Meningeal contribution to migraine pain: a magnetic resonance angiography study.

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.10.1093/brain/awy300_video1awy300media15983750185001.

Clinical importance of the middle meningeal artery: A review of the literature.

The middle meningeal artery (MMA) is a very important artery in neurosurgery. Many diseases, including dural arteriovenous fistula (DAVF), pseudoaneurysm, true aneurysm, traumatic arteriovenous fistula (AVF), moyamoya disease (MMD), recurrent chronic subdural hematoma (CSDH), migraine and meningioma, can involve the MMA. In these diseases, the lesions occur in either the MMA itself and treatment is necessary, or the MMA is used as the pathway to treat the lesions; therefore, the MMA is very important to the development and treatment of a variety of neurosurgical diseases. However, no systematic review describing the importance of MMA has been published. In this study, we used the PUBMED database to perform a review of the literature on the MMA to increase our understanding of its role in neurosurgery. After performing this review, we found that the MMA was commonly used to access DAVFs and meningiomas. Pseudoaneurysms and true aneurysms in the MMA can be effectively treated via endovascular or surgical removal. In MMD, the MMA plays a very important role in the development of collateral circulation and indirect revascularization. For recurrent CDSHs, after burr hole irrigation and drainage have failed, MMA embolization may be attempted. The MMA can also contribute to the occurrence and treatment of migraines. Because the ophthalmic artery can ectopically originate from the MMA, caution must be taken to avoid causing damage to the MMA during operations.

A ruptured aneurysm arising at the leptomeningeal collateral circulation from the extracranial vertebral artery to the posterior inferior cerebellar artery associated with bilateral vertebral artery occlusion.

We report an extremely rare case of a small ruptured aneurysm of the leptomeningeal collateral circulation from the vertebral artery (VA) to the posterior inferior cerebellar artery (PICA); this aneurysm was associated with bilateral VA occlusion. A 72-year-old woman with sudden headache, nausea, and subarachnoid hemorrhage (SAH) was admitted to our hospital. On admission, no evidence of cerebral signs or cranial nerve palsy was found. Computed tomography imaging showed SAH predominantly in the posterior fossa, and digital subtraction angiography revealed bilateral VA occlusion and the left VA aneurysm located proximal to the VA union. In addition, a small aneurysm was observed at the leptomeningeal collateral circulation located between the extracranial left VA and the left PICA. The patient underwent radical surgery on the day of the onset of the symptoms associated with SAH. However, the VA aneurysm was unruptured and surgically trapped. The small aneurysm arising at the leptomeningeal collateral circulation was ruptured during the surgery and was electrocoagulated; the collateral circulation was preserved, and no neurologic deficits were observed. The postoperative course was uneventful. SAH with the occlusion of major vessels should be diagnosed with utmost caution to allow preoperative neurologic and radiological assessments.

Functional and molecular characterization of prostaglandin E2 dilatory receptors in the rat craniovascular system in relevance to migraine.

INTRODUCTION: Migraine pain is thought to involve an increase in trigeminal nerve terminal activity around large cerebral and meningeal arteries, leading to vasodilatation. Because prostaglandin E(2) (PGE(2)) is elevated in cephalic venous blood during migraine attacks, and is also capable of inducing headache in healthy volunteers, we hypothesize that PGE(2) dilatory receptors, EP(2) and EP(4), mediate the response. MATERIALS AND METHODS: By the use of specific agonists and antagonists, the dilatory effect of PGE(2) was characterized in rat cranial arteries by use of in vivo and in vitro methods. Furthermore, EP(2) and EP(4) quantitative messenger RNA (mRNA) receptor expression was studied in the rat craniovascular system. RESULTS: Our results suggest that EP(4), and to a lesser degree EP(2), receptors mediate the dilatory effect of PGE(2) in the craniovascular system in rats. Thus, antagonism of these receptors might be of therapeutic relevance in migraine.

Distribution of artemin and GFRalpha3 labeled nerve fibers in the dura mater of rat: artemin and GFRalpha3 in the dura.

OBJECTIVE: We examined the distribution of artemin and its receptor, glial cell line-derived neurotrophic factor family receptor alpha3 (GFRalpha3), in the dura mater of rats. BACKGROUND: Artemin, a member of the glial cell line-derived neurotrophic factor family, is a vasculature-derived growth factor shown to regulate migration of sympathetic neuroblasts and targeting of sympathetic innervation. The artemin receptor, GFRalpha3, is present in both sympathetic efferents and a subpopulation of nociceptive afferents. Recent evidence has shown that artemin may contribute to inflammatory hyperalgesia. The extent to which artemin is present in the dural vasculature and its relationship to GFRalpha3 containing fibers have yet to be investigated. METHODS: We used retrograde labeling, double and triple labeling with immunohistochemistry on the dura mater and trigeminal ganglia of female Sprague-Dawley rats. RESULTS: Artemin-like immunoreactivity (-LI) was detected in the smooth muscle of dural vasculature. GFRalpha3-LI was present in nerve fibers that closely associated with tyrosine hydroxylase or calcitonin gene-related peptide (CGRP). CGRP-LI and transient receptor potential ion channel 1 (TRPV1)-LI were present in all GFRalpha3-positive dural afferents, which constituted 22% of the total population of dural afferents. CONCLUSIONS: These anatomical results support the hypothesis that artemin contributes to dural afferent activity, and possibly migraine pain, through modulation of both primary afferent and sympathetic systems.

DynaCT Enhancement of Subdural Membranes After Middle Meningeal Artery Embolization: Insights into Pathophysiology.

OBJECTIVE: Middle meningeal artery (MMA) embolization could be an effective method of inhibiting neovascularization of the subdural capsular membrane and preventing hematoma maintenance. We sought to better understand how the MMA might affect subdural hematoma physiology and how this process might be modified by embolization. METHODS: We performed a retrospective review of 27 patients with 29 subdural hematomas (SDHs) who had undergone MMA embolization from July 2018 to May 2019. Of the 27 patients, 8 had undergone postembolization DynaCT imaging studies and were included in the present study. RESULTS: The average patient age was 75 years. The baseline noncontrast-enhanced cranial computed tomography (CT) scans showed the presence of a hematoma membrane in all 8 patients. The postembolization DynaCT scans of all patients demonstrated enhancement of all 4 components (i.e., dura, capsular membrane, septations, and subdural hematoma fluid). All patients had a minimum of 60-day imaging and clinical follow-up data available. The average decrease in SDH volume at the last follow-up examination was 87% compared with that at baseline. A significant difference was found between the average baseline and average last follow-up SDH volume (P < 0.0001, paired t test) in all 8 patients. The average interval from the date of the procedure to the last follow-up scan was 89 days (range, 61-122 days). No patient experienced postembolization complications, subsequent SDH drainage, or mortality. CONCLUSIONS: Our data lend support to the theory of contiguous vascular networks between the MMA and SDH membranes. Targeting these leaky vascular networks might remove the source of hematoma accumulation. These data add to the pathophysiological understanding of the disease and suggests potential insights into the mechanism of action of MMA embolization.

Evolution of Developmental Venous Anomalies in the Setting of a Torcular Dural Arteriovenous Fistula and Cerebrofacial Venous Metameric Syndrome.

BACKGROUND: We describe evolution of a developmental venous anomaly (DVA) over time in a patient with a complex intracranial vascular malformation. CASE DESCRIPTION: A 26-year-old male patient initially presented with a scalp vascular malformation and was later diagnosed to have a torcular dural arteriovenous fistula resembling a dural sinus malformation. The dural fistula increased in size over 4 years. The dural fistula also was associated with multiple complex developmental venous anomalies draining the bilateral cerebral hemispheres and cerebellum. The DVA was only faintly demonstrated on the baseline magnetic resonance imaging but appeared to increase in size and extent over time as the dural arteriovenous fistula developed more aggressive angioarchitecture features. In addition to the evolution manifestation of the DVAs, the patient developed multiple de novo cavernous malformations in the venous radicles of the DVA. Increased venous hypertension in the superficial venous system from the dural fistula likely resulted in growth of the DVAs, as they served as the primary means of venous drainage for the bilateral cerebral hemispheres. The patient also had reopening of the persistent falcine sinus, which was not present at baseline. CONCLUSIONS: This would be the first reported case of growth or evolution of a DVA in association with a dural arteriovenous fistula in an adult patient and highlights the dynamic nature of both the medullary venous and dural venous sinuses of the cerebral venous system, even into adulthood.

Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan.

BACKGROUND AND PURPOSE: Triptans are 5-HT1B/1D receptor agonists (that also display 5-HT1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan. EXPERIMENTAL APPROACH: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT1A , 5-HT1B , 5-HT1D , 5-ht1E , 5-HT1F , 5-HT2A , 5-HT2B , and 5-HT7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration-response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured. KEY RESULTS: Lasmiditan showed high selectivity for 5-HT1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested. CONCLUSIONS AND IMPLICATIONS: Lasmiditan is a selective 5-HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans.

Intracranial dural arterio-venous fistula.

Intracranial dural arteriovenous fistulae are rare, acquired lesions that may present with intracranial haemorrhage or progressive neurological deficits. Their cause is uncertain, although they are often associated with intracranial venous thrombosis. Their importance lies in the fact that they are potentially curable by endovascular or neurosurgical procedures, but easily missed on routine brain imaging. In addition, clinical presentation is variable, with no easily recognisable "syndrome". A high index of suspicion is therefore required, as well as familiarity with the characteristic radiological abnormalities seen on appropriate imaging.

Effect of two novel CGRP-binding compounds in a closed cranial window rat model.

We investigated the in vivo effects of two novel calcitonin gene-related peptide (CGRP) binding molecules in the genuine closed cranial window model in the rat. The RNA-Spiegelmer (NOX-C89) and the monoclonal CGRP antibody are CGRP scavengers and might be used as an alternative to CGRP-receptor antagonists in the treatment of migraine. Rats were anaesthetized and a closed cranial window established. Changes in dural and pial artery diameter and mean arterial blood pressure were measured simultaneously. Infusion of the RNA-Spiegelmer or the CGRP antibody alone had no effect on the arteries or the mean arterial blood pressure. We then used a bolus of 0.3 microg/kg CGRP (n=6) or electrical stimulation (25 V, 5 Hz, 1 ms pulse width and of 10 s of duration) (n=6) to induce dilatation of dural and pial arteries (mediated via CGRP-receptors). Pre-treatment with the RNA-Spiegelmer inhibited CGRP-induced vasodilatation of the dural artery (from 38+/-17% to 7+/-3%) and the pial artery (from 14+/-1% to 3+/-2%) (P<0.05). The RNA-Spiegelmer, however, did not significantly inhibit dilatation induced by electrical stimulation (P>0.05). The CGRP antibody caused a significant reduction of the dural artery diameter caused by intravenous CGRP-infusion (from 23+/-5% to 12+/-3%) (P<0.05), but did not inhibit dilatation caused by electrical stimulation (P>0.05). In conclusion, the CGRP scavengers effectively inhibited the effect of circulating CGRP but do not modify the effect of electrical stimulation and the consequent liberation of CGRP from perivascular sensory nerve fibres.

Expression of angiogenic growth factor in the rat DAVF model.

OBJECTIVE: The precise mechanisms responsible for the development and growth of dural arteriovenous fistula (DAVF) remain unclear, but it has been hypothesized that vascular endothelial growth factor (VEGF) might be involved in the pathogenesis. The aim of this study was to examine the expression of VEGF in the rat DAVF model. METHODS: Forty-five Sprague-Dawley rats were used in two experiments. In Experiment 1 (n = 20, including sham-operated controls), VEGF expression was analysed by Western blots in three different rat DAVF models: model I: common carotid artery-external jugular vein (CCA-EJV) anastomosis (n = 5); model II: sagittal sinus thrombosis and bipolar coagulation of the vein draining the transverse sinus (n = 5); model III: CCA-EJV anastomosis and bipolar coagulation of the vein draining the transverse sinus and sagittal sinus thrombosis to induce venous hypertension (n = 5). Based on the results of Experiment 1, Western blots were performed at weekly intervals 1, 2 and 3 weeks in Experiment 2 following induction of venous hypertension in model III (n = 5 at each time point and n = 5 sham controls); in addition, VEGF expression was immunohistochemically examined in the dura and the brain near the occluded sinus in five model III animals after 1 week. RESULTS: In Experiment 1, Western blot analysis showed barely detectable bands with molecular weights of 45 kD, corresponding to VEGF, in the sham group, but the highest level of VEGF was induced in model III, followed by models I and II (model III>model I>model II). In Experiment 2, the expression of VEGF peaked 1 week after induction of venous hypertension in model III, decreasing in a linear fashion over 2 and 3 weeks (week 1>weeks 2 and 3). The expression of immunoreactive VEGF was restricted in the connective tissue and the endothelial layer of the dura matter, cerebral cortical tissue and neurons of the basal ganglia. CONCLUSION: Our results strongly suggest a possible contribution of an angiogenic factor to the growth of DAVF. Venous ischemia by venous hypertension might be a mechanism for inducing up-regulation of angiogenic factor expression.

Development of unusual collateral channel from the posterior meningeal artery after endovascular proximal occlusion of the posterior inferior cerebellar artery.

A 38-year-old man presented with a dissecting aneurysm of the left proximal posterior inferior cerebellar artery (PICA) manifesting as Wallenberg's syndrome. The patient was treated by endovascular occlusion of the aneurysm and parent artery. Immediately after the treatment, the PICA territory was supplied by collateral circulation via the ipsilateral anterior inferior cerebellar artery. Seven days later, endogenous revascularization of the distal PICA territory had occurred via collateral circulation from the posterior meningeal artery (PMA). This unusual collateral circulation was thought to occur through a pre-existing anastomotic channel between the primitive vessels of the PICA and the PMA during subclinical hypoperfusion of the distal PICA territory. This unusual case demonstrates the potential for delayed development of collateral circulation from the PMA to the PICA territory.

Complementary Relation Between Direct and Indirect Bypass in Progress of Collateral Circulation in Moyamoya Disease.

BACKGROUND: One of the important aims of surgery for moyamoya disease is to establish indirect revascularization. The purpose of this study was to assess the progress of the middle meningeal artery (MMA) after our novel preservation method and to evaluate the relation between direct and indirect bypass in the chronic stage. METHODS: A total of 24 hemispheric sides of 19 patients with moyamoya disease were included in this study. Craniotomy was performed with preservation of the MMA during the procedure, then direct bypass was carried out. The relationship between anatomic variations of the MMA and success rate of preserving the MMA during craniotomy was noted. The alteration of the MMA and superficial temporal artery (STA) diameters was then evaluated using magnetic resonance imaging, and the correlation between the MMA and the STA in the chronic stage was examined. RESULTS: In total, the MMA was preserved during craniotomy in 20 hemispheric sides (83.3%). During the 3-year follow-up period, the MMA and STA diameters were significantly increased. At 3 years after surgery, the alteration of the MMA diameter was significantly more marked in pediatric cases than in adult cases, and MMA diameter was moderately but significantly negatively correlated with STA diameter. CONCLUSIONS: In moyamoya disease, the MMA could be developed as a pathway for indirect revascularization even after simple preservation, especially in pediatric patients. The progress of the MMA and the STA occurs through their synergistic interaction, and the balance might be decided based on their complementary relations in the chronic stage.

An update on migraine pathophysiology and mechanism-based pharmacotherapeutics for migraine.

The pathophysiologic mechanisms of migraine are complex but appear to primarily involve the trigeminovascular system. Within this system, a number of factors may contribute to the generation and perpetuation of pathophysiologic changes leading to migraine. Current migraine medications exert their therapeutic benefit via actions at various points relating to these pathophysiologic changes. However, no single agent currently exists that targets all the hypothesized anatomical and cellular mechanisms of the migraine process. A future strategy for achieving optimal therapeutic effect and improving clinical outcomes in migraine involves rational targeting of the multiple mechanisms involved in its pathophysiology; conceptually, this may require concomitant use of multiple pharmacotherapeutic agents.

Trigeminocardiac reflex caused by selective angiography of the middle meningeal artery.

We describe an interesting case of trigeminocardiac reflex (TCR) caused by selective angiography of the middle meningeal artery (MMA). A 28-year-old woman presented with a symptomatic meningioma. Preoperative tumour embolisation was performed. In the procedure, when selective MMA angiography was done with Omnipaque 300 mg I/mL for 3 mL by manual injection, the patient complained of flashing lights in her eye followed by vomiting and bradycardia down to 40 bpm without increased intracranial pressure signs. On selective MMA angiography, the choroidal crescent and arteries of the periorbital region were opacified by anastomosis from the MMA via the meningo-ophthalmic artery. We diagnosed that her symptoms were caused by selective MMA angiography leading to high pressure stimulation towards the ophthalmic nerve innervation around the orbit as a TCR. We suggest that the operator should be prepared to manage TCR during treatment with expected selective MMA angiography, and gentle low pressure contrast injection should be attempted.

Anatomy of the Middle Meningeal Artery

Introduction The middle meningeal artery (MMA) is an important artery in neurosurgery. As the largest branch of the maxillary artery, it provides nutrition to the meninges and to the frontal and parietal regions. Diseases, including dural arteriovenous fistula (DAVF), pseudoaneurysm, true aneurysm, traumatic arteriovenous fistula (TAVF), Moya-Moya disease (MMD), recurrent chronic subdural hematoma (CSDH), migraine, and meningioma,may be related to the MMA. The aim of the present study is to describe the anatomy of the MMA and to correlate it with brain diseases. Methods A literature review was performed using the PubMed, Scielo, Scientific Direct, Ebsco, LILACS, TripDataBase and Cochrane databases, with the following descriptors: neurosurgery, neuroanatomy, meninges and blood supply. Discussion The MMA is embedded in a cranial groove, and traumatic or iatrogenic factors can result in MMA-associated pseudoaneurysms or arteriovenous fistulas (AVFs). In hemodynamic stress, true aneurysms can develop. Arteriovenous fistulas, pseudoaneurysms, and true aneurysms can be effectively treated by endovascular or surgical removal. In MMD, the MMA plays a role in the development and in the improvement of collateral circulation. Finally, in cases of CSDH, when standard surgery and drainage fail, MMA embolization can constitute a great alternative. Conclusion The MMA is a relevant structure for the understanding of neurosurgical diseases. In conclusion, every neurosurgeon must know the anatomy of the MMA sufficiently to correlate it with the diagnosed pathology, thus obtaining treatment effectiveness and preventing brain lesion.

Magnetic resonance angiography evaluation of external carotid artery tributaries in moyamoya disease.

BACKGROUND AND PURPOSE: High-resolution magnetic resonance (MR) image has been introduced to diagnose and follow-up moyamoya disease and visualized moyamoya vessels and internal carotid artery stenosis. This study was performed to assess the utility of MR angiography (MRA) for the evaluation of anastomotic channels through the external carotid artery (ECA) in moyamoya disease patients. METHODS: Twenty patients with moyamoya disease were reviewed. The cortical anastomosis and superficial temporal artery (STA), middle meningeal artery, and deep temporal artery by MRA were evaluated and were compared with those by digital subtraction angiography if obtained. Fifteen patients (24 hemispheres) underwent bypass surgery, including encephaloduroarteriosynangiosis in 14 hemispheres and STA-middle cerebral artery anastomosis with encephalomyosinangiosis in 10 hemispheres. Five patients did not undergo any surgery. RESULTS: MRA could show these vessels and the patency of anastomosis formed by the surgery and also showed naturally formed anastomosis and ECA tributaries in the patients who did not undergo any surgery. CONCLUSION: MRA provides useful information for follow-up evaluation on the development of the ECA system in moyamoya disease.

Permeability Imaging as a Biomarker of Leptomeningeal Collateral Flow in Patients with Intracranial Arterial Stenosis.

Different methods of angiography are of great clinical utility; however, it still remains unstandardized as which method would be suitable to determine cerebral collateral circulation. Here we compared digital subtraction angiography (DSA), computer tomography angiography (CTA) and dynamic contrast-enhanced T1-weighted imaging magnetic resonance imaging (MRI) findings in seven patients with severe intracranial arterial stenosis, and determine whether volume transfer constant (K(trans)) maps of permeability imaging could be used as the biomarkers of cerebral collateral circulation. We retrospectively reviewed seven adult patients with severe intracranial arterial stenosis or occlusion with a complete parenchymal and vascular imaging work-up. DSA, CTA source imaging (CTA-SI), arterial spin labeling (ASL), and K(trans) maps were used to assess their collateral flow. Cohen's Kappa coefficient was calculated to test the consistency of their collateral scores. A reasonable agreement was found between DSA and K(trans) maps (Kappa = 0.502, P < 0.001) when all 15 regional vascular sites were included, and a better agreement found after exclusion of perforating artery territories (N = 10 sites, Kappa = 0.766, P < 0.001). The agreement between CTA-SI and DSA was moderate on all 15 sites (Kappa = 0.413, P < 0.001) and 10 sites (Kappa = 0.329, P < 0.001). The agreement between ASL and DSA was least favorable, no matter for all 15 sites (Kappa = 0.270, P < 0.001) or 10 sites (Kappa = 0.205, P = 0.002). K(trans) maps are useful and promising for leptomeningeal collateral assessment, when compared to CTA-SI or ASL. Further studies are requited for verify its validity in a large registry of patients.

Extracranial blood flow, pain and tenderness in migraine. Clinical and experimental studies.

Migraine pain has traditionally been ascribed to dilatation of primarily extracranial arteries. Such dilatation has, however, not been demonstrated so far. Studies of microcirculation reveal no major hyperperfusion or ischemia in the temporal muscle or the subcutaneous tissue in the temporal region during attacks of migraine. However, a reduction in the orthostatic reactivity of the subcutaneous arterioles was observed on the side of the headache. Increased tenderness of the pericranial myofascial tissues is observed during migraine attacks, particularly on the side of the headache. Increased tension of pericranial muscles on the other hand is not a constant finding and migraine attacks are not induced by experimentally increased tension of the temporal and masseter muscles. Extracranial pain and tenderness may, however, be induced experimentally by intramuscular injections of hypertonic saline and potassium chloride as well as of endogenous substances like bradykinin with 5-hydroxytryptamine and bradykinin with substance P. The extracranial arteries and myofascial structures are both supplied by unmyelinated trigeminal sensory nerve fibers containing a variety of neuropeptides which are released during migraine attacks. Axonal reflexes between extracranial arteries and neighbouring myofascial tissues as well as referred pain mechanisms may account for the observed tenderness during migraine attacks.