Headache


C 2006 by American Headache Society
Published by Blackwell Publishing

ISSN 0017-8748
doi: 10.1111/j.1526-4610.2006.00510.x

Brief Communication
Cerebral Vasoreactivity is Influenced by the Prandial State
Among Migraineurs
Rodolfo de S. Coelho; Ciro M. Gomes; Ricardo A. Teixeira, MD, PhD
Objective.To test if the cerebral vasoreactivity among migraineurs is influenced by the prandial state.
Design and Methods.Eight patients with migraine without aura were studied (mean age = 23.75 years;
range = 19 to 32 years; 6 women). We also studied 8 healthy controls (mean age = 20.63 years; range = 18 to
22 years; 3 women), with no history of migraine. Cerebral vasoreactivity was measured on the right side by the
breath holding index (BHI) using an EZ-Dop transcranial Doppler instrument, with a 2-MHz transducer fitted
on a headband. Serum glucose levels were measured after a 10-hour fasting period and then 10 minutes after a
standardized breakfast.
Results.In both groups, we found a postprandial (PP) glycemia enhancement ( P < .02). Migraineurs showed
enhanced PP cerebral vasoreactivity when compared to the fasting state (FS) (BHI-PP = 1.46; BHI-FS = 1.16;
P = .02). Among controls, we found a trade to enhancement, but without statistic significance (BHI-PP = 1.28;
BHI-FS = 1.11; P = .30). Glucose levels were not significantly correlated to cerebral vasoreactivity in any of the
groups ( P > .05).
Conclusion.Our findings suggest that migraineurs have a higher reactivity to hypercapnia during the PP
period.
Key words: migraine, cerebral vasoreactivity, fasting state
Abbreviations:

BHI breath holding index, PP postprandial, FS fasting state, BFV blood flow velocity, NO nitric
oxide

(Headache 2006;46:1191-1194)

Although migraine affects around 12% of the general population, its physiopathology is not completely
elucidated.1 Many triggering factors have been described and diet factors have been evoked as very common precipitants.2
The relationship between migraine attacks and
prandial state can be, at least in part, explained by

From the Universidade Catolica

de Braslia, Brasilia, Distrito
Federal, Brazil (Mr. Coelho, Mr. Gomes, and Mr. Teixeira); Department of Neurology, Hospital Santa Luzia, Braslia, Distrito
Federal, Brazil (Mr. Teixeira).
Address all correspondence to Dr. Ricardo Afonso Teixeira,
Hospital Santa Luzia, Departamento de Ensino e Pesquisa,
SHLS 716 conj E lote 05 CEP 70390-903, BrasiliaDF Brazil.
Accepted for publication March 31, 2006.

different cerebrovascular responsiveness according to

different serum glucose levels. Some experimental
studies have addressed this relationship and most of
them show that there is an impaired vasoreactivity in
hypoglycemic states in animals.3-6
As far as we know, there is no study which has
evaluated if migraineurs have different cerebral vasoreactivity during distinct prandial states. The aim of
this study was to test the hypothesis that cerebral vasoreactivity among migraineurs is influenced by the
prandial state.

SUBJECTS AND METHODS

Eight patients (mean age = 23.75 years; range =
19 to 32 years; 6 women) with migraine without aura

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1192
diagnosed according to the criteria of the International Headache Society7 were evaluated. They were
completely healthy otherwise, without migraine attacks in the last 7 days and with no use of prophylactic medication at all. Eight healthy individuals (mean
age = 20.63 years; range = 18 to 22 years; 3 women)
with no history of headache were enrolled as the control group. None of the participants was a tobacco
consumer.
The participants were instructed to abstain from
the use of alcohol for at least 24 hours prior to the
study and to be in the fasting state (FS) for at least
10 hours before the measurements. Written informed consent was obtained from all participants.
All examinations were performed in a quiet room
in the morning (8 a.m.) with subjects lying on a comfortable supine position, without any visual or auditory stimulation. We started the experiment measuring the glucose levels of the individuals with a glucometer (ACCU-CHEK Advantage ). Basal blood
flow velocity (BFV) was initially measured after 3
minutes of rest. The recordings were made using a
single channel transcranial Doppler instrument (EZDopDWL Elektronische Systeme GmbH), with the
transducer fitted on a headband and placed over the
temporal window of the right side. Then, cerebral
vasoreactivity was assessed through the right middle cerebral artery using the breath holding index
(BHI).8 For calculation of the BHI, participants were
asked to hold their breath for 30 seconds after a normal inspiration, and the maximum increase in BFV
was registered. All of them were able to hold their
breath for the required time. The average of 3 consecutive BHIs registered 3 minutes apart was calculated. Then, participants were given a standardized
breakfast that included a loaf of bread and 350 cm3
of natural peach juice. Ten minutes after they finished
the meal, glucose levels and 3 other BHI measurements were recorded, respecting the same 3-minute
interval.
ANOVA test was applied for comparison on continuous variables among migraineurs and controls. We
used the Pearson correlation test to assess correlation
between glucose levels and BHI. The significance level
was .05.

RESULTS
All participants were headache free during the
measurements. BHI and serum glucose levels during
FS were not significantly different between patients
and healthy controls. Glucose levels were significantly
enhanced after meal among controls (P = .001) and
patients (P < .001).
Postprandial (PP) BHI was significantly higher
when compared to the FS among migraineurs (BHIPP = 1.46; BHI-FS = 1.16; P = .02). Among controls,
BHI was slightly increased, but it was not statistically
significant (BHI-PP = 1.28; BHI-FS = 1.11; P = .30).
Neither group showed any significant correlation between serum glucose levels and cerebral response to
hypercapnia (P > .05) (Table).
DISCUSSION
Our study suggests that migraineurs have an enhanced response to hypercapnia during the PP state.
Among controls, we found a trend to vasoreactivity
enhancement, but it did not reach statistical power.
Previous works have addressed the issue related
to cerebral vasoreactivity and glucose levels. Park et al
showed that, in piglets, during hypoglycemia the cerebrovascular vasodilatation response to hypercapnia is
attenuated when compared to the response under normoglycemic conditions.4 In addition, Siesjo et al reported that there is a regional loss of cerebrovascular
vasoconstriction when rat models are hyperventilated
to an arterial carbon dioxide tension of 25 to 28 Torr
during severe hypoglycemia.5 Sieber et al described
that hypoglycemia to a glucose level of <30 mg/dL
prevents the cerebral vasoconstrictor response during
Table.Mean Values of Serum Glucose Levels and BHI of
Migraineurs and Controls

Migraineurs

BHI

Glucose levels

FS
PP
P
FS
PP
P

1.16
1.46
.02
86.87
127.75
<.001

Controls

1.11
1.28
.30
85.12
113
.001

.74
.14
.64
.11

Headache
hypocapnia in pentobarbital-anesthetized dogs.3 In
contrast, Nilsson et al suggested that, during short hypercapnic challenges (30 seconds), hypoglycemia does
not alter the cerebrovascular response in the brain
of rats.6 These conflicting results could be in part explained by methodological differences, since different
animal models and techniques were used to measure
cerebral vasoreactivity.
Lines of evidence point to a possible role of insulin
in the nitric oxide (NO) mediated vasorelaxation.9
Shinozaki et al have described that insulin enhances
the synthesis of tetrahydribiopterin, a cofactor of NO
synthases, resulting in the release of NO by the endothelial cells and decrease of the NO degradation.9
The enhancement of NO levels due to insulin stimulation could explain our findings of PP enhanced vasoreactivity in both groups. Furthermore, it is known
that NO provokes a more pronounced vasodilatatory
response in migraine sufferers,10 in agreement with
the enhanced vasoreactivity of the migraine group reported by us.
Another possible explanation for the enhanced PP
vasoreactivity observed among migraineurs is a state
of vagal hyperactivity during the headache-free period.11 Blat et al suggested that the vagal nerve inhibits
insulin secretion during the FS.12 Vagal hyperactivity
among migraineurs could further inhibit insulin secretion in the FS. On the other hand, vagal nerve stimulates insulin secretion during the PP state,13 and it
could hypothetically lead to an enhanced vasodilatatory response in migraine sufferers due to a vagal hyperactivity and higher release of NO.9 This hypothesis
is supported by a recent study that showed increased
insulin and glucose blood concentrations among migraineurs during oral glucose tolerance test as well
as an impaired insulin sensitivity.14 Our study showed
that migraineurs had a slight enhancement of the PP
glucose levels when compared to controls, although it
did not reach statistical significance. We cannot, however, draw conclusions about the role of insulin in our
results, since it was not measured during our experiment.
We could not find any previous study that had
compared the cerebral vasoreactivity of migraineurs
after a meal. However, it is well assumed that both the
FS and specific dietary elements can trigger migraine

1193
attacks. We interpret our results as an enhancement
on cerebral vasoreactivity in response to meal ingestion among migraineurs. Maybe, this could be a useful
test to check what kinds of food are more susceptible
to trigger pain attacks in an individual with migraine.
It is worthwhile to emphasize that the meal offered
to our patients did not contain any classic migraine dietary triggers, such as vasoactive amines, monosodium
glutamate, aspartame, and sodium nitrate.
One of the limitations of our study is that cardiovascular parameters were not continuously measured
during the experiment. However, the possible influence of a PP hypotension is not expected, since this
is not a common feature in young healthy individuals. Heart rate and blood pressure were both measured just before the beginning of the experiment, and
all participants had normal values. Another limitation
of our study is that the gender sample was not exactly the same in the 2 groups. It has been reported
that women during the ovulatory phase of the menstrual cycle have enhanced BHI values when compared to male controls.15 The possible different menstrual cycle phases among women in the 2 groups could
have influenced our results. However, in none of our
groups male and female were BHI values significantly
different.
In conclusion, our results suggest that cerebral vasoreactivity is influenced by the prandial state among
migraineurs. Further studies with a larger sample are
needed to evaluate the influence of glucose on cerebral
vasoreactivity and how the prandial state influences
the triggering mechanisms of migraine attacks.
Conflict of Interest: None

REFERENCES
1. Breslau N, Rasmussen BK. The impact of migraine:
Epidemiology, risk factors and co-morbidities. Neurology. 2001;56(6 suppl 1):S4-S12.
2. Robbins L. Precipitating factors in migraine: A
retrospective review of 494 patients. Headache.
1994;34:214-216.
3. Sieber FE, Derrer SA, Saudek CD, Traystman RJ.
Effect of hypoglycemia on cerebral metabolism and
carbon dioxide responsivity. Am J Physiol. 1989;256(3
Pt 2):H697-H706.
4. Park TS, Gonzales ER, Shah AR, Gidday JM.

July/August 2006

1194

5.

6.

7.

8.

9.

Hypoglycemia selectively abolishes hypoxic reactivity of pial arterioles in piglets: Role of adenosine. Am
J Physiol. 1995;268(2 Pt 2):H871-H878.
Siesjo BK, Ingvar M, Pelligrino D. Regional differences in vascular autoregulation in the rat brain in
severe insulin-induced hypoglycemia. J Cereb Blood
Flow Metab. 1983;3:478-485.
Nilsson BC, Agardh CD, Ingvar M, Siesjo BK. Cerebrovascular response during and following severe
insulin-induced hypoglycemia: CO2 sensitivity, autoregulation, and influence of prostaglandin synthesis
inhibition. Acta Physiol Scand. 1981;111:455-463.
Headache Classification Subcommittee of the International Headache Society. The international
classification of headache disorders. Cephalalgia.
2004;24(suppl 1):1-150.
Markus HS, Harrison MJG. Estimation of cerebrovascular reactivity using trancranial Doppler, including the use of breath-holding as the vasodilatory
stimulus. Stroke. 1992;23:668-673.
Shinozaki K, Kashiwagi A, Nishio Y, et al. Abnormal
biopterin metabolism is a major cause of impaired

10.

11.

12.

13.
14.

15.

endothelium-dependent relaxation through nitric oxide/O2 imbalance in insulin-resistant rat aorta. Diabetes. 1999;48:2437-2445.
Thomsen LL, Iversen HK, Brinck TA, Olesen L.
Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalagia. 1993;13:395399.
Benjelloun H, Birouk N, Slaoui I, et al. Autonomic
profile of patients with migraine. Neurophysiol Clin.
2005;35:127-134.
Blat S, Malbert CH. The vagus is inhibitory of insulin
secretion under fasting conditions. Am J Physiol Endocrinol Metab. 2001;281:E782-E788.
Cherrington AD. Control of glucose uptake and release by the liver in vivo. Diabetes. 1999;48:1198-1214.
Rainero I, Limone P, Ferrero M, et al. Insulin sensitivity is impaired in patients with migraine. Cephalalgia.
2005;25:593-597.
Diomedi M, Cupini LM, Rizzato B, Ferrante F, Giacomini P, Silvestrini M. Influence of physiologic oscillation of estrogens on cerebral hemodynamics. J
Neurol Sci. 2001;185:49-53.