The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence,... Show moreThe middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks. Show less
Christensen, C.E.; Younis, S.; Lindberg, U.; Boer, V.O.; Koning, P. de; Petersen, E.T.; ... ; Ashina, M. 2019
After publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found... Show moreAfter publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found below. Show less
Christensen, C.E.; Younis, S.; Lindberg, U.; Boer, V.O.; Koning, P. de; Petersen, E.T.; ... ; Ashina, M. 2019
BackgroundSildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0tesla (T) MR angiography. Here we hypothesized that an... Show moreBackgroundSildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.MethodsFive subjects completed two sessions at respectively 3.0T and 7.0T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design.ResultsStandard deviations of arterial circumference revealed no difference between 3.0T and 7.0T measurements (p=0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p<0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0T and 7.0T.ConclusionsOur findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies.Trial registrationThe study is part of a parent study, which is registered at ClinicalTrials.gov (NCT03143465). Show less
Christensen, C.E.; Amin, F.M.; Younis, S.; Lindberg, U.; Koning, P. de; Petersen, E.T.; ... ; Ashina, M. 2019
Background Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have... Show moreBackground Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined invivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery.Methods In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days.Results Twelve healthy volunteers completed the study. The area under the curve(Baseline-120min) was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p=0.013; sildenafil, p=0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p=0.0003; sildenafil, p=0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T-30min) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T-30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T-30min) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil (T-120min).Conclusion An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil. Show less
Khan, S.; Amin, F.M.; Christensen, C.E.; Ghanizada, H.; Younis, S.; Olinger, A.C.R.; ... ; Ashina, M. 2019
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... Show moreThe 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.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 (ICA(cerebral) and ICA(cavernous)), 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. Show less
Khan, S.; Amin, F.M.; Christensen, C.E.; Ghanizada, H.; Younis, S.; Andersen, A.C.R.; ... ; Ashina, M. 2018
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... Show moreObjective: 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; 69: 635-645 Show less
Asghar, M.S.; Hansen, A.E.; Kapijimpanga, T.; Geest, R.J. van der; Koning, P. van der; Larsson, H.B.W.; ... ; Ashina, M. 2010
Background: Calcitonin gene-related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However... Show moreBackground: Calcitonin gene-related peptide (CGRP) plays a fundamental role in the pathophysiology of neurovascular headaches. CGRP infusion causes headache and dilation of cranial vessels. However, it is unknown to what extent CGRP-induced vasodilation contributes to immediate head pain and whether the migraine-specific abortive drug sumatriptan, a 5-hydroxytryptamine 1B/1D agonist, inhibits CGRP-induced immediate vasodilation and headache. Methods: We performed a double-blind, randomized, placebo-controlled, crossover study in 18 healthy volunteers. We recorded circumference changes of the middle meningeal artery (MMA) and middle cerebral artery (MCA) using magnetic resonance angiography before and after infusion (20 minutes) of 1.5 mu g/min human alpha CGRP or placebo (isotonic saline) as well as after a 6-mg sumatriptan subcutaneous injection. Results: Compared with placebo, CGRP caused significant dilation of MMA (p = 0.006) and no dilation of MCA (p = 0.69). Sumatriptan caused a marked contraction of MMA (15%-25.2%) and marginal contraction of MCA (3.9% to 5.3%). Explorative analysis revealed that sumatriptan had a more selective action on MMA compared with MCA on the CGRP day (p < 0.0001) and on the placebo day (p = 0.007). Conclusion: These data suggest that exogenous CGRP dilates extracranial vessels and not intracranial, and that sumatriptan exerts part of its antinociceptive action by constricting MMA and not MCA. Classification of evidence: This study provides Class I evidence that IV GCRP causes dilation of the MMA but not the MCA in healthy volunteers, and that sumatriptan reverses the dilation of the MMA caused by CGRP. Neurology (R) 2010;75:1520-1526 Show less
