preceded Broca (1865) in this
discovery. It is now well recognized that the hemispheres
not only differ in their mode of cognitive and emotion-related
processing (Gainotti, 1972, 1983; Trevarthen, 1990), but that
brain asymmetry is a multimodal phenomenon (Davidson,
1995), including a higher degree of somatosensory processing
(Hari et al., 1997; Pauli et al., 1999; Coghill et al., 2001) and
autonomic–physiologically related functions, such as cardiac
control (Critchley et al., 2000).
The autonomic control of the heart is modulated by certain
parts of the cerebral hemisphere, such as the insula, amyg-
dala and lateral hypothalamus (Oppenheimer et al., 1992),
the right hemisphere predominantly deals with the sympa-
thetic system, while the left hemisphere deals with the para-
sympathetic system (Oppenheimer et al., 1992, 1996; Naver
et al., 1996; Hilz et al., 2001). The two hemispheres maintain

Brain Vol. 127 No. 9 # Guarantors of Brain 2004; all rights reserved
2100 Y. Avnon et al.
a homeostatic balance between themselves in regulating the
sympathetic, parasympathetic and baroreflex functions (Hilz
et al., 2001). This equilibrium is compromised in patients
with unilateral brain injury; autonomic asymmetry is evident
in patients with intracranial tumours, cerebral trauma, ence-
phalitis (Oppenheimer et al., 1990; Benarroch, 1997), uni-
lateral temporal lobe epilepsy (Tinuper et al., 2001; Lee,
2002) and stroke (Lane et al., 1992; Korpelainen et al.,
1993; Barron et al., 1994; Naver et al., 1996; Robinson
et al., 1997; Tokgozoglu et al., 1999). Lateralization in cer-
ebral cardiac control was also demonstrated in epilepsy
patients undergoing inactivation procedure (Wada test)
(Zamrini et al., 1990; Yoon et al., 1997; Hilz et al.,
2001). In these studies, inactivation of the right hemisphere
was associated with reduced sympathetic tone, manifested
as decreased heart rate (HR) and blood pressure (BP) and
increases in high frequency (HF) of HR and BP. Left hemi-
sphere inactivation, on the other hand, was associated with
reduced parasympathetic tone, manifested as increased HR
and BP, increases in low frequency (LF) of HR and BP, and a
shift in the sympathovagal balance towards sympathetic pre-
dominance manifested as increased LF/HF ratio of HR. The
association of right cerebral hemisphere diseases with tachy-
cardia mechanisms was investigated by Oppenheimer and
colleagues, who demonstrated in humans that tachycardia
and pressor responses were more often elicitable by stimula-
tion of the right insular cortex, while stimulation of the left
insular cortex was associated with bradycardia and depressor
responses (Oppenheimer et al., 1992).
Migraine is a benign disease, with mostly unilateral head-
ache, in which hemispheric arousal is documented during
attacks, and to some extent also outside attacks (Welch
et al., 1990; Schoenen, 1997, 1998; Aurora et al., 1998; Has-
singer et al., 1999). Autonomic abnormalities can therefore be
expected, and were indeed documented in these patients,
including abnormal cardiovascular reflexes to haemodynamic
challenges, altered heart rate variation, pupillary reactivity,
vascular reactivity, electrodermal activity and altered catecho-
lamine levels (Ffg-Moller et al., 1978; Fanciullacci, 1979;
Gotoh et al., 1984; Havanka-Kanniainen, 1986; Havanka-Kan-
niainen et al., 1986; Drummond, 1987, 1990, 1991, 1997;
Boiardi et al., 1988; Mikamo et al., 1989; Appel et al.,
1992; Martin et al., 1992; Pogacnik et al., 1993; Shechter
et al., 2002). This is in addition to the commonly observed
increased parasympathetic signs of lacrimation, facial flushing
and rhinorrhoea (International Headache Society Classifica-
tion, 2004; Barbanti et al., 2002). The subgroup of strictly
unilateral migraineurs is a natural clinical example of hemi-
spheric imbalance (Crisp, 1981; Crisp et al., 1985, 1989; Gru-
zelier et al., 1987). However, there is little evidence that
localization of pain to one side of the head is associated
with disturbed functioning of the corresponding hemisphere.
The trigemino-parasympathetic reflex (Drummond, 1992,
1995, 1997; Drummond and Lance, 1992; Avnon et al.,
2003) was studied in the present work in unilateral
migraineurs between attacks, measuring cutaneous vascular
and systemic cardiovascular responses to painful stimulation
with soapy eyedrops, in order to assess whether the
painful hemisphere expresses an alteration in its relevant
autonomic control.
Method
Subjects
Unilateral migraineurs were recruited through advertisements or
were employees of the medical centre or the university. All
patients signed informed consent, which was approved by the
Ministry of Heath and Rambam Medical Center Human Subjects
Committee. Thirty females who met the International Headache
Society classification for migraine (1988) (and retrospectively also
met the 2004 classification) with aura (eight patients) or without
aura (21 patients), age range 21–50 years (mean 32.1 6 8.7), were
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recruited after screening. Exclusion criteria were: (i) cardiovas-
cular, renal or central and peripheral nervous system disorders,
(ii) chronic use of medications for reasons other than migraine,
(iii) use of prophylactic treatment for migraine; and (iv) eye and
skin disorders. Subjects were questioned in detail to evaluate the
migraine type, laterality of pain and the associated symptoms.
Fifteen patients had headache restricted to the right side and
15 patients had a headache restricted to the left side. Some of
these patients were participants in a previous study in our labora-
tory (Avnon et al., 2003). Photo-, phono- or osmophobia was
present in all. Most patients suffered from nausea and vomiting
during their attacks, and about half of them had increased skin
sensitivity in the face and scalp during attacks. Headache
frequency ranged between one and eight attacks per month
(mean 2.8 6 1.9) and the duration of attacks ranged between
4 h and 3–4 days (mean 28.9 6 18.2 h). Average duration of
affliction with migraine was 14.8 6 8.5 years. Six patients
reported having pronounced parasympathetic symptoms, such as
tear production and nasal congestion/stuffiness during their
attacks. The majority of patients had a family history of migraine,
and in about 50% of the patients some attacks occurred
during their menstrual period. There were no demographic and
clinical differences between right-sided compared with left-side
migraineurs. One left-sided migraine patient was eventually
excluded from analysis because her forehead vascular responses
were far larger than 2 SD above the mean. All migraineurs were
studied during a headache-free interval (at least 1 week after their
last attack). Patients were requested to report if they developed an
attack during the successive 3 days after the experiment. However,
none called. We also checked by randomly calling 20 patients,
none of whom reported an attack.
Procedures
This single-session experiment was carried out in a quiet air-condi-
tioned room in the laboratory, and conducted during the morning. The
procedure used is fully described in our previous study (Avnon et al.,
2003). In brief, two optic pulse sensors (photoplethysmography) were
attached, one at each side of the forehead 1 cm above the eyebrows and
3 cm lateral to the midline, and a third sensor was attached to the
palmar aspect of the middle phalanx of the right middle finger. A
continuous BP cuff (Finapres, Ohmeda, USA) was attached to the left
middle finger, to evaluate heart rate and blood pressure values on a
beat-to-beat basis.

After the subject had rested in a supine position for a few minutes,
we recorded 10 min of baseline PPG signals and cardiovascular para-
meters. Then, we activated the parasympathetic system by instillation
of one drop of diluted soap (Drummond, 1992, 1993; Avnon et al.,
2003) into the conjunctival sac of one eye at a time. The soapy eyedrop
was washed away with saline solution after 2 min. As a control, a drop
of sterile saline was also administered to the eye, in single-blinded
fashion, in a random sequence. After 15–30 min the other eye was
similarly stimulated. This procedure was performed twice, in order to
assess adaptation of the response. Patients were asked to estimate pain
intensity for each drop, numerically, on a scale of 0 (no pain) to 10
(the most unbearable pain), following its administration.
Photoplethysmography (PPG)
PPG is a method that detects changes in arterial blood volume induced
by cardiac activity by measuring the oscillatory changes in light
reflection through the tissue. The PPG probes, described elsewhere
(Nitzan et al., 1998; Babchenko et al., 2001; Avnon et al., 2003),
consist of an infrared light source (LED) at 865 nm wavelength
(Fujitsu, Japan) and a photodetector (Hamamatsu, S1223-01). The
probes were attached to the skin of the forehead and finger as pre-
viously described. The maximum value of the PPG signal (attained at
end of diastole) represents the baseline (BL). The PPG amplitude
(AM) is the difference between the PPG values at its maximum
(end-diastole) and at minimum (during systole), and is indicative
of arterial compliance. We used an index consisting of the ratio of
the two parameters, AM/BL, providing a parameter that is related to
the amplitude of the tissue blood volume changes (Nitzan et al., 1998).
Changes in the trigemino-parasympathetic or sympathetic activa-
tion were evaluated by the measurement (in the forehead or finger,
respectively) of the percentage change in AM/BL; the value of AM/
BL during manipulation (AM/BLm) minus the value of AM/BL before
manipulation (baseline) (AM/BLb) divided by the value of AM/BL
before manipulation, expressed as a percentage: change (%) in
AM/BL = 100  (AM/BLm
AM/BLb)/AM/BLb.
The vascular and cardiovascular responses to ocular irritation were
evaluated at three time points: the peak of the response (the maximum
change), which occurred immediately after drop instillation, and 1 and
2 min afterwards. The 1 and 2 min points provided a measure for the
duration and extent of the response.
Statistical analysis
The study was designed to produce data regarding multiple parasym-
pathetic parameters, under baseline and during activation in migrain-
eurs and controls. Each parameter (except pain rating) was expressed
as a percentage change from baseline (premanipulation period value).
Subject classification (type of migraine or control) served as the
independent variable.
Initial inspection of the various parameters determined the normal-
ity of the data distributions, which is important for subsequent param-
etric statistical analyses.
We performed a preliminary series of individual, repeated
measures (or mixed model) analyses of variance (ANOVAs), with
associated post hoc Tukey–Kramer HSD (honestly significant dif-
ference) tests, to assess parasympathetic changes between subject
classifications.
Regression and correlation analyses were also employed to exam-
ine the relationship between various combinations of parasympathetic
parameters, pain ratings, cardiovascular parameters, and other
responses.
Autonomic asymmetry in migraine 2101
Results are given as least square mean 6 SE. P < 0.05 was con-
sidered statistically significant.
Results
Forehead vascular responses to ocular irritation
Overall response differences between left- and
right-side migraineurs
Preliminary analyses did not indicate significant differences
between the first and second stimuli to right and left eyes, or
between eyes. Therefore, these four readings were combined in
the analyses.
Left-side migraineurs had significantly higher responses
compared with right-side migraineurs; Peak ipsilateral (to
stimulation) forehead vascular response (percentage change
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in AM/BL) obtained from stimulation of each of the eyes
(an average of four readings) of left-side migraineurs
was þ 60.1 6 6.4% compared with þ 41.9 6 6.4% (P =
0.05) in right-side migraineurs. Similar patterns were observed
at 1 min (þ32.9 6 5.0% versus þ 15.6 6 5.5%, P = 0.02) and
2 min after soap instillation (þ20.3 6 3.1% versus þ 7.3 6
3.2%, P = 0.007) (Fig. 1A). Higher vascular responses in left-
side migraineurs were also noted on the contralateral side of the
forehead, but reached significance only 1 min after stimulation
(Fig. 1B).
Subanalyses of the forehead response to
soapy stimulation data
(i) The first application seemed to induce a higher response
than the second application, but there were no statistically
significant differences in the vascular response between
first and second soap application to each eye. Therefore, we
collapsed the data between the first and the second stimuli
together (a combination of two readings).
(ii) The immediate response to stimulation of the left eye in
left-side migraineurs was higher than the immediate
response to stimulation of the right eye in right-side
migraineurs (þ69.7 6 6.2% versus þ 42.8 6 6.1%,
P = 0.05). Subsequent readings did not reach significance
at 1 (þ40.4 6 6.0% versus þ 18.5 6 5.9%, NS) or 2 min
(þ23.9 6 3.8% versus þ 10.9 6 3.8%, NS) after soapy
drop administration (Table 1, Fig. 2).
Within the left-side migraineurs group, there was no statis-
tically different ipsilateral forehead response between sides,
regardless of stimulation side. The same pattern was seen for
right migraineurs (Table 1).
Vascular responses to saline eye drop
Saline eye drops produced vascular changes that were similar
though milder and of shorter duration compared with the
soapy eye drop. No differences were found between groups
or between sides.
2102 Y. Avnon et al.

NS

NS

Fig. 2 Vascular responses to a soapy eye drop from the ipsilateral

side of the forehead obtained by stimulating the eye on the

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B symptomatic side of left-side and right-side migraine patients
NS (average of two responses). Left-side migraineurs had higher
vasodilatation than right-side migraineurs at the immediate
response time point (P = 0.05) (least-squares mean 6 SE).

Pain ratings to ocular irritation

Pain rating to soapy eye drop in the left-sided migraine group
was 6.2 6 0.5 (range 3–10) and did not differ from that in the
right-sided migraine group, with a rating of 5.3 6 0.5 (range
2–10) (P = 0.57). Group (left-sided and right-sided migraine)
and individual ratings were similar for the right and the left eye
and for the first and second soapy eye drops to each eye. Pain
rating to soapy eye drop did not differ between sides, neither
between symptomatic and non-symptomatic sides, in each
migraine group.
Instillation of a saline drop in either eye produced no pain or
Fig. 1 Vascular responses (% increase in AM/BL, i.e. vasodilatation) mild pain sensation, which was not different between left-side
to a soapy eye drop (average of four responses per subject; two (0.8 6 0.2) and right-side migraine patients (0.3 6 0.2) (least-
from each eye) from the ipsilateral (A) and contralateral (B) sides
of the forehead were significantly higher in left-side migraineurs squares mean 6 SE).
(n = 14) than in right-side migraineurs (n = 15) (least-squares
mean 6 SE). Note the different scales of the y-axis for each graph.
Vascular response to ocular irritation measured
from the finger
Digital blood volume decreased immediately after soapy drop
Table 1 Ipsilateral forehead vascular responses to a soapy instillation, as pulse amplitude (AM) decreased and the value
eye drop obtained from right- and left-side migraine of BL increased, resulting in a decrease in the parameter AM/
patients BL, with early return to prestimulus values. There were no
differences between sides in initial and successive instillations.
Left-side Right-side
migraineurs migraineurs There were no differences (average of all responses) between
(n = 14) (n = 15) right-side (–17.7 6 4.1%) and left-side migraineurs (–15.9 6
4.2%) (Fig. 3).
Response to left 69.7 6 6% 40.9 6 7% Saline eye drops produced a slight and short-lasting decrease
P=0.05
eye stimulation
NS ƒƒ NS in the parameter AM/BL (vasoconstriction) in the finger, which
!

ƒƒ!
ƒ

Response to right 50.4 6 6%

ƒ 42.8 6 6% was similar in magnitude between groups, and between sides
eye stimulation P=0.05 in each group.
Average response to right 60.1 6 6 ƒƒ
ƒ! 41.9 6 6%
and left eye stimulation
Heart rate responses to ocular irritation
Results are given as percentage change in amplitude/baseline
(AM/BL; i.e. vasodilatation), least-squares mean 6 SE. See text Heart rate decreased slightly in response to the soapy eye drop
for comments. Significant results indicate P < 0.05 (Tukey-Kramer (i.e. increase in heart period) in the two migraine groups. The
HSD). increase in heart period was significantly higher in the left-side

Immediate 1 minute 2 minutes
% Change in AM/BL from the finger
0 The trigemino-parasympathetic reflex is characterized by
-5
-10 NS
NS
-15
-20 L-migraine (n =14)
NS R-migraine (n=15)
-25
Fig. 3 Finger vascular responses to a soapy eye drop. No
significant differences in percentage decrease in AM/BL (vaso-
constriction) were found between groups when either eye was
stimulated (least-squares mean 6 SE).
Fig. 4 All patients had bradycardia in response to a soapy eye drop,
and left-side migraineurs had a significantly greater increase in
heart period than right-side migraineurs (least-squares mean 6 SE).
migraine group compared with the right-side migraine group at
the immediate response time (þ6.2 6 1.1% versus þ 3.1 6
1.1%, P = 0.04) and at 1 min (þ4.4 6 0.8% versus þ 2.1 6
0.8%, P = 0.05), and with a trend towards significance at 2 min
(þ2.7 6 1.0% versus þ 0.04 6 0.96%, P = 0.06) (Fig. 4). The
heart period changes were significantly correlated (r = 0.57, P =
0.002) with the forehead vascular changes in response to soapy
eye drops.
Discussion
Our results demonstrate differences in cutaneous and cardiac
parasympathetic responses between strictly right and left side
symptomatic migraine patients; left-side migraineurs had
higher forehead vasodilatation and more pronounced brady-
cardia in response to ocular irritation compared with right-
side migraineurs, indicating higher somato-parasympathetic
responsiveness. Right-side migraineurs, however, did not
express an increase in the somato-sympathetic reflex, as meas-
ured by finger vasoconstriction.
Autonomic asymmetry in migraine 2103
The somato-autonomic reflexes
facial vasodilatory and secretory responses, mediated by
parasympathetic innervation, evoked by a painful stimulation
to the tongue, lips, tooth pulp, nasal mucosa or eyes
(Drummond, 1992, 1993, 1995; Drummond and Lance,
1992; Kemppainen et al., 1994; Shoji, 1996; Izumi, 1999;
Izumi et al., 2002; Avnon et al., 2003). In this study, we
instilled a diluted soapy eye drop and recorded the vasodilator
response of the facial skin. The efferent part of the reflex is
mediated by parasympathetic fibres employing primarily
vasoactive intestinal peptide (Goadsby and Macdonald,
1985; Goadsby and Edvinsson, 1994) and possibly also nitric
oxide (Nozaki et al., 1993) as neurotransmitters. These efferent
parasympathetic fibres originate from the superior salivatory
nucleus in the brainstem (Spencer et al., 1990), travel with the
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facial nerve and synapse at the sphenopalatine ganglion
(Suzuki et al., 1988), often also called the pterygopalatine
ganglion (Warwick and Williams, 1973). Thereafter they
distribute to the end organs via several rami. Animal studies
have documented this reflex activity and its pathways: elec-
trical stimulation of the ophthalmic division of the trigeminal
nerve (Gonzalez et al., 1975; Lambert et al., 1984), the trigem-
inal ganglion (Lambert et al., 1984; Goadsby et al., 1988;
Goadsby and Edvinsson, 1993, 1994) or the greater superficial
petrosal nerve (Lambert et al., 1984) increased release of
jugular vein vasoactive peptides, facial flushing and forehead
temperature and reduced carotid resistance. A similar finding
of augmented bilateral forehead vasodilatation in response to
a unilateral painful cutaneous or mucosal stimulation in the
ophthalmic territory was documented in ictal and inter-ictal
cluster and migraine patients (Drummond and Lance, 1992;
Drummond, 1995, 1997). The bilaterality is in line with the
anatomy of the parasympathetic innervation, since these fibres
cross over in the brainstem (Lambert et al., 1984), and since in
the rat at least each of the sphenopalatine ganglia innervate
vessels on the ipsilateral and (to a lesser extent) the contral-
ateral cerebral side (Suzuki and Hardebo, 1991).
The somato-parasympathetic reflex has been suggested to be
involved in some of the vascular changes during headache, and
to mediate the flushing, lacrimation and rhinorrhoea
commonly observed during cluster headache and some
migraine attacks (Drummond, 1992, 1995, 1997; Goadsby
and Edvinsson, 1994).
Apart from differences in parasympathetic activity, the
differences found between right and left migraineurs in
forehead vascular responses could potentially result from
differences in: (i) pain perception and processing, (ii)
sensory C-fibre-based axon reflex responses; and (iii)
sympathetic vasodilator responses. Our left- and right-side
migraineurs reported similar pain rating in response to the
soapy eye drops for both sides. This is in keeping with many
reports that found no difference between the two sides
in stimulus-evoked pain in pain-free migraineurs
(Drummond, 1987; Jensen et al., 1988; Schoenen et al.,
1989; Marlowe, 1992; Bovim, 1992; Drummond, 1997;
2104 Y. Avnon et al.
Vanagaite et al., 1997; Vingen et al., 1998; Becser et al.,
1998; Katsarava et al., 2002; Sandrini et al., 2002; Milanov
and Bogdanova, 2003). Our finding of similar pain ratings
in response to ocular irritation for right and left
migraineurs excludes the afferent factor from any explana-
tion of our results.
Regarding axon reflex mechanism, Lambert and colleagues
reported that only a small proportion of the vascular response to
trigeminal stimulation is due to antidromic release of vaso-
active substances from pain sensors in a cat model (Lambert
et al., 1984). Furthermore, absence of forehead vascular
response to ocular irritation on the injury side in patients
with facial nerve palsy, where parasympathetic fibres are com-
promised while sensory fibres are spared, rules out the anti-
dromic mechanism as a mediator of this vasodilatation
(Drummond, 1992). Moreover, an afferently mediated axon
reflex vasodilatation should be limited to the territory of sti-
mulation and not cross to remote areas, such as the contralateral
side, whereas our previous (Avnon et al., 2003) and present
results show significant contralateral forehead vasodilatation
in response to ocular irritation. In line with this, Satoh-Kur-
iwada and colleagues also observed a significant contralateral
vasodilatation in the maxillary gingiva in response to electrical
tooth stimulation in humans (Satoh-Kuriwada et al., 2003).
They also excluded an axon reflex-mediated mechanism and
proposed that the gingival vascular response is a centrally
mediated parasympathetic reflex.
Sympathetic vasodilator involvement in the facial vascular
response can also be ruled out. In sympathectomized animal
models, electrical stimulation of the trigeminal nerve evokes a
reflex vasodilatation in the lower lip, submandibular gland and
palatal mucosa, which is necessarily non-sympathetic (Izumi
and Karita, 1992, 1994; Date et al., 2000). In human studies,
stellate ganglion blockade had no effect on the forehead
vascular response to ocular irritation, which was similar on
the blocked and intact sides (Drummond, 1993). Similarly,
surgical sympathectomy in humans did not alter the maxillary
gingival blood flow increase in response to electrical stimula-
tion of the mandibular tooth pulp (Satoh-Kuriwada et al.,
2003). These two human studies demonstrate that sympathetic
efferents do not participate in the centrally mediated reflex
vasodilatation following painful facial/orofacial stimulation.
Our findings are also in line with this concept, as similar
sympathetically derived finger vasoconstriction was shown
for right-and left-side migraineurs, in contrast to different
facial vasodilatation.
For the vasoconstrictor somato-sympathetic reflex, a
somatic stimulus, usually painful, is used to evoke a vasocon-
strictive sympathetic response. In the present study we used the
soapy eye drop as the painful stimulus to evoke both reflexes,
and a finger PPG signal as a reflection of the resulting vaso-
constriction of the sympathetic response. Our patients had an
average decrease of 17 6 4.2% in finger pulse amplitude
in response to soapy drop irritation. A decrease of similar
order of magnitude has been reported due to painful stimulation
at various sites (Cohen et al., 1978; Feuerstein et al., 1982;
Kroner-Herwig et al., 1988; Kemppainen et al., 1994; Avnon
et al., 2003).
In a previous study (Avnon et al., 2003) our group has
shown that unilateral migraineurs, pooled together regard-
less of migraine side, had a smaller vasodilatory response of
the facial skin compared with controls and with migraineurs
with alternating and bilateral head pain. We suggested an
augmented inhibitory interaction between the two loci
coerulei in the brainstem as a possible explanation to that
finding. Patients in the present study, some of whom also
served in our previous study, demonstrated the same pattern,
as both the right- and the left-sided groups had less
vasodilatation than controls. It seems, though, that the
reciprocal inhibition is not symmetrical, as left-side migrai-
neurs expressed a higher degree of vasodilatation compared
with the right-sided migraineurs. This could stem from
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augmentation of the parasympathetic tone at various levels
of the left side of the CNS at the insula, hypothalamus and/
or the brainstem.
Suprabulbar control of the parasympathetic
reflex
The anatomy of the somato-parasympathetic reflex has been
described at the brainstem level, and has so far been
considered symmetrical. Our data show, for the first time,
asymmetry of this reflex, which cannot be explained by
known brainstem physiology and is, therefore, most likely
under the control of higher centres, possibly the hypotha-
lamus. The hypothalamus contains neuronal groups that
project to autonomic centres of the brainstem and spinal
cord (Swanson, 1987, 1991), and among its many autonomic
functions it is involved in modulation of autonomic reflexes
such as the baroreceptor (Spyer, 1990) and light (Hey et al.,
1985) reflexes. Indirect data suggest that it might also be
involved in the somato-parasympathetic reflexes in animals;
Matsuo and Kusano (1984) reported that the lateral hypotha-
lamus is involved in modulation of the parasympathetic
gustatory–salivary reflex by demonstrating that electrical
stimulation of the lateral hypothalamus increased neural
activity of preganglionic parasympathetic fibres as well as
salivary secretion, in response to stimulation of the tongue
with high concentration of chemical solutions (NaCl, HCl),
and in response to pinching the tongue in rats. Chyi and
colleagues investigated transmitter mechanisms involved in
vasodilatation in extracranial vascular beds due to dorsal
facial area activation (Chyi et al., 1995). Among their find-
ings, they reported that in decerebrated cats greater vasodi-
latation was produced by activation of the dorsal facial area
compared with the vasodilatation produced in intact cats.
They reported that the vasodilatation was mediated through
parasympathetic mechanisms, and suggested that intercolli-
cular decerebration might eliminate an inhibitory influence
from higher structures to the dorsal facial area (Chyi et al.,
1995). This idea was supported by the observations of Izumi
and Karita (1997), who studied the effects of electrical

stimulation of the anterior hypothalamus on lip blood flow.
Such stimulation elicited attenuation of the lip blood flow
increase reflexly evoked by lingual nerve stimulation. Izumi
and Karita (1997) suggested that the anterior hypothalamus
could inhibit parasympathetic reflex vasodilatation in the
orofacial area region. Collectively, these data indicate the
existence of a modulatory mechanism by which the hypotha-
lamus can influence parasympathetic reflex vasodilatation in
the cranial and extracranial vasculature.
Several human studies by May and colleagues also support
hypothalamic involvement in the trigeminal reflex (May et al.,
1998, 1999, 2000). PET studies (May et al., 1998, 2000) during
nitoglycerin-evoked cluster attack, accompanied by ipsilateral
autonomic facial symptoms, demonstrated unique activation
of the ipsilateral hypothalamus, in addition to activation of
various brain areas involved in pain processing. Similar
ipsilateral hypothalamic activation, measured by functional
MRI, was demonstrated in a patient during a spontaneous
attack of short-lasting neuralgiform headache with conjunc-
tival injection and tear production (May et al., 1999).
Bradycardia in response to facial stimulation
Bradycardia was evoked in normal subjects in response to
instillation of diluted soap in the eye (Nordin and Fagius,
1995). Bradycardia is also evoked in the diving reflex as a
response to facial immersion in ice water (Gandevia et al.,
1978; Finley et al., 1979). Similarly, the oculocardiac reflex
elicited by pressure applied directly to the closed eyelid
(Aschner, 1908), and the reflex elicited by nasopharyngeal
stimulation (Gandevia et al., 1978) are known to slow the
heart rate. The evoked bradycardia in these reflexes is mediated
mainly by the vagus nerve; the increased vagal activity in
response to the diving reflex is abolished by section of the
vagal nerve or by atropine administration and is not affected
by sympathetic blockade by propranolol or phentolamine
(Finley et al., 1979). The greater extent of bradycardia in
our left-side patients compared with the right-side patients
could also be explained by predominance of the left side
autonomic pathways.
Autonomic differences between right and
left-sided migraine patients
Several studies are in line with our findings of different auto-
nomic tone between right- and left-sided migraine patients.
Gruzelier and colleagues measured interictal skin electroder-
mal responses in unilateral migraineurs, and found that
left-sided pain was associated with under-responsiveness
and fast habituation while right-sided pain was associated
with over-responsiveness and slow habituation (Gruzelier
et al., 1987). They suggested that the extent of sympathetic
response was predictive of the laterality of pain in migraine.
A recent transcranial Doppler study by Chernyshev and
colleagues also demonstrated autonomic differences between
right- and left-side migraineurs during the headache-free
Autonomic asymmetry in migraine 2105
period (Chernyshev et al., 2001). They measured blood flow
velocity and pulsatility index (PI, maximum systolic flow
velocity minus minimum diastolic flow velocity divided to
mean flow velocity) and found that the PI of the middle cerebral
artery on the headache side in right-side migraineurs was
higher than the corresponding PI index in the left-side migrain-
eurs. In addition, mean flow velocity of the basilar artery was
higher in patients with right-sided headache than in the
left-sided group.
The association between the laterality of pain and laterality
in hemisphere function was elegantly highlighted by Fasmer
and Oedegaard (2002). They studied migraine patients with
comorbid unipolar depressive and bipolar disorders. They
found that among the unipolar patients, in whom the right
hemisphere seems to predominate in several cognitive
functions, the migraine pain was predominantly located on
Downloaded from http://brain.oxfordjournals.org/ by guest on December 16, 2013
the right side of the head. In turn, for bipolar patients, in
whom the left hemisphere may be more active, the migraine
pain was predominantly located on the left side of the head.
These results may suggest that the side of migraine pain is
associated with the activity level of the corresponding
hemisphere. In accordance with the findings of Fasmer and
Oedegaard (2002), Crisp (1981) demonstrated that patients
with left-sided migraine had low levels of anxiety and depres-
sion compared with other migraine patients. Activation of the
left hemisphere is associated with positive emotions
(Cummings, 1993; Davidson, 1995; Canli et al., 1998;
Davidson and Irwin, 1999), and lesions of left frontal–
subcortical circuits or of anterior temporal lobe regions
often result in depression. Yet Brandt and colleagues failed
to find personality or emotional differences attributable to
headache laterality (Brandt et al., 1990).
Interestingly, a relation of autonomic imbalance with later-
ality of pain was found in cluster headache patients (Micieli
et al., 1993). Micieli and colleagues evaluated the relation
between 24 h HR changes during both cluster and remission
periods, in relation to the side of pain. They found that pain on
the right side resulted in a reduction in HR variability (day to
night changes) when compared with the left-side patients, in
both the cluster and the remission period. A trend to a high
degree of arrhythmia was observed in the right-side cluster
headache patients. In contrast to the above findings, they
also noted that the daytime HR of right-side patients was
significantly lower than that of the controls and the left-side
patients. Micielli and colleagues concluded that cluster
headache is associated with autonomic imbalance (Micieli
et al., 1993). The results of Micielli and colleagues demon-
strate autonomic differences between right- and left-side
cluster headache patients, with probable greater sympathetic
predominance for the right- compared with the left-side
patients. Laterality of autonomic function in cluster headache
may result from an influence of the ipsilateral hypothalamus
(May et al., 1998, 2000).
In conclusion, this study demonstrates that left-side migrain-
eurs have a predominant parasympathetic activation in res-
ponse to pain compared with right-side migraineurs. This
2106 Y. Avnon et al.
could stem from greater reactivity of left-sided autonomic
centres. The side of the migraine, however, does not affect
the extent of sympathetic activation. This might be related
to the more generalized character of the sympathetic response
compared with the more localized character of the parasym-
pathetic function (Low, 1997). Since both parasympathetic
and sympathetic fibres innervate cerebral vessels and can
influence brain metabolism and oxygenation, this lateralized
differential effect might be of importance in the pathogenesis
of migraine.
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