Evidence for a vascular factor in migraine Asghar, Mohammad S.; Hansen, Adam E.; Amin, Faisal M. ...
Annals of neurology,
April 2011, Volume:
69, Issue:
4
Journal Article
Peer reviewed
Open access
Objective
It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of ...extra‐ and intracranial vessels in migraine without aura patients.
Methods
A novel high‐resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5‐hydroxytryptamine agonist).
Results
We found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p
< 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half‐sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval CI, 4.16–20.83%) and of MCA of 12.88% (95% CI, 3.49–22.27%) and no dilatation on the nonheadache side of MMA (95% CI, −4.27 to 11.53%) and MCA (95% CI, −6.7 to 14.28%). In double‐sided headache we found bilateral vasodilatation of both MMA and MCA (p
< 0.001).
Interpretation
These data show that migraine without aura is associated with dilatation of extra‐ and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology. ANN NEUROL 2011
Summary Background Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial ...and intracranial arteries during attacks of migraine without aura. Methods In this cross-sectional study, we recruited patients aged 18–60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical ) arteries. The intracranial arterial segments were the cavernous (ICAcavernous ) and cerebral (ICAcerebral ) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov , number NCT01471314. Findings Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% 95% CI −5·7 to 8·2 p=0·985, STA 3·6% –3·7 to 11·0 p=0·532, MMA 1·7% –1·7 to 5·2 p=0·341, and ICAcervical 2·3% –0·3 to 4·9 p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% 6·4 to 19·6 p=0·001, ICAcerebral 11·5% 5·6 to 17·3 p=0·0004, and ICAcavernous 11·4% 5·3 to 17·5 p=0·001), except for the BA (1·6% –2·7 to 5·9 p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% 0·7–20·3 p=0·044, ICAcerebral (14·4% 4·6–24·1 p=0·013), and ICAcavernous (9·1% 3·9–14·4 p=0·003) but not of the extracranial arteries (ECA, 2·1% –3·8 to 9·2 p=0·238, STA, 3·6% –3·7 to 10·8 p=0·525, MMA, 2·7% –1·3 to 5·6 p=0·531, and ICAcervical , 5·0% –0·5 to 10·4 p=0·119). Interpretation Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation. Funding University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.
Intravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what ...extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded blood-oxygenation-level-dependent (BOLD) signals in the brain by functional MRI after infusion of CGRP in a double-blind placebo-controlled crossover study of 27 healthy volunteers. BOLD-signals were recorded in response to noxious heat stimuli in the V1-area of the trigeminal nerve. In addition, we measured BOLD-signals after injection of sumatriptan (5-HT1B/1D antagonist).
Brain activation to noxious heat stimuli following CGRP infusion compared to baseline resulted in increased BOLD-signal in insula and brainstem, and decreased BOLD-signal in the caudate nuclei, thalamus and cingulate cortex. Sumatriptan injection reversed these changes.
The changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli.
Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide are structurally and functionally closely related but show differences in migraine-inducing ...properties. Mechanisms responsible for the difference in migraine induction are unknown. Here, for the first time, we present a head-to-head comparison study of the immediate and long-lasting observations of the migraine-inducing, arterial, physiological and biochemical responses comparing PACAP38 and vasoactive intestinal polypeptide. In a double-blind crossover study 24 female migraine patients without aura were randomly allocated to intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We recorded incidence of migraine during and after infusion (0-24 h). Magnetic resonance angiography of selected extra- and intracranial arteries, blood samples (plasma PACAP38 and vasoactive intestinal polypeptide and serum tryptase), and vital signs (blood pressure, heart rate, respiratory frequency, and end-tidal pressure of CO2) was recorded before and up to 5 h after infusion. Twenty-two patients mean age 24 years (range 19-36) completed the study on both days. Sixteen patients (73%) reported migraine-like attacks after PACAP38 and four after vasoactive intestinal polypeptide (18%) infusion (P = 0.002). Three of four patients, who reported migraine-like attacks after vasoactive intestinal polypeptide, also reported attacks after PACAP38. Both peptides induced marked dilatation of the extracranial (P < 0.05), but not intracranial arteries (P > 0.05). PACAP38-induced vasodilatation was longer lasting (>2 h), whereas vasoactive intestinal polypeptide-induced dilatation was normalized after 2 h. We recorded elevated plasma PACAP38 at 1 h after the start of PACAP38 infusion only in those patients who later reported migraine attacks. Blood levels of vasoactive intestinal polypeptide and tryptase were unchanged after PACAP38 infusion. In conclusion, PACAP38-induced migraine was associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before onset of migraine-like attacks. PACAP38 has a much higher affinity for the PAC1 receptor and we therefore suggest that migraine induction by PACAP38 may be because of activation of the PAC1 receptor, which may be a future anti-migraine drug target.
Dynamic contrast-enhanced magnetic resonance imaging (DCE–MRI) is increasingly used to estimate permeability in situations with subtle blood–brain barrier (BBB) leakage. However, the method's ability ...to differentiate such low values from zero is unknown, and no consensus exists on optimal selection of total measurement duration, temporal resolution, and modeling approach under varying physiologic circumstances. To estimate accuracy and precision of the DCE–MRI method we generated simulated data using a two-compartment model and progressively down-sampled and truncated the data to mimic low temporal resolution and short total measurement duration. Model fit was performed with the Patlak, the extended Tofts, and the Tikhonov two-compartment (Tik-2CM) models. Overall, 17 healthy controls were scanned to obtain in vivo data. Long total measurement duration (15 minutes) and high temporal resolution (1.25 seconds) greatly improved accuracy and precision for all three models, enabling us to differentiate values of permeability as low as 0.1 ml/100 g/min from zero. The Patlak model yielded highest accuracy and precision for permeability values <0.3 ml/100 g/min, but for higher values the Tik-2CM performed best. Our results emphasize the importance of optimal parameter setup and model selection when characterizing low BBB permeability.
The goal of the present study was to examine the cerebral metabolism and vascular reactivity during extended breath-holds (ranging from 2 min 32 s to 7 min 0 s) and during a hypoxic challenge in ...freedivers and non-diver controls. Magnetic resonance imaging was used to measure the global cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2), and magnetic resonance spectroscopy was used to measure the cerebral lactate, glutamate+glutamine, N-acetylaspartate and phosphocreatine+creatine concentrations in the occipital lobe. Fifteen freedivers and seventeen non-diver controls participated. The freedivers showed remarkable increases in CBF (107%) during the breath-holds, compensating for arterial desaturation, and sustained cerebral oxygen delivery (CDO2). CMRO2 was unaffected throughout the breath-holds. During the hypoxic challenge, the freedivers had larger increases in blood flow in the sagittal sinus than the non-divers, and could sustain normal CDO2. No differences were found in lactate production, global CBF or CMRO2. We conclude that the mechanism for sustaining brain function during breath-holding in freedivers involves an extraordinary increase in perfusion, and that freedivers present evidence for higher cerebrovascular reactivity, but not for higher lactate-producing glycolysis during a hypoxic challenge compared to controls.
Key points
The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system.
BBB permeability changes occur in health and disease but ...measurement of BBB permeability in humans is not straightforward.
Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant Ki.
Here evidence is provided that Ki as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage.
These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease.
Blood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant Ki. To validate this method we compared measured Ki with biological expectations, namely (1) higher Ki in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher Ki in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher Ki in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole‐brain 3D DCE‐MRI at 3 T. Ki and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. Ki was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). Ki was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland–Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra‐class correlation coefficient showed moderate single measure consistency (0.610). Ki behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of Ki measured by DCE‐MRI as a marker of overall BBB leakage.
Key points
The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system.
BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward.
Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant Ki.
Here evidence is provided that Ki as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage.
These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease.
The origin of migraine pain is unknown, but may involve the dura mater. In unilateral migraine without aura, Khan et al. report that the middle meningeal artery is the only artery with greater ...circumference increase on the pain side versus non-pain side, suggesting a meningeal contribution to migraine headache.
Abstract
The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel calibre on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3 T high resolution magnetic resonance angiography. The middle meningeal artery was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal and external carotid arteries as additional extracranial segments, and the middle cerebral, the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar arteries as intracranial arterial segments. Magnetic resonance angiography scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 h after migraine onset. Thirty patients underwent magnetic resonance angiography scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans. At migraine onset, only the middle meningeal artery exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (P = 0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (P > 0.05), but exhibited bilateral dilation. Sumatriptan constricted all extracerebral arteries (P < 0.05). In the late phase of migraine, we found sustained bilateral dilation of the middle meningeal artery. In conclusion, onset of migraine is associated with increase in middle meningeal artery circumference specific to the head pain side. Our findings suggest that vasodilation of the middle meningeal artery may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.
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