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Abstract

In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders.

Keywords

Blood–brain barrier cerebral blood flow migraine parasympathetic nervous system sympathetic nervous system

Introduction

Migraine is a frequent primary headache disorder, with higher prevalence in females (15.5%) than males (4.5%),¹ and associated with clinical symptoms (typical headache, and phonophobia/photophobia/nausea/vomiting that occur over 4–72 h).² On the contrary, cluster headache is more prevalent in males than females for most age groups.³ The origin of headache attacks is still under discussion, with particular focus on whether they represent a vascular or neurogenic disorder.^4,5 During the different phases of the migraine attack (premonitory and during attacks), there are variations in cerebral blood flow (CBF), coinciding with changes in brain activity, observed in the somatosensory cortex, brainstem and thalamus.^6,7 In headache-free periods (inter-ictal), elevated CBF in the primary somatosensory cortex has been reported for migraineurs. This effect was positively correlated to headache attack frequency, but also to the number of cutaneous allodynia symptoms.⁶ During headache attacks, autonomic and sensory ganglia are known to be variably activated and sensitized,^8,9 which gives rise to neurotransmitter release, believed to be important in the migraine pathophysiology.^10,11 In particular, trigeminal ganglion (TG) stimulation in cats resulted in increased CBF and calcitonin gene-related peptide (CGRP) release.¹² Several signaling molecules are involved in both migraine and innervation of the cerebral vasculature.

The cerebral vasculature is known to be innervated by (i) sympathetic nerves storing adenosine triphosphate (ATP), noradrenaline and neuropeptide Y (NPY), (ii) parasympathetic nerves with acetylcholine, vasoactive intestinal peptide (VIP), peptide histidine methionine, pituitary adenylate cyclase-activating peptide (PACAP) and nitric oxide (NO), and (iii) sensory nerves containing CGRP, PACAP, NO, substance P (SP) and neurokinin A (NKA).^13,14 The extrinsic innervation ends close to the entry of the vasculature into the brain parenchyma; a transition zone in the Virchow-Robin space. Moreover, the intraparenchymal nerve supply to arterioles and microvessels stems primarily from central nervous system (CNS) neurons.¹⁴ Therefore, it is necessary to discuss migraine in the light of extrinsic and intrinsic neural inputs, and their role in regulation of CBF.

The link between headache, CNS symptoms, intracranial vessel diameter and regulation of blood flow has long been pursued. In general, primary headaches are considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations.^15–17 Several primary headache theories have been proposed over time, with the purpose of elucidating the underlying cause of headache attacks and associated characteristics. Early studies on involvement of extracranial vasodilation and a link between intracranial vasospasm and cortical spreading depression (CSD) in migraine with aura led to the vascular theory of migraine, originally forwarded by Wolff in the early 1940s.^18,19 Although a pure vascular theory has now lost its role as the leading hypothesis to explain migraine, involvement of extracranial and intracranial vasculature has persisted over time as an etiological or coexisting factor.^20,21 Direct experimental evidence, contrary to the vascular theory, came from a magnetic resonance angiography study showing no/minor alterations in the diameter of meningeal and cerebral arteries in genuine migraine attacks.²² Nevertheless, this study is not entirely conclusive, as the intracranial middle meningeal artery (MMA) was not measured due to technical limitations.²³

Today CSD remains one of the possible early links between vascular observations and the neurogenic theory. CSD is a self-propagating wave of neuronal and glial cortical depolarization resulting in biophysical and biochemical alterations such as changes in parenchymal blood flow and ionic concentrations.²⁴ The aura, a clinical symptom (mostly visual) seen in about 20–30% migraineurs,²⁵ is supposedly due to CSD.^26,27 It has been suggested that CSD directly activates trigeminal sensory nerve terminals in dura mater/meninges followed by trigeminovascular system activation.^24,28 For decades, activation and sensitization of the trigeminovascular system have been considered a pathophysiological mechanism/consequence behind primary headaches.^29–31 Interestingly, CSD not only affects meningeal arteries, but also cortical cerebral arterioles and CBF.³² An alternative hypothesis involves activation of CNS regions by CSD which in turn, via thalamus and brainstem, causes activation of the trigeminovascular system with dural inflammation being secondary to the CNS activation. Moreover, during the headache phase in genuine attacks, waves of flow reductions slowly spread over the cortex bilaterally. This pattern resembled CSD even though the subject did not have obvious aura symptoms.³³ Other studies also report the occurrence of local depression of CBF in migraine.³⁴ More details on this research topic has been discussed by Pietrobon and Moskowitz^26,27 and by Ayata and Lauritzen.³⁵

Today, leading scientists advocate that already in the premonitory phase of an acute migraine attack, distinct blood flow alterations within, e.g. hypothalamus-thalamus and the adjacent brainstem (periaqueductal gray) can be observed.^36,37 The proposal of a “migraine generator” originates from Weiller et al.³⁸ demonstrating activation of brain regions such as the periaqueductal gray, raphe nuclei, and locus coeruleus in the early phase of a migraine attack. Following injection of sumatriptan for acute treatment of migraine, pain subsided but the areas remained activated. After some hours, the pain returned, probably due to disappearance of the triptan from the involved receptors.³⁸ Thus, evidence suggests that migraine pathophysiology includes dysfunction of subcortical structures such as diencephalic and brainstem nuclei which can modulate the trigeminovascular system and perhaps also participate in CSD generation.³⁹

Complexity of neurovascular coupling and CBF

Brain homeostasis is known to be controlled by a tight regulation between neuronal function, local blood flow and maintenance of neurovascular coupling.^40,41 More precisely, the CBF is controlled by (i) autoregulation, maintenance of adequate CBF regardless of blood pressure (BP) fluctuations (within some limits),^42,43 (ii) chemical and metabolic factors, e.g. interstitial pH⁴⁴ and CO₂,⁴⁵ and (iii) neurogenic factors such as perivascular innervation.^46,47 Regulatory mechanisms of CBF depend on variations in the rate of local brain metabolism.⁴⁸

The changes of CBF in primary headaches are obviously not as drastic as observed in ischemic stroke. Weiller et al.³⁸ reported minor changes in cortical blood flow which was significant only if all migraine patients were normalized and grouped (about 5% of resting flow). In migraineurs with aura, a reduction in CBF was observed closely in time to the aura symptoms.^49,50 In the interictal period, Loehrer et al.⁵¹ reported a higher total and parenchymal CBF in migraineurs compared to controls, suggested to be driven by a higher basilar artery flow. In experimental animals, induction of CSD causes an abrupt rise in CBF within a minute followed by depression of function and flow.⁵²

Relevant for primary headaches, an association between neurovascular dysfunction and CSD has been proposed.^52,53 It is important to clarify that the intraparenchymal neurovascular system is distinctly different from that of the large cerebral arteries and arterioles located around the brain and leading into the intraparenchymal system.^14,41 The extraparenchymal vasculature (arteries belonging to the circle of Willis, and arteries located on the cortical surface) receives a dense supply of perivascular nerves that originate in cranial ganglia.⁴⁷ The intraparenchymal neurovascular system is thin and mainly contains pericytes and endothelial cells. Their connections with the local environment come from local neurons and astrocytes, inter alia. They are not supplied by innervation from the cranial ganglia, and⁴⁷ hence there are two different sites of neuronal regulation of the cerebral circulation.

Extrinsic and intrinsic cerebral vasculature: Neurogenic factors and neurotransmitter release

Extrinsic perivascular nerves in the cerebral circulation and dura mater

Three centuries ago, Thomas Willis noted nerve profiles on major cerebral arteries and speculated on a role in regulation of brain blood flow.⁵⁴ The role of perivascular nerves took a step forward in 1967 when Nielsen and Owman⁵⁵ demonstrated sympathetic noradrenaline-containing perivascular nerves. As a result, a new era began with analysis and demonstration of a multitude of associated receptors.⁵⁶ Originally, it was thought that they were an anomaly based on experiments showing that denervation had no effect on basic regulation of flow-metabolism coupling, chemical control or autoregulation.^47,57 However, it is now known that the upper and lower limits of autoregulation are modified by sympathetic nerves arising from the superior cervical ganglia (SCG).⁵⁸ The parasympathetic fibers originate from the sphenopalatine (SPG) and otic ganglia (OTG), storing acetylcholine and numerous neuropeptides (the first to be found was VIP⁵⁹). Currently, these ganglia have been linked to facial symptoms in, e.g. cluster headache.⁶⁰ The third system innervating the cerebral circulation is the sensory system which originates in the TG.¹³ For long, we were seeking a role of this system, and in 1986, we reported that it was a reflex designated to counterbalance any reductions in local CBF.⁶¹ Recent work has focused on understanding of the intimate coupling process. CBF alterations, induced by neuronal responses, have been studied by functional magnetic resonance imaging (fMRI) as an indirect measure of neurovascular coupling.⁶² Transient photophobia was investigated by fMRI in a healthy human subject and was found to be associated with trigeminal system activation.⁶³

Advances in our understanding of the neuronal innervation of the extraparenchymal cerebral vasculature

In the 1970s, characterization of neurotransmitters in perivascular nerve fibers was demonstrated in more detail due to the availability of novel histochemical methodologies, immunohistochemistry in particular. This increased the theoretical understanding of possible pathophysiological mechanisms involved in primary headaches (e.g. regulatory mechanisms of CBF). The origin of perivascular nerve endings on cerebral vasculature^64,65 has been investigated by a nerve tracing and immunohistochemical localization study. Using True Blue applied on the vessel walls, we traced the dye to both uni- and bilateral ganglia, and showed co-localizations with NPY (sympathetic), VIP (parasympathetic) and SP and CGRP (sensory).^66–68 The brainstem was subsequently analyzed using transganglionic tracers and the sensory system was found to localize in the trigeminal nucleus caudalis and brainstem C1-3, laminae I-II.^69–71 Innervation studies of the trigeminal system showed that CGRP and SP originate in the TG.⁷² Another study showed that PACAP-containing rat nerve fibers, innervating the extrinsic cerebral vasculature, primarily originate from neurons in the parasympathetic SPG and OTG and to a lesser extent from neurons in the sensory TG.⁶⁴ Most of PACAP and VIP were expressed in the SPG and OTG while PACAP only showed minor expression in TG,⁷³ also shown in man.^74,75 The TG has, by far, retained most focus over time when investigating the pathophysiology of primary headaches. Neuronal sensory innervation of cerebral blood vessels, by vasoactive neuropeptides, has been linked to the TG.^64,72 Electrical stimulation of TG resulted in increased CGRP, PACAP, SP and NKA levels,^29,76–78 in agreement with immunohistochemical localization studies investigating TG and perivascular nerve fibers.^64,79,80 PACAP immunoreactivity was also found in nerve fibers on cerebral arteries in cats.⁸¹ Interestingly, PACAP-38 was increased in the plasma and trigeminal nucleus caudalis, but not in the TG itself or in the spinal cord⁷⁸ indicating stimulated signaling pathways upon TG activation.

Somatic afferents of the trigeminal nerve innervate considerable regions of the face, scalp, and meninges amongst others.⁸² In coherence, increased ipsilateral facial skin blood flow is induced by experimental activation of TG in rats.⁸³ The trigeminal nerve is linked with the SPG,^84,85 which has gained interest, particularly in cluster headache research. Repetitive transnasal blockade of SPG has shown effectiveness in treating both cluster headache⁸⁶ and chronic migraine.^87,88 The structure is located in the pterygopalatine fossa below the maxillary nerve (trigeminal nerve branch, V₂) where sympathetic and parasympathetic nerve fibers pass through. The superior salivary nucleus in the pons is connected to the SPG through nerve fibers⁸² followed by nerve projections to the cranial vasculature from the parasympathetic ganglion.³⁹ Nerve projections originating from the SPG were traced to the internal ethmoidal, internal carotid and cerebral arteries by anterograde labelling of nerve fibers.⁸⁹ A study observed increased CBF in the ipsilateral and contralateral parietal cortex as a response to electrical SPG stimulation in rats⁹⁰ possibly as a response to neurotransmitter release.⁹¹ Immunohistochemical localization studies revealed expression of PACAP, VIP and NO synthase (NOS) in rat and human SPG^85,92 and expression of CGRP nerve fibers likely from the TG.⁸⁴ SPG extirpation, on the other hand, affects expression of VIP and acetylcholine in cerebrovascular structures.⁹³ Together these results indicate that there is a link between autonomic and sensory ganglia, CBF and migraine.

Nerve projections from the SCG, cervical C2 dorsal root ganglia (DRG) and OTG onto extrinsic cerebral arteries have been studied by retrograde tracing showing that the ganglia contain NPY, CGRP and SP, and VIP immunoreactive neurons, respectively.⁶⁶ The effects of these ganglia have been investigated less intensively compared to that of the TG and SPG with respect to primary headaches. In general, sympathetic nervous activity has been associated with cerebrovascular constriction and parasympathetic nervous activity with cerebrovascular dilation⁴¹ of which parasympathetic activation is known to result in sympathetic hypoactivity and vice versa.⁹⁴ DRG has been associated with neuropathic pain as a response to pathological changes in the structure.⁹⁵ Since headache only seems to arise as a response to C1–C3 nerve innervations referred to as cervicogenic headache, the DRG of interest are the ones positioned at the C1–C3 level of the cervical spine.^96,97 Autonomic and sensory ganglionic innervation of intracranial vessels by neuronal messenger molecules is illustrated in Figure 1.

Figure 1.

Overview of innervation of intracranial vasculature. (a) Whole-mounted intracranial vessel immunohistochemically processed using anti-transmitter antibodies. Asterisk point at transmitter innervation of a nerve, and also at the region of perpendicular section shown in Figure 3(b). (b) An intracranial vessel (from the inside and out): endothelium (red), lamina elastic interna (green), unstained smooth muscle cells, transmitter immunoreactive nerves (red) and nuclei (blue). Transmitter innervation is displayed by schematic drawings of neurons. Abbreviations: Ach: acetylcholine; ATP: adenosine triphosphate; CGRP: calcitonin gene-related peptide; NA: noradrenaline; NKA: neurokinin A; NO: nitric oxide; NPY: neuropeptide Y; PACAP: pituitary adenylate cyclase-activating polypeptide; SP: substance P; VIP: vasoactive intestinal peptide.

At this stage, it is pertinent to state that we, so far, have discussed innervation of the extraparenchymal system regulating the major cerebral and meningeal circulation. The current view on intraparenchymal regulation is still under analysis; so far, the prevailing view is a balance between local neuron and astrocyte activity, both in terms of their metabolism and direct activation of pericytes, smooth muscle cells and endothelium actions.^98,99

Vasoconstrictive agents

In the relation to the development of a headache/migraine, the primary focus has been on vasodilating neurotransmitters. However, vasoconstrictive neurotransmitters are important in regulation of CBF and could also counteract a possible migraine-induced dilation. Therefore, studies have been performed on endothelin-1 (ET-1),¹⁰⁰ NPY¹⁰¹ and 5-hydroxytryptamine (5-HT).^102,103

High plasma levels of ET-1 have been recorded in the beginning of a migraine attack, which then decrease significantly over time. Increased levels of ET-1 have been proposed to account for part of local vasoconstriction observed early during migraine attacks.¹⁰⁴ It might be a counterbalance-mechanism to ganglionic release of vasodilatory neurotransmitters in order to maintain vascular tone, possibly until vasodilation overpowers the vasoconstrictive properties, e.g. of ET-1. There are currently two lines of research carried out regarding ET-1 and its receptors: (i) Uddman et al.¹⁰⁵ showed presence of ET receptors in TG neuronal cell bodies, and (ii) the drug industry developed and tested ET receptor blockade in migraine; however, the result was not positive.¹⁰⁶ NPY has been detected in nerve fibers on human cerebral arteries, in addition to CGRP, SP and VIP, reporting expressional variations between the neuropeptides (Figure 1).⁸⁰

Studies of 5-HT (or serotonin) indicate that migraine with aura leads to lower interictal 5-hydroxytryptophan (5-HTP) plasma levels, a serotonin precursor, compared to controls and migraineurs without aura.¹⁰⁷ Multiple studies have shown low interictal 5-HT levels with elevations recorded during attacks, however, with conflicting results.¹⁰⁸ Intravenous 5-HT and 5-HTP injection lead to symptomatic pain relief in migraineurs, however, with substantially varying outcome, for example with different injection rates.¹⁰³ The triptans (5-HT analogues) were further developed, and have been a partial successful treatment in migraine. The 5-HT_1B/1D agonists are still the preferred treatments for acute migraine headaches.

Vasodilating agents

Numerous studies have examined the effects of vasodilator agents in patients in order to find key candidates that cause specific migraine attacks. Over the years, glyceryl trinitrate (GTN) and other headache-inducing agents have attracted much interest. It has been known for centuries, that GTN causes headache, in particular noted with workers in the dynamite industry. It is well known by clinicians that GTN, used to treat angina pectoris, results in headache at an early point in time. However, in a study in healthy volunteers, Daugaard et al.¹⁰⁹ reported that after 20 min of intravenous infusion, the recording of GTN-induced headache and a subsequent reduction in headache, a late phase called migraine-like headache occurred after some hours. Subsequently, >10 other agents have been tested in human pharmacological models resulting, not only in extracranial vessel dilatation, but also in different types of headache.¹¹⁰ Of particular interest, CGRP has attracted vast attention since the 1980s in the search for underlying mechanisms explaining part of primary headache etiologies.¹¹¹ In cerebral arteries and arterioles (more precisely the middle cerebral arteries (MCA) and pial vessels), studies demonstrate that vasodilation caused by CGRP was more prominent and potent compared to that of SP and VIP.^61,112 CGRP was also more potent compared to NKA, NKB, PACAP-38, dynorphine, galanin, peptide histidine methionine/isoleucine and nociceptin. Over time, this trend was observed in multiple studies investigating the effect of CGRP in headache disorders. Lately, this resulted in tests of CGRP receptor antagonists for prophylaxis and acute treatment of migraine.¹¹³ Following CGRP, PACAP was isolated from ovine hypothalamic tissues.¹¹⁴ Originally, PACAP was shown to have its main expression in the SPG and OTG, in parallel with VIP.⁷⁴ While VIP is not present in the trigeminal system, a subpopulation of CGRP positive neurons expresses PACAP-38 in the TG.⁷⁹ Interestingly, PACAP immunoreactivity was also seen along with CGRP, SP and neuronal NOS in the trigeminal nucleus caudalis and C1-2 laminae I-II, which are the central projection areas from the TG.¹¹⁵ Infusion of PACAP-38 demonstrated vasodilation of extracranial arteries (external carotid artery and superficial temporal artery), but not intracranial arteries (internal carotid artery, basilar artery and MCA) using magnetic resonance angiography.^116,117 In humans without a history of headache/migraine, 89% and 100% of the subjects developed headache in the immediate and delayed phase, respectively.¹¹⁶ In functional studies, it was demonstrated that PACAP-38 and PACAP-27 both possess vasodilatory effects on MCA. It was suggested that the neuropeptides were involved in neuronal regulation of CBF reporting increases in CBF, as a response to PACAP-38 injection.⁸¹ In addition to direct vasoactive effects, the use of PACAP knockout (−/−) mice has provided insight into the role of PACAP in migraine. PACAP has an essential role in activation and sensitization of the trigeminovascular system but also in occurrence of photophobia and vasodilatory responses.¹¹⁸ Both α-CGRP and PACAP knockout (−/−) mice are viable, which suggest the presence of compensatory mechanisms. This might explain why there are so few adverse effects of the drugs that target CGRP and its receptor in humans.

The effect of exogenous administration of vasoactive peptides

Intravenous CGRP/PACAP-38 administration triggers migraine-like attacks in migraine subjects.^117,119 Furthermore, MMA vasodilation has been detected upon α-CGRP and PACAP-38 infusions.^116,120,121 The MMA consists of several segments: An extracranial (branch from the external carotid artery), intraosseous and intracranial part¹²² of which we mainly are interested in the intracranial part due to the focus on CBF in primary headaches. Moreover, the inability of infused neuropeptides to influence intracranial arteries in vivo is proposed to be due to an incapability to pass the blood–brain barrier (BBB) based on intravenous infusion and myograph studies.^117,123 Tuor et al.¹²⁴ investigated intracarotid/intracerebral NPY injection in rats and detected a cortical CBF reduction, although emphasizing that the change is only observable if NPY is administrated on the abluminal side of the BBB. In 2011, a myograph study revisited vasodilation of cerebral arteries, and observed vasodilation induced by PACAP and VIP.¹²⁵ In vivo, vasodilatory effects of VIP are, however, not as pronounced as the ones for PACAP-38.¹¹⁷ In contrast, PACAP-38 did not produce vasodilation in isolated human intracranial MMA.¹²⁶ It is worth pointing out that intravenous infusion of VIP (18%) did not result in generation of migraine-like attacks to the same extent as intravenous infusion of CGRP and PACAP-38 (63–73%) in migraineurs without aura, even though vasodilation was recorded.^117,119,127

Plasma–protein extravasation

Neurotransmitter release has been associated with plasma–protein extravasation,^120,128,129 which might cause local edema.^130–132 Extravasation has been described as follows: “proteins accumulate in the extravascular space when the rate of delivery exceeds the rate of dispersion into the surrounding tissue.”¹³³ Electrical TG and SPG stimulation have been associated with plasma–protein extravasation predominantly around small blood vessels in dura mater (which lacks BBB), with SP and NKA believed to be the most influential molecules involved.^134,135 In contrast, CGRP did not induce plasma–protein extravasation,¹³⁶ but only vasodilatation. Perivascular projections from the TG have been detected on meningeal blood vessels in cats by tracing horseradish peroxidase,⁶⁵ and in rats using True Blue.⁶⁶ Moreover, induction of CSD, believed to stimulate trigeminal axons, resulted in plasma–protein extravasation in dura mater in rats.¹³⁰ Intracranial plasma extravasation has also been detected during a migraine attack in a female patient with episodic migraine evaluated by single photon emission computerized tomography.¹³⁷ Perivascular neurotransmitter release might affect vascular permeability since intravenous SP injection enhanced dural vascular permeability in rats possibly as a response to alterations of endothelial cells. Widening of intercellular junctions, elevated amount of gaps and vesicles and structural modifications of endothelial cells might occur.¹³⁸ More than a decade ago, neurokinins were considered the key molecules, and neurogenic inflammation the mechanism and target for migraine therapy.^139,140 However, after the industry produced a series of specific neurokinin blockers and tested them in migraine (without significant effect), this line of research was abandoned.¹⁴¹ In fact, SP was at this time not considered a major peptide involved in pain.¹⁴²

Integration of vasoconstrictors and vasodilators

In headache-free periods, research on blood samples revealed a significantly higher neurotransmitter baseline level of CGRP, SP and VIP in migraineurs when compared to controls,^143–146 and significantly lower baseline levels of ET-1.¹⁴⁷ In chronic migraine, interictal VIP levels were significantly increased, whereas interictal PACAP levels were not significantly different between groups (chronic migraine, episodic migraine and controls).¹⁴⁸

CGRP in particular, is released in excess during headache attacks.^{10,11,149,150} As a response to CGRP depletion in mice, elevated baseline systolic BP and mean arterial pressure have been reported thereby revealing general effects of CGRP on vascular function.¹⁵¹ Even though CGRP has been reported to be the main peptide in primary headaches, PACAP is also considered an important player. A significant change in the neuropeptide plasma levels was seen when comparing the interictal and ictal phase in migraine and cluster headache.^150,152,153 In clinical tests, intravenous PACAP-38 infusion resulted in decreased MCA blood flow velocity in the beginning of the ictal phase (experimental).¹⁵⁴ Relative release of CGRP, PACAP, SP and VIP in migraine is summarized in Figure 2.

Figure 2.

Summary of neurotransmitter release into the bloodstream in episodic and chronic migraine. Neurotransmitter baselines of calcitonin gene-related peptide (CGRP),^{11,143,145,146,155,258} pituitary adenylate cyclase-activating polypeptide (PACAP),^148,150,259 substance P (SP)^11,146,258 and vasoactive intestinal peptide (VIP)^143,148 in episodic migraine (a) and chronic migraine (b) comparing the interictal headache period with healthy controls (measured as ratio). Neurotransmitter release of CGRP,^{10,11,149,150} PACAP¹⁵⁰ and SP¹¹ in episodic migraine (c) comparing the ictal with the interictal headache period (measured as ratio).

Even though migraine and cluster headache have been associated with autonomic and sensory neurotransmitter release during attacks,^{10–12,15,29,104,155,156} there still exists some degree of inconsistency between the findings.¹⁵⁷ Our view is mainly based on the very short half-life of released neuromodulators in plasma, high levels of peptidases in the blood and lack of proper site of sampling, important factors to consider for the detection of an effect and to obtain consistent results across studies.^158,159 Moreover, because of the inability of peptides to pass the BBB, it is likely that neuropeptide release from cranial ganglia emanates from sites outside the BBB. In addition, Hoffmann et al.¹⁶⁰ investigated the effect of destroying primary trigeminal afferents on CGRP release into the jugular vein and cerebrospinal fluid, and suggested that stimulus-induced CGRP release mainly come from trigeminal afferents.

Multiple studies report an interconnection between neurotransmitter release in migraine, but also between neurotransmitter release and symptomatology/clinical phenotypes.^146,161,162 To summarize, CGRP, PACAP, SP and VIP are considered cerebrovascular dilators, and ET-1, NPY and 5-HT cerebrovascular constrictors. However, potency and site of action vary between neurotransmitters. The observed neurotransmitter fluctuations have been proposed as a failing self-defense response¹⁶³ and being due to dysfunctional biosynthesis (e.g. de novo synthesis), release and uptake.¹⁰⁷

Possible importance of the endothelium

Endothelial dysfunction in migraine has been suggested by some authors.¹⁶⁴ Indeed, a considerable number of patients show signs of dysfunctional endothelial cells in cerebral arteries evaluated using a breath holding or reactive hyperaemia index.^165,166 Increases in CBF cause flow-mediated dilation induced by production of NO in endothelial cells, as a response to shear forces, which depend on blood flow and velocity, and pressure on the vessel walls. If the regulatory mechanisms of CBF cannot keep up with changes in physiological conditions, cellular stress, morphological abnormalities and altered gene expression patterns might occur and give rise to inflammatory responses.^167,168 Parameters such as intima-media thickness, flow-mediated dilation, intracellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) have all been described as important factors in the evaluation of endothelial function. Elevated serum levels of VCAM and ICAM have been linked to migraine in children and young adults.¹⁶⁹ Cellular adhesion molecules are essential for immune cell transmigration across the BBB.^170,171 Interestingly, there is a strong correlation between serum levels of ICAM-1 and interleukin 6 (IL-6) (proinflammatory cytokine) during migraine attacks; however, no correlation was observed in the headache-free period¹⁷² suggesting shared regulatory ictal mechanisms. In addition, tumor necrosis factor α (TNF-α) (proinflammatory molecule) results in increased VCAM-1 expression in human cerebral endothelial cells.¹⁷⁰

Inflammation and BBB integrity and permeability

At present there is only limited evidence that points to an altered BBB permeability in migraineurs.^173–175 BBB integrity has been investigated in animal models by means of Evans blue.¹⁷⁶ The marker revealed that cranial ganglia are not protected by the BBB including the TG,^79,175 while the brain and cerebral vessels have a patent BBB. Figure 3 visualizes the spinal cord and selected ganglia from Sprague-Dawley male rats in relation to the BBB. It shows that TG, C1-C3 DRG, SPG, OTG and SCG are located outside the BBB (blue structures colored primarily by the Evans blue albumin complex, but also other protein complexes,¹⁷⁶ which indicates endothelial permeability). SPG stimulation is known to give rise to vasodilation and increased CBF, but these changes do not seem to affect the BBB permeability in rats.⁹¹ Experimentally induced dural inflammation, and secondarily ganglionic inflammation, does not seem to alter BBB passage either,¹⁷⁵ even though inflammatory pain has been linked to BBB damage.^177,178

Figure 3.

Sensory and autonomic ganglia in rats outside the blood–brain barrier (BBB) evaluated by means of in vivo staining with Evans Blue. (a) Trigeminal nerves, encircled by white dashed lines, after removal of the brain (dorsal view). The trigeminal nerves are covered by dura mater,⁸² colored by Evans Blue and thus outside the BBB. (b) Trigeminal nerve (removal of dura mater) revealing Evans Blue leakage at sites of the trigeminal ganglion (black arrows). (c) Spinal cord, brainstem and cerebellum (dorsal view) protected by the BBB (not colored by Evans Blue). Dura mater, encasing the spinal cord, is stained by Evans Blue (outside the BBB). The cervical nerves C1–C3 are marked and the C3 dorsal root ganglion (DRG) visible. (d,e) C1–C3 DRG, not protected by the BBB (blue), after removal of dura mater. (f,g) Sphenopalatine ganglion (SPG) (black arrows) located below the maxillary nerve (white arrow).⁸² The SPG is also outside the BBB (colored by Evans Blue). (h) Superior cervical ganglion (black arrow) not protected by the BBB (blue). (I) Otic ganglion (black arrow), outside the BBB (blue), positioned on the medial surface of the mandibular nerve (white arrow). The methodology is described by Eftekhari et al.⁷⁹

If BBB disruption occurs in an episodic disorder such as migraine, it would for example occur through endothelial tight junctions to result in increased permeability.¹⁷⁹ CGRP, SP and interleukin 1β (IL-1β), involved in primary headache pathophysiology, seem to have an effect on the brain endothelial permeability.¹⁸⁰

In an ischemic stroke model, results indicate that expression of tight junction proteins gets enhanced when inhibiting matrix metallopeptidase (MMP), which points to BBB restoration.¹⁸¹ Focusing on primary headaches, specific MMP-2 and MMP-9 gene or haplotype polymorphisms have been associated with increased levels of MMP-2^{1
82} and MMP-9^{1
83} in the blood of migraineurs and are believed to be associated with alteration in BBB patency (however only studied in peripheral blood samples). Another study reported that CSD resulted in elevated MMP-9 in the ipsilateral cortex suggesting subsequent disruption of the BBB. Plasma protein leakage and edema were also observed, but not in MMP-9 null mice.¹⁸⁴ An ex vivo study revealed that cytokines (e.g. TNF and interleukin subtypes) also might contribute to disruption of the BBB. A NeuroVascular Unit microfluidic two chamber system (vascular and brain chamber) was used to investigate the effect of inflammation on the BBB. TNF and interleukin subtypes were released as a response to lipopolysaccharide exposure, but the release varied in regards to chamber and exposure time when comparing each cytokine separately.¹⁸⁵ Brown et al.¹⁸⁵ suggested that cytokine release patterns possibly are involved in alteration of membrane permeability over time.¹⁸⁵

In a BBB study involving gadolinium-enhanced MRI, cortical opening of the BBB and edema was identified in a familial hemiplegic migraine (FHM) type 2 patient where the attack was classified as severe.¹³² However, there are no clinical studies to date that link primary headaches and opening of the BBB. This is reviewed by Edvinsson and Tfelt-Hansen.¹⁷⁴ In agreement, Schankin et al.¹⁷³ recently found no change in the BBB (interictally and ictally) in acute GTN-induced migraine attacks in humans. This field requires more studies in order to prove or disprove the effect of primary headaches on BBB integrity and permeability.

Internal and external factors and genetic predisposition in primary headaches

Internal and external factors and genetic predisposition are known to affect the susceptibility to develop primary headaches. Therefore, individual variation in regards to response to triggers, neuronal hyperexcitability and vascular regulation might exist. Figure 4 illustrates a proposed hypothesis of migraine development due to variable predispositions from genetic and environmental factors. It is evident when comparing subject B-D (migraineurs), that there can be individual differences in the factors leading to development of migraine, and hence they will probably respond differently to treatment strategies (e.g. medication). Therefore, creation of individual treatment strategies might be beneficial for treating primary headache disorders.

Figure 4.

Genetic and environmental factors and migraine predisposition. Migraine conditions are primarily considered polygenic complex disorders of which genetic (inherited) and environmental risk factors, as well as interactions, constitute headache predisposition. (a) The bar plot illustrates a proposed hypothesis of individual migraine development. The migraine threshold, termed cutoff, shows the point at which subjects are diagnosed with migraine (ratio ≥ 1). Subject A is a non-migraineur and subject B-D migraineurs. (b) Subject B has developed migraine due to an equal predisposition from genetic (50%) and environmental factors (50%), subject C mainly due to environmental predisposition (92%) and subject D mainly due to genetic predisposition (75%).

Neuronal hyperexcitability and over-activated neuronal circuits are considered functional abnormalities in migraine and believed to be important in triggering headache/migraine attacks.¹⁸⁶ More information on multiple internal and external headache triggers (e.g. sleep disturbance, stress, light, odors) can be found in thorough reviews by Ho et al.¹⁵ and Borkum.¹⁸⁷ Migraine patients have subjectively reported a link between headache attacks and triggers (e.g. alcohol, food, visual triggers, stress/tiredness, environment), categorized by a principal component analysis.¹⁸⁸ Migraine triggers have been proposed to lead to fluctuations in neurotransmitter levels and hypersensitivity in specific regions of the brain.^12,15 In humans, short exposure to noise resulted in sensitization in subjects without headache; however, prolonged exposure led to desensitization. For headache patients, the trend was not clear.¹⁸⁹ The effect of stress in rats included satellite glial cell (SGC) activation and elevated SP expression in the TG. IL-1β and interleukin 1 receptor type 1 (IL-1R1) expression in TG neurons were also elevated.¹⁹⁰

Development of migraine and cluster headache also seems to be age- and gender-dependent,^3,191,192 e.g. with particular dependence on gender hormones (e.g. rate of estrogen withdrawal in females).¹⁹³ During the menstrual cycle, fluctuations in steroid hormones seem to be associated with changes in cerebrovascular reactivity of which vasodilation primarily is observed in the right hemisphere.¹⁹⁴ Regarding the effect of age and sex on cerebrovascular regulation, inconsistency exists between human studies. One study reported that these two factors did not seem to affect cerebrovascular regulation to any major extent,¹⁹⁵ while another study suggested an effect of age on BP and CBF.¹⁹⁶ Moreover, neuronal activity and CBF are coupled tightly to brain metabolism.^197,198 Increased brain activity causes increased local energy expenditure and is thus correlated with increased local CBF. For long, it has been discussed which physiological parameter comes first, metabolism or flow? Recent studies suggest that they indeed may be closely coupled.^62,199 Moreover, Gantenbein et al.²⁰⁰ put forward a hypothesis stating that processing of sensory stimuli in migraine has a higher energy demand for neuronal function compared to that of healthy subjects, possibly linked to the theory of neuronal hyperexcitability.

In terms of genetic migraine predisposition, there are several lines of evidence including rare mutations in known proteins, single nucleotide polymorphisms and microsatellite markers. For the rare condition FHM, there are now at least three subtypes (FHM1-3) reporting gene mutations of calcium voltage-gated channel subunit alpha1 A (CACNA1A), ATPase Na⁺/K⁺ transporting subunit alpha 2 (ATP1A2) and sodium voltage-gated channel alpha subunit 1 (SCN1A).²⁰¹ The subtypes seem to share the potential to modify glutamate signaling in the CNS, making the neurons more susceptible to depolarize (cortical hyperexcitability).²⁰² The first mutation (FHM1) was detected in locus 19p13²⁰³ which relates to the P/Q calcium channel in the CNS, and affects calcium-dependent facilitation and synaptic plasticity.²⁰⁴ In a genetic family study, a considerable number of individuals (86%), carrying a mutation in ATP1A2, were diagnosed with FHM,²⁰⁵ which implies a high effect size.

More recently, genome-wide association studies (GWAS) have revolutionized the discovery of susceptibility variants for common traits and diseases (low-moderate effect size of markers), including primary headaches.^16,17 The first GWAS paper investigating single nucleotide polymorphisms implicated in primary headaches, and consequently pathological mechanisms, was published in 2010 according to the GWAS catalog.²⁰⁶ Numerous headache-related single nucleotide polymorphisms and suggested migraine candidate genes (e.g. LDL receptor related protein 1 (LRP1), gap junction protein alpha 1 (GJA1), phosphatase and actin regulator 1 (PHACTR1)) have been identified and are involved in molecular mechanisms of ion homeostasis, oxidative stress and regulation of vascular tone.^207,208 Although the vascular theory is no longer the primary theory on the origin of migraine, GWAS show that several candidate migraine genes are indeed related to the vasculature, based on data from recent meta-analyses.^207,208 Table 1 summarizes selected candidate migraine genes detected by GWAS and their relation to cerebral vasculature in order to reveal potential interconnected biological mechanisms and effects on vascular function. The candidate genes seem to be involved in vascular diseases/disorders (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), arteriovenous malformations (AVMs)), hemodynamics, regulation of transport across the BBB, neurogenesis and gliogenesis amongst others (Table 1). Other genome wide scans have been carried out investigating microsatellite markers in a cluster headache cohort. The hypocretin receptor 2 (HCRTR2) was detected as a candidate cluster headache gene,²⁰⁹ also detected by other genetic studies.^210,211 HCRTR2 has also been associated with heart failure. The findings included (i) upregulation of HCRTR2 in dilated cardiomyopathy in humans and (ii) dysfunctional diastolic BP in HCRTR2 transcription-disrupted mice.²¹² In addition, ADCYAP1R1, a PACAP receptor gene believed to be involved in signal transmission in migraine, was detected by GWAS to be associated with the susceptibility to develop cluster headache.¹⁷ These findings could again give life to the importance of the vasculature in primary headaches, maybe with focus on hemodynamics and regulation of intracerebral flow and the neurovascular unit.

Table 1.

Selected candidate migraine genes detected by GWAS meta-analyses.

Candidate genes	Gene description	Potential linkage to cerebral vasculature and primary headaches	References
HTRA1*^a	HtrA serine peptidase 1	▪ Associated with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), a cerebral small vessel disease.	^{222,260–262}
		▪ CARASIL: Reported vascular smooth muscle cell (vSMC) loss, change of small vessels in cerebral write matter and basal ganglia, and extracellular matrix breakdown.
		▪ Migraine with aura has been referred to as a central feature of CADASIL, the autosomal dominant variant.
GJA1*	Gap junction protein alpha 1 (also known as gap junction protein connexin43)	▪ Functions in synaptic transmission and homeostasis of the brain/immune system.	^263,264
		▪ Connexin43 (a main astroglial connexin) forming gap junction channels and hemichannels involved in (dys)regulation of BBB transportation in human endothelial cells.	^263,264
		▪ Detected, especially, in the end-feet^b of astrocytes, interacting with the endothelium, implicated in maintenance of BBB integrity.
HEY2*^a	Hes related family bHLH transcription factor with YRPW motif 2	▪ HEY2 is expressed in the cerebral cortex and cranial ganglia, and believed to be involved in neuro- and gliogenesis in the developing brain, but also cognitive impairment.	^265,266
HEY2*^a		▪ HEY regulated genes are involved in neurogenesis, apoptosis and vascular development.	^265,266
JAG1*	Jagged 1	▪ Associated with cerebral arteriovenous malformations (AVMs) and endothelial differentiation.	^267–269
JAG1*	Jagged 1	▪ Lesions in AVMs might be linked to increased blood flow and vessel wall shear stress, hemodynamic factors. These hemodynamic factors might trigger release of angiogenic factors and inflammatory markers.	^267–269
LRP1**^a	Low density lipoprotein receptor-related protein 1	▪ LRP1 is involved in amyloid uptake by vSMCs and possibly cerebral amyloid angiopathy.	^270,271
LRP1**^a	Low density lipoprotein receptor-related protein 1	▪ Cerebral amyloid angiopathy might be implicated in late onset of aura reporting occipital haemorrhage and subcortex haemosiderin deposition.	^270,271
NRP1*	Neuropilin 1	▪ Implicated in vascular development (e.g. angiogenesis and vascularization) and formation of arteriovenous connections.	^272,273
NRP1*	Neuropilin 1	▪ Knockdown of NRP1 in human brain microvascular endothelial cells affected chemokine levels through TNF-α and IFNγ, inflammatory responses. It also showed that NRP1 is involved in BBB function, (de)myelination of neurons and lymphocyte infiltration.	^272,273
RNF213*	Ring finger protein 213	▪ Link between RNF213 and intracranial vasculopathies.	^274–277
		▪ RNF213 variants affect the susceptibility to develop intracranial atherosclerotic stenosis and moyamoya disease.
		▪ Migraine-like attacks with aura observed in a female patient showing signs of moyamoya disease evaluated by computed tomography and angiograms.
SLC24A3*	Solute carrier family 24 member 3 (also known as NCKX3)	▪ NCKX3 (Na⁺–Ca²⁺ exchanger dependent on K⁺) is believed to be involved in vision and olfaction through its regulatory effects on calcium homeostasis and thus Ca²⁺ flux.	^278,279
SLC24A3*	Solute carrier family 24 member 3 (also known as NCKX3)	▪ Gene variants associated with variations in systolic blood pressure possibly through altered vascular tone as a response to changes in intracellular Ca²⁺ concentrations. This implies that NCKX3 might be involved in the vasoconstriction and vasodilation system.	^278,279
TGFBR2**	Transforming growth factor beta receptor 2,	▪ Implicated in intracerebral haemorrhages, expression of angiogenic factors, BBB integrity and permeability, vessel morphology including vascular branching investigated in conditional TGFBR2 knock-out mice (neural deletion of TGFBR2). This implies potential neurovascular interactions.	^280,281
TGFBR2**	Transforming growth factor beta receptor 2,	▪ Gene variants of TGFBR2 suggested being involved in cerebral cavernous malformation (CCM) type 1 in terms of severity of the disease but also phenotypic variability.	^280,281

GWAS: genome-wide association studies.

Note: Results indicate involvement of the selected candidate genes in vascular disease/disorder, smooth muscle contractility or regulation of vascular tone amongst others (*Gormley et al.²⁰⁸; **Anttila et al.²⁰⁷ and Gormley et al.²⁰⁸)

Reported as ARMS2 –HTRA1, HEY2 –NCOA7 and LRP1 -STAT6-SDR9C7 in Gormley et al.,²⁰⁸ respectively.

End-feet defined as “specialized foot-processes of perivascular astrocytes that are closely opposed to the outer surface of brain microvessels, and have specialized functions in inducing and regulating the BBB” by Abbott et al.²⁸²

Neuronal hyperexcitability and vascular regulation

Neurophysiological alterations such as altered neural plasticity, hyperexcitability and lack of habituation to sensory stimuli have been associated with primary headaches.^213–215 Recent research focuses on the epigenome, which is believed to affect the susceptibility to develop migraine,²¹⁶ with the field being at an emerging state. For example, a stressful environment during childhood has been linked to stress-induced alterations of homeostasis systems and development of migraine later in life²¹⁷ thereby including the psychological aspect of primary headaches. One postulation is that epigenetic changes, occurring as a response to chronic stress, results in hyperexcitable neurons,²¹⁸ thereby linking the epigenome to the CSD and trigeminovascular theory. However, methylation patterns have been found to vary considerably both between tissues and genes reported in a study investigating migraine-related genes.²¹⁹

Focusing on vascular diseases, hypoperfusion in the white matter has been observed in CADASIL patients,²²⁰ who seem to have prolonged and more frequent CSD²²¹ possibly due to parenchymal hyperexcitability.³⁵ Interestingly, a study showed that migraine is present in 75% of CADASIL patients of which many reported aura. The migraine aura seemed to increase the odds of encephalopathy.²²² Moreover, a microvascular vasoconstrictor anomaly has been associated with CADASIL in noradrenaline and angiotensin pathways, but not with a vasodilator anomaly.²²³ There are also some gender differences; brain vessels from males seem to be more sensitive to vasoconstrictors (angiotensin II and endothelin) than from females.²²⁴ Overall, these parameters might predispose individuals to enhanced migraine susceptibility or vice versa.

As a response to neuronal hyperexcitability, one would expect increased neurotransmitter release from perivascular ganglionic nerve endings on the cerebral vasculature. Moreover, neurotransmitters might be released directly into the extracellular space surrounding the neuronal cell bodies in the ganglia, triggered by neuronal depolarization evoking SGC activation through neurotransmitter-receptor binding.^225,226 CGRP evoked release of NO and inflammatory responses in these glial cells, which was blocked by a CGRP receptor antagonist.²²⁶ The exact functional role of SGCs is still unknown; however, they are believed to be involved in control of the neuronal microenvironment.^190,227 Neuronal excitability has been associated with SGC activation²²⁷ and various pain syndromes seem to be related to diverse activation states of the glial cells.²²⁸ The SGCs may thus be an important player in the sensitization process and chronification of migraine, in addition to the phenomena discussed in the previous sections. The SGCs constitute >90% of the total number of cells in the TG, and are linked to neurons via gap junctions (e.g. connexin) implicated in cell-cell signaling.^226,229 Connexin, but also pannexin are involved in neuronal excitability and synaptic plasticity in the CNS forming gap junctions/hemichannels facilitating neuronal transmission.^230,231 Experimental CSD provoked opening of pannexin1 channels, which was suggested to affect activation of the trigeminovascular system.²³² Ashina et al.¹⁴⁵ suggested that migraineurs suffer from abnormal neurogenic vascular control enduringly or permanently. Figure 5 gives an overview of possible pathophysiological effects, which occur due to migraine susceptible gene pools and external and internal headache triggers, all resulting in altered CBF.

Figure 5.

Genetic headache predisposition, headache triggers and cerebral blood flow (CBF). Potential effects of and link between genetic headache susceptibility (input: green), extrinsic and intrinsic headache triggers (input: green) and CBF (output: red) through multiple pathophysiological steps (simplified flow diagram).

Primary headaches and sensitization

There are several primary headache disorders; migraine and trigeminal autonomic cephalgias (cluster headache, chronic paroxysmal hemicranias, inter alia) of which all are characterized by pain varying in duration, location and quality with accompanied autonomic and sensory neurological signs/symptoms depending on the diagnosis.² Cluster headache patients experience autonomic symptoms such as rhinorrhea, lacrimation and abnormal sweating (parasympathetic influence) and miosis and ptosis (sympathetic influence).^2,233 Cranial sensory symptoms include experience of allodynia, and abnormalities in sensory perception of visual, olfactory and auditory stimuli.²³⁴ This implies involvement of the parasympathetic, sympathetic and sensory nervous systems which form complex functional units implicated in processing of impulses.²³⁵

During the headache attack phase, ganglia such as the TG and SPG, located outside the BBB, are activated and sensitized. The discovery of the sensitization process was pioneered by Burstein et al.²³⁶ Basically, upon repeated activation/stimulation (heat, cold or pressure stimuli), the subsequent response to the same stimulus was enhanced, being referred to as sensitization. Sensitization has been associated with release of neurotransmitters, including CGRP, and could be a part of the mechanism behind allodynia.²³⁶ Despite that the sensory trigeminal system contains several messenger molecules (e.g. CGRP, SP/NKA, PACAP and NO), only CGRP seems to be clearly associated with headache in migraine attacks.^156,237,238 So far, release of CGRP/PACAP has only been positively linked to acute attacks of migraine, or in bouts of cluster headache.^{12,150,152,153,156,157} Moreover, patients with nasal congestion and rhinorrhea show release of VIP,²³⁷ which is observed in chronic migraine as well.¹⁴³ Putatively, other molecules such as NO and cytokines are involved.^149,239

Perivascular nerve terminals originating from sensory, parasympathetic and sympathetic ganglia, believed to be involved in primary headaches, have been observed on cerebral arteries and arterioles.⁴⁷ In addition to the involvement of multiple neurotransmitters in CBF regulation, they are part of: (i) the neurovascular unit in the brain parenchyma, and (ii) larger arteries belonging to the circle of Willis and pial cortex arterioles.

Chronification of pain in primary headaches

Migraine experienced at least 15 days per month for >3 months is considered chronic. Chronic cluster headache, on the other hand, should last for at least a year with or without remission periods (<1 month).² Chronic headache and headache frequency correlated significantly in adults²⁴⁰ possibly due to the detrimental effects of pathophysiological changes (e.g. trigeminovascular activation and sensitization) arising during headache attacks. In coherence, chronic migraine seems to increase with age.^241,242 Trigeminovascular activation has also been observed as a response to inflammation, which could be involved in headache progression.²⁴³ At a cellular level, systemic inflammation of L4/5 DRG, involved in transmission of sensory signal, seems to modify the SGCs. Abnormal growth, formation of new gap junctions and increased ATP sensitivity of SGCs could potentially contribute to pain.²⁴⁴ Structural and functional modification of SGCs might be connected to cellular stress and inflammation.^190,243,245 Other findings suggest that SGC activation, as a response to inflammation, results in modulated excitability of neurons in TG and DRG.^244,246 We hypothesize that neurogenic inflammation might have a reinforcing effect on neuronal hyperexcitability, a feed-forward loop, probably contributing to development of chronic headache.

The chronic pain state of the brain is believed to result in further structural, functional and chemical modifications. Chronic pain might arise due to impairment of pathways in the CNS, but also of the peripheral nervous system, which collectively manifest phenotypically as altered sensation, emotion and cognition or modulated pain response.²⁴⁷ These changes are believed to be involved in disease progression from the episodic to chronic state. Therefore, it appears to be important for the future migraine management strategy to treat primary headaches early to avoid chronification bearing in mind that many primary headaches are considered complex polygenic disorders.

Episodic to chronic headache: Neurogenic inflammation and chronification

It is often argued, based on clinical observations, that a “migraine highway” is present in many patients. In the beginning, occasional attacks occur which, over the years, become frequent episodic migraine with up to 14 migraine headache days per month (according to ICHD-III beta²). This may, in some cases, expand even more, sometimes associated with migraine medication overuse.^248,249 The mechanisms involved are still not clear. Vasodilation, release of vasoactive peptides and plasma-protein extravasation constitute factors that are involved in development of inflammatory responses, also referred to as neurogenic inflammation,^76,139,250 which can be triggered by electrical stimulation of ganglia.⁷⁶ Research shows that PACAP-38 is involved in central sensitization,¹⁵⁴ neuronal and satellite glial cyclic adenosine monophosphate (cAMP) production in TG,²⁵¹ and neurogenic inflammation.²⁵² CGRP and VIP are associated with cAMP accumulation occurring simultaneously with cerebral vasodilation.¹¹² Sarchielli et al.¹⁰ showed that cAMP and cGMP release occurred after release of CGRP, NKA and nitrites in migraine attacks measured in internal jugular venous blood. In addition, both CGRP and cAMP induced NO and inducible NOS release from TG glial cells in culture.²²⁶ However, single nucleotide polymorphisms in the neuronal NOS gene do not seem to increase the risk of migraine.²⁵³ Moreover, in migraineurs, release of other inflammatory markers such as interleukin (IL) subtypes (e.g. IL-1β, IL-6, IL-10) and TNF have been observed,^239,254 which seems to be most likely in frequent or chronic migraine. A tendency of higher lymphocyte number in the peripheral blood was observed in chronic migraine compared to episodic migraine suggested to be linked to the inflammatory state of the patients.²⁵⁵ In the calvarial periosteum of chronic migraineurs, gene expression of proinflammatory markers was increased (e.g. IL-6, IL-1 receptor type 2 (IL1R2), C-C motif chemokine ligand 2 (CCL2), C-X3-C motif chemokine ligand 1 (CX3CL1)), whereas gene expression of markers involved in suppression of inflammation was decreased.²⁵⁶ Some of these markers might affect nociception. In addition, results show that application of IL-1β to the meninges is involved in activation and sensitization of nociceptors, which was not observed to the same degree for IL-6.²⁵⁷

Summary

Primary headaches are considered cerebral neurovascular disorders of which abnormal brain activity and CBF changes have been observed. CBF changes might occur as a response to pathophysiological changes such as neuronal hyperexcitability and autoregulatory impairment. GWAS studies, investigating the susceptibility to develop migraine, revealed suggestive candidate genes related to vascular diseases/mechanisms. One might postulate that some headache attacks are linked to underlying undiscovered vascular diseases. On the other hand, neuronal abnormalities have an effect on vascular mechanisms and function. Even though the original vascular theory is considered to be secondary in nature, these findings still emphasize the importance of the vasculature in primary headaches.

To summarize, this review gives rise to the following connections between primary headaches and CBF: (i) headache attacks start in the CNS and result in activated and sensitized ganglia and neurotransmitter release (e.g. CGRP, PACAP), (ii) the intracranial cerebral vasculature (large cerebral arteries and arterioles on the surface of the brain) is supplied with perivascular nerve fibers originating from the sensory, sympathetic and parasympathetic nervous systems, (iii) neurovascular activation putatively gives rise to vasoconstrictive/vasodilative phases and altered CBF and metabolism in the affected brain regions, (iv) neurotransmitter release seems to affect cAMP levels followed by inflammatory responses, but also plasma–protein extravasation in certain areas such as the dura mater (if SP is released), and (v) inflammation might reinforce neuronal hyperexcitability, pathological alterations and cellular dysfunctions through a feed-forward loop and thus contribute to chronification from the episodic state.

Finally, from a treatment perspective, it is important to detect and treat primary headache disorders in time in order to avoid chronification. Furthermore, new treatment strategies are required, which take into account that some individuals are genetically predisposed to develop primary headaches while others, primarily, might develop it as a response to environmental stimuli (e.g. stress).

Footnotes

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by grants from the Lundbeck foundation (Denmark), Swedish research council (grant no 5958) and Heart-Lung foundation.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Pressman

Jacobson

Eguilos

et al.

Prevalence of migraine in a diverse community – electronic methods for migraine ascertainment in a large integrated health plan. Cephalalgia 2016; 36: 325–234.

IHC. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

Manzoni

Taga

Russo

et al.

Age of onset of episodic and chronic cluster headache – a review of a large case series from a single headache centre. J Headache Pain 2016; 17: 44.

Magon

May

Stankewitz

et al.

Morphological abnormalities of thalamic subnuclei in migraine: a multicenter MRI study at 3 Tesla. J Neurosci 2015; 35: 13800–13806.

Olesen

Burstein

Ashina

et al.

Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 2009; 8: 679–690.

Hodkinson

Veggeberg

Wilcox

et al.

Primary somatosensory cortices contain altered patterns of regional cerebral blood flow in the interictal phase of migraine. PLoS One 2015; 10: e0137971.

Hodkinson

Veggeberg

Kucyi

et al.

Cortico-cortical connections of primary sensory areas and associated symptoms in migraine. eNeuro 2016; 3(6). DOI: 10.1523/ENEURO.0163-16.2016.

Schytz

Barlose

Guo

et al.

Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans. Cephalalgia 2013; 33: 831–841.

Felisati

Arnone

Lozza

et al.

Sphenopalatine endoscopic ganglion block: a revision of a traditional technique for cluster headache. Laryngoscope 2006; 116: 1447–1450.

10.

Sarchielli

Alberti

Codini

et al.

Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 2000; 20: 907–918.

11.

Gallai

Sarchielli

Floridi

et al.

Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 1995; 15: 384–390.

12.

Goadsby

Edvinsson

. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48–56.

13.

Edvinsson

Uddman

. Neurobiology in primary headaches. Brain Res Brain Res Rev 2005; 48: 438–456.

14.

Edvinsson

Villalon

MaassenVanDenBrink

. Basic mechanisms of migraine and its acute treatment. Pharmacol Ther 2012; 136: 319–333.

15.

Edvinsson

Goadsby

. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 2010; 6: 573–582.

16.

Anttila

Stefansson

Kallela

et al.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 2010; 42: 869–873.

17.

Bacchelli

Cainazzo

Cameli

et al.

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. J Headache Pain 2016; 17: 114.

18.

Leo

AAP

. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359–390.

19.

Wolff

. Headache and other head pain, New York: Oxford University Press, 1948.

20.

Olesen

Larsen

Lauritzen

. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9: 344–352.

21.

Shevel

. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm 2011; 118: 525–530.

22.

Amin

Asghar

Hougaard

et al.

Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 2013; 12: 454–461.

23.

MaassenVanDenBrink

Ibrahimi

Edvinsson

. Intracranial and extracranial arteries in migraine. Lancet Neurol 2013; 12: 847–848.

24.

Costa

Tozzi

Rainero

et al.

Cortical spreading depression as a target for anti-migraine agents. J Headache Pain 2013; 14: 62.

25.

Genizi

Khourieh Matar

Zelnik

et al.

Frequency of pediatric migraine with aura in a clinic-based sample. Headache 2016; 56: 113–117.

26.

Pietrobon

Moskowitz

. Pathophysiology of migraine. Annu Rev Physiol 2013; 75: 365–391.

27.

Pietrobon

Moskowitz

. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci 2014; 15: 379–393.

28.

Moskowitz MA. Pathophysiology of headache – past and present. Headache 2007; April(47 Suppl 1): S58–S63.

29.

Goadsby

Edvinsson

Ekman

. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23: 193–196.

30.

Moskowitz

Buzzi

Sakas

et al.

Pain mechanisms underlying vascular headaches. Progress Report 1989. Rev Neurol 1989; 145: 181–193.

31.

Moskowitz

. Defining a pathway to discovery from bench to bedside: the trigeminovascular system and sensitization. Headache 2008; 48: 688–690.

32.

Nielsen

Fabricius

Lauritzen

. Scanning laser-Doppler flowmetry of rat cerebral circulation during cortical spreading depression. J Vasc Res 2000; 37: 513–522.

33.

Woods

Iacoboni

Mazziotta

. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689–1692.

34.

Olesen

Lauritzen

Tfelt-Hansen

et al.

Spreading cerebral oligemia in classical- and normal cerebral blood flow in common migraine. Headache 1982; 22: 242–248.

35.

Ayata

Lauritzen

. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev 2015; 95: 953–993.

36.

Maniyar

Sprenger

Monteith

et al.

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 2014; 137: 232–241.

37.

Schulte

May

. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 2016; 139: 1987–1993.

38.

Weiller

May

Limmroth

et al.

Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658–660.

39.

Akerman

Holland

Goadsby

. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011; 12: 570–584.

40.

Jullienne

Badaut

. Molecular contributions to neurovascular unit dysfunctions after brain injuries: lessons for target-specific drug development. Future Neurol 2013; 8: 677–689.

41.

Hamel

. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 2006; 100: 1059–1064.

42.

Aaslid

Lindegaard

Sorteberg

et al.

Cerebral autoregulation dynamics in humans. Stroke 1989; 20: 45–52.

43.

Paulson

Strandgaard

Edvinsson

. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990; 2: 161–192.

44.

Skinhoj

. Regulation of cerebral blood flow as a single function of the interstitial pH in the brain. A hypothesis. Acta Neurol Scand 1966; 42: 604–607.

45.

Shapiro

Wasserman

Patterson

Jr . Mechanism and pattern of human cerebrovascular regulation after rapid changes in blood CO2 tension. J Clin Invest 1966; 45: 913–922.

46.

Azevedo

Rosengarten

Santos

et al.

Interplay of cerebral autoregulation and neurovascular coupling evaluated by functional TCD in different orthostatic conditions. J Neurol 2007; 254: 236–241.

47.

Edvinsson

Krause

. Cerebral blood flow and metabolism, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2002.

48.

Edward

. The cerebral circulation. Br J Anaesth 2001; 1: 5.

49.

Olesen

Friberg

Olsen

et al.

Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 1990; 28: 791–798.

50.

Sanchez del Rio

Bakker

et al.

Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701–707.

51.

Loehrer

Vernooij

van der Lugt

et al.

Migraine and cerebral blood flow in the general population. Cephalalgia 2015; 35: 190–198.

52.

Piilgaard

Lauritzen

. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J Cereb Blood Flow Metab 2009; 29: 1517–1527.

53.

Chang

Shook

Biag

et al.

Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain 2010; 133: 996–1012.

54.

Willis T. Cerebri Anatome: cui accessit nervorum descriptio et usus. London: Londini: typis Ja. Flesher, impensis Jo. Martyn & Ja. Allestry apud insigne Campanae in Ciemeterio D. Pauli, 1664, p.538.

55.

Nielsen

Owman

. Adrenergic innervation of pial arteries related to the circle of Willis in the cat. Brain Res 1967; 6: 773–776.

56.

Edvinsson

MacKenzie

. Amine mechanisms in the cerebral circulation. Pharmacol Rev 1976; 28: 275–348.

57.

Edvinsson

LM ET

McCulloch

. Cerebral blood flow and metabolism, New York: Raven Press, 1993.

58.

Harper

Lassen

MacKenzie

et al.

Proceedings: the upper limit of ‘autoregulation’ of cerebral blood flow in the baboon. J Physiol 1973; 234: 61p–62p.

59.

Larsson

Edvinsson

Fahrenkrug

et al.

Immunohistochemical localization of a vasodilatory polypeptide (VIP) in cerebrovascular nerves. Brain Res 1976; 113: 400–404.

60.

Goadsby

Edvinsson

. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994; 117(Pt 3): 427–434.

61.

McCulloch

Uddman

Kingman

et al.

Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA 1986; 83: 5731–5735.

62.

Whittaker

Driver

Bright

et al.

The absolute CBF response to activation is preserved during elevated perfusion: implications for neurovascular coupling measures. Neuroimage 2016; 125: 198–207.

63.

Moulton

Becerra

Borsook

. An fMRI case report of photophobia: activation of the trigeminal nociceptive pathway. Pain 2009; 145: 358–363.

64.

Baeres

Moller

. Origin of PACAP-immunoreactive nerve fibers innervating the subarachnoidal blood vessels of the rat brain. J Cereb Blood Flow Metab 2004; 24: 628–635.

65.

Mayberg

Langer

Zervas

et al.

Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 1981; 213: 228–230.

66.

Uddman

Hara

Edvinsson

. Neuronal pathways to the rat middle meningeal artery revealed by retrograde tracing and immunocytochemistry. J Auton Nerv Syst 1989; 26: 69–75.

67.

Uddman

Edvinsson

. Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev 1989; 1: 230–252.

68.

Edvinsson

Hara

Uddman

. Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 1989; 9: 212–218.

69.

Liu

Zhang

Broman

et al.

Central projections of sensory innervation of the rat superficial temporal artery. Brain Res 2003; 966: 126–133.

70.

Liu

Broman

Edvinsson

. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 2004; 129: 431–437.

71.

Liu

Broman

Edvinsson

. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res 2008; 1208: 103–110.

72.

Uddman

Edvinsson

Ekman

et al.

Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 1985; 62: 131–136.

73.

Edvinsson

Elsas

Suzuki

et al.

Origin and co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat. Microsc Res Tech 2001; 53: 221–228.

74.

Uddman

Tajti

Moller

et al.

Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res 1999; 826: 193–199.

75.

Tajti

Uddman

Moller

et al.

Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 1999; 76: 176–183.

76.

Samsam

Covenas

Csillik

et al.

Depletion of substance P, neurokinin A and calcitonin gene-related peptide from the contralateral and ipsilateral caudal trigeminal nucleus following unilateral electrical stimulation of the trigeminal ganglion; a possible neurophysiological and neuroanatomical link to generalized head pain. J Chem Neuroanat 2001; 21: 161–169.

77.

Samsam

Covenas

Ahangari

et al.

Simultaneous depletion of neurokinin A, substance P and calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat during electrical stimulation of the trigeminal ganglion. Pain 2000; 84: 389–395.

78.

Tuka

Helyes

Markovics

et al.

Peripheral and central alterations of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat in response to activation of the trigeminovascular system. Peptides 2012; 33: 307–316.

79.

Eftekhari

Salvatore

Johansson

et al.

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res 2015; 1600: 93–109.

80.

Edvinsson

Ekman

Jansen

et al.

Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann Neurol 1987; 21: 431–437.

81.

Uddman

Goadsby

Jansen

et al.

PACAP, a VIP-like peptide: immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J Cereb Blood Flow Metab 1993; 13: 291–297.

82.

Shankland

2nd . The trigeminal nerve. Part I: an over-view. Cranio 2000; 18: 238–248.

83.

Escott

Beattie

Connor

et al.

Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res 1995; 669: 93–99.

84.

Csati

Tajti

Tuka

et al.

Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion – interaction with the sensory system. Brain Res 2012; 1435: 29–39.

85.

Csati

Tajti

Kuris

et al.

Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion. Neuroscience 2012; 202: 158–168.

86.

Pipolo C, Bussone G, Leone M, et al. Sphenopalatine endoscopic ganglion block in cluster headache: a reevaluation of the procedure after 5 years. Neurol Sci 2010; June(31 Suppl 1): S197–S199.

87.

Cady

Saper

Dexter

et al.

A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360((R)) as acute treatment for chronic migraine. Headache 2015; 55: 101–116.

88.

Cady

Saper

Dexter

et al.

Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine. Headache 2015; 55: 529–542.

89.

Hara

Zhang

Kuroyanagi

et al.

Parasympathetic cerebrovascular innervation: an anterograde tracing from the sphenopalatine ganglion in the rat. Neurosurgery 1993; 32: 822–827. discussion 7.

90.

Seylaz

Hara

Pinard

et al.

Effect of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat. J Cereb Blood Flow Metab 1988; 8: 875–878.

91.

Levi

Schoknecht

Prager

et al.

Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model. PLoS One 2012; 7: e39636.

92.

Steinberg

Frederiksen

Blixt

et al.

Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets. J Headache Pain 2016; 17: 78.

93.

Hara

Jansen

Ekman

et al.

Acetylcholine and vasoactive intestinal peptide in cerebral blood vessels: effect of extirpation of the sphenopalatine ganglion. J Cereb Blood Flow Metab 1989; 9: 204–211.

94.

Hardebo

Suzuki

Ekblad

et al.

Vasoactive intestinal polypeptide and acetylcholine coexist with neuropeptide Y, dopamine-beta-hydroxylase, tyrosine hydroxylase, substance P or calcitonin gene-related peptide in neuronal subpopulations in cranial parasympathetic ganglia of rat. Cell Tissue Res 1992; 267: 291–300.

95.

Zhang

Xie

et al.

Inflammatory changes in paravertebral sympathetic ganglia in two rat pain models. Neurosci Bull Epub ahead of print 22 May 2017. DOI: 10.1007/s12264-017-0142-1.

96.

Bogduk

. The anatomical basis for cervicogenic headache. J Manipulative Physiol Ther 1992; 15: 67–70.

97.

Calhoun

Ford

Millen

et al.

The prevalence of neck pain in migraine. Headache 2010; 50: 1273–1277.

98.

Filosa

Morrison

Iddings

et al.

Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience 2016; 323: 96–109.

99.

Iadecola

Nedergaard

. Glial regulation of the cerebral microvasculature. Nat Neurosci 2007; 10: 1369–1376.

100.

Faraci

. Effects of endothelin and vasopressin on cerebral blood vessels. Am J Physiol 1989; 257: H799–H803.

101.

Edvinsson

. Characterization of the contractile effect of neuropeptide Y in feline cerebral arteries. Acta Physiol Scand 1985; 125: 33–41.

102.

Nagasawa

Handa

Naruo

et al.

Experimental cerebral vasospasm. Part 2. Contractility of spastic arterial wall. Stroke 1983; 14: 579–84.

103.

Kimball

Friedman

Vallejo

. Effect of serotonin in migraine patients. Neurology 1960; 10: 107–111.

104.

Kallela

Farkkila

Saijonmaa

et al.

Endothelin in migraine patients. Cephalalgia 1998; 18: 329–332.

105.

Uddman

Tajti

Cardell

et al.

Endothelin ETA and ETB receptor expression in the human trigeminal ganglion. Neuro Endocrinol Lett 2006; 27: 345–349.

106.

May

Goadsby

. Pharmacological opportunities and pitfalls in the therapy of migraine. Curr Opin Neurol 2001; 14: 341–345.

107.

Nagata

Shibata

Hamada

et al.

Plasma 5-hydroxytryptamine (5-HT) in migraine during an attack-free period. Headache 2006; 46: 592–596.

108.

Deen

Christensen

Hougaard

et al.

Serotonergic mechanisms in the migraine brain – a systematic review. Cephalalgia 2017; 37: 251–264.

109.

Daugaard

Thomsen

Iversen

et al.

Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate. Cephalalgia 2009; 29: 1294–300.

110.

Ashina

Hansen

Olesen

. Pearls and pitfalls in human pharmacological models of migraine: 30 years’ experience. Cephalalgia 2013; 33: 540–553.

111.

Edvinsson

. Functional role of perivascular peptides in the control of cerebral circulation. Trends Neurosci 1985; 8: 126–131.

112.

Edvinsson

Fredholm

Hamel

et al.

Perivascular peptides relax cerebral arteries concomitant with stimulation of cyclic adenosine monophosphate accumulation or release of an endothelium-derived relaxing factor in the cat. Neurosci Lett 1985; 58: 213–217.

113.

Doods

Arndt

Rudolf

et al.

CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol Sci 2007; 28: 580–587.

114.

Miyata

Arimura

Dahl

et al.

Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 1989; 164: 567–574.

115.

Uddman

Tajti

Hou

et al.

Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 2002; 22: 112–116.

116.

Amin

Asghar

Guo

et al.

Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia 2012; 32: 140–149.

117.

Amin

Hougaard

Schytz

et al.

Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 2014; 137: 779–794.

118.

Markovics

Kormos

Gaszner

et al.

Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 2012; 45: 633–644.

119.

Guo

Vollesen

Olesen

et al.

Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain 2016; 157: 2773–2781.

120.

Asghar

Hansen

Kapijimpanga

et al.

Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology 2010; 75: 1520–1526.

121.

Bhatt

Gupta

Olesen

et al.

PACAP-38 infusion causes sustained vasodilation of the middle meningeal artery in the rat: possible involvement of mast cells. Cephalalgia 2014; 34: 877–886.

122.

Kornieieva

Hadidy

Zhuravlova

. Variability of the middle meningeal artery subject to the shape of skull. J Neurol Surg B Skull Base 2015; 76: 451–458.

123.

Edvinsson

Nilsson

Jansen-Olesen

. Inhibitory effect of BIBN4096BS, CGRP(8-37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery. Br J Pharmacol 2007; 150: 633–640.

124.

Tuor

Edvinsson

McCulloch

. Neuropeptide Y and cerebral blood flow. Lancet 1985; 1: 1271.

125.

Baun

Hay-Schmidt

Edvinsson

et al.

Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat. Eur J Pharmacol 2011; 670: 186–194.

126.

Grande

Labruijere

Haanes

et al.

Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds. J Headache Pain 2014; 15: 22.

127.

Edvinsson

Ekman

. Distribution and dilatory effect of vasoactive intestinal polypeptide (VIP) in human cerebral arteries. Peptides 1984; 5: 329–331.

128.

Schuh-Hofer

Boehnke

Reuter

et al.

A fluorescence-based method to assess plasma protein extravasation in rat dura mater using confocal laser scanning microscopy. Brain Res Brain Res Protoc 2003; 12: 77–82.

129.

Hoehlig

Johnson

Pryazhnikov

et al.

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation. Br J Pharmacol 2015; 172: 3086–3098.

130.

Bolay

Reuter

Dunn

et al.

Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8: 136–142.

131.

Peitl

Nemeth

Szolcsanyi

et al.

Sensory nitrergic meningeal vasodilatation and non-nitrergic plasma extravasation in anaesthesized rats. Eur J Pharmacol 2004; 497: 293–299.

132.

Dreier

Jurkat-Rott

Petzold

et al.

Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 2005; 64: 2145–2147.

133.

Welsh

Muthard

Stalker

et al.

A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature. Blood 2016; 127: 1598–1605.

134.

Delepine

Aubineau

. Plasma protein extravasation induced in the rat dura mater by stimulation of the parasympathetic sphenopalatine ganglion. Exp Neurol 1997; 147: 389–400.

135.

Markowitz

Saito

Moskowitz

. Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci 1987; 7: 4129–4136.

136.

Levy

Burstein

Strassman

. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 2005; 58: 698–705.

137.

Knotkova

Pappagallo

. Imaging intracranial plasma extravasation in a migraine patient: a case report. Pain Med 2007; 8: 383–387.

138.

Ghabriel

Leigh

et al.

Substance P-induced enhanced permeability of dura mater microvessels is accompanied by pronounced ultrastructural changes, but is not dependent on the density of endothelial cell anionic sites. Acta Neuropathol 1999; 97: 297–305.

139.

Markowitz

Saito

Moskowitz

. Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia 1988; 8: 83–91.

140.

Lee

Moskowitz

. Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater. Brain Res 1993; 626: 303–305.

141.

Diener

Gendolla

Juptner

et al.

Emerging treatments in headache. Eur Neurol 1997; 38: 167–174.

142.

Tajti

Szok

Majlath

et al.

Migraine and neuropeptides. Neuropeptides 2015; 52: 19–30.

143.

Cernuda-Morollon

Martinez-Camblor

Ramon

et al.

CGRP and VIP levels as predictors of efficacy of Onabotulinumtoxin type A in chronic migraine. Headache 2014; 54: 987–995.

144.

Cernuda-Morollon

Martinez-Camblor

Alvarez

et al.

Increased VIP levels in peripheral blood outside migraine attacks as a potential biomarker of cranial parasympathetic activation in chronic migraine. Cephalalgia 2015; 35: 310–316.

145.

Ashina

Bendtsen

Jensen

et al.

Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 2000; 86: 133–138.

146.

Jang

Park

Kho

et al.

Plasma and saliva levels of nerve growth factor and neuropeptides in chronic migraine patients. Oral Dis 2011; 17: 187–193.

147.

Komatsumoto

Nara

. [Lower level of endothelin-1 in migraine with aura]. Rinsho Shinkeigaku 1995; 35: 1250–1252.

148.

Cernuda-Morollon

Riesco

Martinez-Camblor

et al.

No change in interictal PACAP levels in peripheral blood in women with chronic migraine. Headache 2016; 56: 1448–1454.

149.

Rodriguez-Osorio

Sobrino

Brea

et al.

Endothelial progenitor cells: a new key for endothelial dysfunction in migraine. Neurology 2012; 79: 474–479.

150.

Tuka

Helyes

Markovics

et al.

Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia 2013; 33: 1085–1095.

151.

Gangula

Zhao

Supowit

et al.

Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 2000; 35: 470–475.

152.

Zagami

Edvinsson

Goadsby

. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol 2014; 1: 1036–1040.

153.

Tuka

Szabo

Toth

et al.

Release of PACAP-38 in episodic cluster headache patients – an exploratory study. J Headache Pain 2016; 17: 69.

154.

Schytz

Birk

Wienecke

et al.

PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009; 132: 16–25.

155.

Cernuda-Morollon

Larrosa

Ramon

et al.

Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 2013; 81: 1191–1196.

156.

Edvinsson

Goadsby

. Neuropeptides in migraine and cluster headache. Cephalalgia 1994; 14: 320–327.

157.

Goadsby

Edvinsson

Ekman

. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183–187.

158.

Warfvinge

Edvinsson

. Pearls and pitfalls in neural CGRP immunohistochemistry. Cephalalgia 2013; 33: 593–603.

159.

Edvinsson

Ekman

Goadsby

. Measurement of vasoactive neuropeptides in biological materials: problems and pitfalls from 30 years of experience and novel future approaches. Cephalalgia 2010; 30: 761–766.

160.

Hoffmann

Wecker

Neeb

et al.

Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF. Cephalalgia 2012; 32: 659–667.

161.

Jansen-Olesen

Baun

Amrutkar

et al.

PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides 2014; 48: 53–64.

162.

Bellamy

Cady

Durham

. Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache 2006; 46: 24–33.

163.

Arulmozhi

Veeranjaneyulu

Bodhankar

. Migraine: current concepts and emerging therapies. Vascul Pharmacol 2005; 43: 176–187.

164.

Gonzalez-Quintanilla

Toriello

Palacio

et al.

Systemic and cerebral endothelial dysfunction in chronic migraine. A case-control study with an active comparator. Cephalalgia 2016; 36: 552–560.

165.

Rajan

Khurana

Lal

. Interictal cerebral and systemic endothelial dysfunction in patients with migraine: a case-control study. J Neurol Neurosurg Psychiatry 2015; 86: 1253–1257.

166.

Jimenez Caballero

Munoz Escudero

. Peripheral endothelial function and arterial stiffness in patients with chronic migraine: a case-control study. J Headache Pain 2013; 14: 8.

167.

Cybulsky

Marsden

. Effect of disturbed blood flow on endothelial cell gene expression: a role for changes in RNA processing. Arterioscler Thromb Vasc Biol 2014; 34: 1806–1808.

168.

Dirnagl

Lindauer

Villringer

. Role of nitric oxide in the coupling of cerebral blood flow to neuronal activation in rats. Neurosci Lett 1993; 149: 43–46.

169.

Sabri

Dehghan

Yaghini

et al.

Endothelial dysfunction state in migraine headache and neutrally mediated syncope in children and young adults. J Res Med Sci 2015; 20: 771–776.

170.

Kallmann

Hummel

Lindenlaub

et al.

Cytokine-induced modulation of cellular adhesion to human cerebral endothelial cells is mediated by soluble vascular cell adhesion molecule-1. Brain 2000; 123(Pt 4): 687–697.

171.

Weiss

Miller

Cazaubon

et al.

The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 2009; 1788: 842–857.

172.

Wang

Ren

et al.

Association of serum levels of intercellular adhesion molecule-1 and interleukin-6 with migraine. Neurol Sci 2015; 36: 535–540.

173.

Schankin

Maniyar

Seo

et al.

Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain 2016; 139: 1994–2001.

174.

Edvinsson

Tfelt-Hansen

. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–1258.

175.

Lundblad

Haanes

Grande

et al.

Experimental inflammation following dural application of complete Freund’s adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. J Headache Pain 2015; 16: 91.

176.

Saunders

Dziegielewska

Mollgard

et al.

Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives?

Front Neurosci 2015; 9: 385.

177.

Huber

Witt

Hom

et al.

Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 2001; 280: H1241–H1248.

178.

Huber

Hau

Borg

et al.

Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol 2002; 283: H1531–H1537.

179.

Etame

Diaz

Smith

et al.

Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology. Neurosurg Focus 2012; 32: E3.

180.

DosSantos

Holanda-Afonso

Lima

et al.

The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders. Front Cell Neurosci 2014; 8: 302.

181.

Yang

Thompson

Taheri

et al.

Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery. J Cereb Blood Flow Metab 2013; 33: 1104–1114.

182.

Goncalves

Martins-Oliveira

Lacchini

et al.

Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene 2013; 512: 35–40.

183.

Martins-Oliveira

Goncalves

Speciali

et al.

Specific matrix metalloproteinase 9 (MMP-9) haplotype affect the circulating MMP-9 levels in women with migraine. J Neuroimmunol 2012; 252: 89–94.

184.

Gursoy-Ozdemir

Qiu

Matsuoka

et al.

Cortical spreading depression activates and upregulates MMP-9. J Clin Invest 2004; 113: 1447–1455.

185.

Brown

Codreanu

Shi

et al.

Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 2016; 13: 306.

186.

Bolcskei

Farkas

Kocsis

et al.

Recent advancements in anti-migraine drug research: focus on attempts to decrease neuronal hyperexcitability. Recent Pat CNS Drug Discov 2009; 4: 14–36.

187.

Borkum

. Migraine triggers and oxidative stress: a narrative review and synthesis. Headache 2016; 56: 12–35.

188.

Harle

Shepherd

Evans

. Visual stimuli are common triggers of migraine and are associated with pattern glare. Headache 2006; 46: 1431–1440.

189.

Martin

Reece

Forsyth

. Noise as a trigger for headaches: relationship between exposure and sensitivity. Headache 2006; 46: 962–972.

190.

Zhao

Liu

Zhao

et al.

Activation of satellite glial cells in the trigeminal ganglion contributes to masseter mechanical allodynia induced by restraint stress in rats. Neurosci Lett 2015; 602: 150–155.

191.

Macgregor

Rosenberg

Kurth

. Sex-related differences in epidemiological and clinic-based headache studies. Headache 2011; 51: 843–859.

192.

Manzoni

. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia 1998; 18: 138–142.

193.

Pavlovic

Allshouse

Santoro

et al.

Sex hormones in women with and without migraine: evidence of migraine-specific hormone profiles. Neurology 2016; 87: 49–56.

194.

Krejza

Rudzinski

Arkuszewski

et al.

Cerebrovascular reactivity across the menstrual cycle in young healthy women. Neuroradiol J 2013; 26: 413–419.

195.

Madureira

Castro

Azevedo

. Demographic and systemic hemodynamic influences in mechanisms of cerebrovascular regulation in healthy adults. J Stroke Cerebrovasc Dis 2017; 26: 500–508.

196.

Xing

Tarumi

Meijers

et al.

Arterial pressure, heart rate, and cerebral hemodynamics across the adult life span. Hypertension 2017; 69: 712–720.

197.

Kozberg

Hillman

. Neurovascular coupling and energy metabolism in the developing brain. Prog Brain Res 2016; 225: 213–242.

198.

Shu

Sanganahalli

Coman

et al.

New horizons in neurometabolic and neurovascular coupling from calibrated fMRI. Prog Brain Res 2016; 225: 99–122.

199.

Lundengard

Cedersund

Sten

et al.

Mechanistic mathematical modeling tests hypotheses of the neurovascular coupling in fMRI. PLoS Comput Biol 2016; 12: e1004971.

200.

Gantenbein

Sandor

Fritschy

et al.

Sensory information processing may be neuroenergetically more demanding in migraine patients. Neuroreport 2013; 24: 202–205.

201.

de Vries

Freilinger

Vanmolkot

et al.

Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology 2007; 69: 2170–2176.

202.

Pietrobon

. Familial hemiplegic migraine. Neurotherapeutics 2007; 4: 274–284.

203.

Terwindt

Ophoff

van Eijk

et al.

Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001; 56: 1028–1032.

204.

Adams

Rungta

Garcia

et al.

Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel. Proc Natl Acad Sci USA 2010; 107: 18694–18699.

205.

Pelzer

Blom

Stam

et al.

Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation. Cephalalgia 2017; 37: 737–755.

206.

MacArthur

Bowler

Cerezo

et al.

The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res 2017; 45: D896–D901.

207.

Anttila

Winsvold

Gormley

et al.

Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013; 45: 912–917.

208.

Gormley

Anttila

Winsvold

et al.

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 2016; 48: 856–866.

209.

Baumber

Sjostrand

Leone

et al.

A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 2006; 66: 1888–1893.

210.

Weller

Wilbrink

Houwing-Duistermaat

et al.

Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia 2015; 35: 741–747.

211.

Rainero

Gallone

Rubino

et al.

Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache. Headache 2008; 48: 1108–1114.

212.

Perez

Pavlovic

Shang

et al.

Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure. J Am Coll Cardiol 2015; 66: 2522–2533.

213.

Demarquay

Andre-Obadia

Caclin

et al.

[Neurophysiological evaluation of cortical excitability in migraine: a review of the literature]. Rev Neurol 2013; 169: 427–435.

214.

Lai

Protsenko

Cheng

et al.

Neural plasticity in common forms of chronic headaches. Neural Plast 2015; 2015: 205985.

215.

Akerman

Romero-Reyes

Holland

. Current and novel insights into the neurophysiology of migraine and its implications for therapeutics. Pharmacol Ther 2017; 172: 151–170.

216.

Roos-Araujo

Stuart

Lea

et al.

Epigenetics and migraine; complex mitochondrial interactions contributing to disease susceptibility. Gene 2014; 543: 1–7.

217.

Tietjen

Buse

Collins

. Childhood maltreatment in the migraine patient. Curr Treat Options Neurol 2016; 18: 31.

218.

Ochoa-Cortes

Guerrero-Alba

Valdez-Morales

et al.

Chronic stress mediators act synergistically on colonic nociceptive mouse dorsal root ganglia neurons to increase excitability. Neurogastroenterol Motil 2014; 26: 334–345.

219.

Labruijere

Stolk

Verbiest

et al.

Methylation of migraine-related genes in different tissues of the rat. PLoS One 2014; 9: e87616.

220.

Chabriat

Pappata

Ostergaard

et al.

Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke 2000; 31: 1904–1912.

221.

Eikermann-Haerter

Yuzawa

Dilekoz

et al.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol 2011; 69: 413–418.

222.

Tan

Markus

. CADASIL: migraine, encephalopathy, stroke and their inter-relationships. PLoS One 2016; 11: e0157613.

223.

Hussain

Singhal

Markus

et al.

Abnormal vasoconstrictor responses to angiotensin II and noradrenaline in isolated small arteries from patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke 2004; 35: 853–858.

224.

Ahnstedt

Cao

Krause

et al.

Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries. PloS One 2013; 8: e62698.

225.

Takeda

Takahashi

Matsumoto

. Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neurosci Biobehav Rev 2009; 33: 784–792.

226.

Vause

Durham

. Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 2008; 1196: 22–32.

227.

de Corato

Capuano

Curro

et al.

Trigeminal satellite cells modulate neuronal responses to triptans: relevance for migraine therapy. Neuron Glia Biol 2011; 7: 109–116.

228.

Ji RR, Berta T and Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013; December(154 Suppl 1): S10–S28.

229.

Poulsen

Warwick

Duroux

et al.

Oxaliplatin enhances gap junction-mediated coupling in cell cultures of mouse trigeminal ganglia. Exp Cell Res 2015; 336: 94–99.

230.

Ardiles

Flores-Munoz

Toro-Ayala

et al.

Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice. Front Cell Neurosci 2014; 8: 326.

231.

Han

Sun

et al.

Astrocyte-restricted disruption of connexin-43 impairs neuronal plasticity in mouse barrel cortex. Eur J Neurosci 2014; 39: 35–45.

232.

Karatas

Erdener

Gursoy-Ozdemir

et al.

Spreading depression triggers headache by activating neuronal Panx1 channels. Science 2013; 339: 1092–1095.

233.

May

. Update on the diagnosis and management of trigemino-autonomic headaches. J Neurol 2006; 253: 1525–1532.

234.

Harriott

Schwedt

. Migraine is associated with altered processing of sensory stimuli. Curr Pain Headache Rep 2014; 18: 458.

235.

Higbee

. Functional and anatomic relation of sphenopalatine ganglion to the autonomic nervous system. Arch Otolaryngol 1949; 50: 45–58.

236.

Burstein

Yarnitsky

Goor-Aryeh

et al.

An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47: 614–624.

237.

Edvinsson

Goadsby

. Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia 1995; 15: 272–276.

238.

Goadsby

Edvinsson

. Neuropeptide changes in a case of chronic paroxysmal hemicrania – evidence for trigemino-parasympathetic activation. Cephalalgia 1996; 16: 448–450.

239.

Perini

D’Andrea

Galloni

et al.

Plasma cytokine levels in migraineurs and controls. Headache 2005; 45: 926–931.

240.

Scher

Stewart

Ricci

et al.

Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003; 106: 81–89.

241.

Kandil

Hamed

Fadel

et al.

Migraine in Assiut Governorate, Egypt: epidemiology, risk factors, comorbid conditions and predictors of change from episodic to chronic migraine. Neurol Res 2016; 38: 232–241.

242.

Galinski

Sidhoum

Cimerman

et al.

Early diagnosis of migraine necessary in children: 10-year follow-up. Pediatr Neurol 2015; 53: 319–323.

243.

Lukacs

Haanes

Majlath

et al.

Dural administration of inflammatory soup or Complete Freund’s Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion. J Headache Pain 2015; 16: 564.

244.

Blum

Procacci

Conte

et al.

Systemic inflammation alters satellite glial cell function and structure. A possible contribution to pain. Neuroscience 2014; 274: 209–217.

245.

Magni

Merli

Verderio

et al.

P2Y2 receptor antagonists as anti-allodynic agents in acute and sub-chronic trigeminal sensitization: role of satellite glial cells. Glia 2015; 63: 1256–1269.

246.

Takeda

Tanimoto

Kadoi

et al.

Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 2007; 129: 155–166.

247.

Borsook

. Neurological diseases and pain. Brain 2012; 135: 320–344.

248.

Silberstein

Blumenfeld

Cady

et al.

OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci 2013; 331: 48–56.

249.

Diener

Dodick

Goadsby

et al.

Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse. Cephalalgia 2009; 29: 1021–1027.

250.

Phebus LA and Johnson KW. Dural inflammation model of migraine pain. Curr Protoc Neurosci 2001; Chapter 9: Unit9.1.

251.

Walker

Sundrum

Hay

. PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells. Br J Pharmacol 2014; 171: 1521–1533.

252.

Schytz

. Investigation of carbachol and PACAP38 in a human model of migraine. Dan Med Bull 2010; 57: B4223.

253.

Garcia-Martin

Martinez

Serrador

et al.

Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for migraine. Headache 2015; 55: 1209–1217.

254.

Munno

Marinaro

Bassi

et al.

Immunological aspects in migraine: increase of IL-10 plasma levels during attack. Headache 2001; 41: 764–767.

255.

Forcelini

Dantas

Luz

et al.

Analysis of leukocytes in medication-overuse headache, chronic migraine, and episodic migraine. Headache 2011; 51: 1228–1238.

256.

Perry

Blake

Buettner

et al.

Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: implications for extracranial origin of headache. Ann Neurol 2016; 79: 1000–1013.

257.

Zhang

Burstein

Levy

. Local action of the proinflammatory cytokines IL-1beta and IL-6 on intracranial meningeal nociceptors. Cephalalgia 2012; 32: 66–72.

258.

Fusayasu

Kowa

Takeshima

et al.

Increased plasma substance P and CGRP levels, and high ACE activity in migraineurs during headache-free periods. Pain 2007; 128: 209–214.

259.

Han

Dong

Hou

et al.

Interictal plasma pituitary adenylate cyclase-activating polypeptide levels are decreased in migraineurs but remain unchanged in patients with tension-type headache. Clin Chim Acta 2015; 450: 151–154.

260.

Federico

Di Donato

Bianchi

et al.

Hereditary cerebral small vessel diseases: a review. J Neurol Sci 2012; 322: 25–30.

261.

Primo

Graham

Bigger-Allen

et al.

Blood biomarkers in a mouse model of CADASIL. Brain Res 2016; 1644: 118–126.

262.

Verdura

Herve

Scharrer

et al.

Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015; 138: 2347–2358.

263.

Kaneko

Tachikawa

Akaogi

et al.

Contribution of pannexin 1 and connexin 43 hemichannels to extracellular calcium-dependent transport dynamics in human blood-brain barrier endothelial cells. J Pharmacol Exp Ther 2015; 353: 192–200.

264.

Boulay

Cisternino

Cohen-Salmon

. Immunoregulation at the gliovascular unit in the healthy brain: a focus on Connexin 43. Brain Behav Immun 2016; 56: 1–9.

265.

Jordan

Rosenfeld

Lalani

et al.

Duplication of HEY2 in cardiac and neurologic development. Am J Med Genet A 2015; 167a: 2145–2149.

266.

Weber

Wiese

Gessler

. Hey bHLH transcription factors. Curr Top Dev Biol 2014; 110: 285–315.

267.

Weinsheimer

Bendjilali

Nelson

et al.

Genome-wide association study of sporadic brain arteriovenous malformations. J Neurol Neurosurg Psychiatry 2016; 87: 916–923.

268.

Yao

Radparvar

et al.

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency. Proc Natl Acad Sci USA 2013; 110: 19071–19076.

269.

Leblanc

Golanov

Awad

et al.

Biology of vascular malformations of the brain. Stroke 2009; 40: e694–e702.

270.

Ruzali

Kehoe

Love

. LRP1 expression in cerebral cortex, choroid plexus and meningeal blood vessels: relationship to cerebral amyloid angiopathy and APOE status. Neurosci Lett 2012; 525: 123–128.

271.

Samanci

Coban

Baykan

. Late onset aura may herald cerebral amyloid angiopathy: a case report. Cephalalgia 2016; 36: 998–1001.

272.

Plein

Fantin

Ruhrberg

. Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability. Microcirculation 2014; 21: 315–323.

273.

Wang

Cao

Mangalam

et al.

Neuropilin-1 modulates interferon-gamma-stimulated signaling in brain microvascular endothelial cells. J Cell Sci 2016; 129: 3911–3921.

274.

Zhang

Liu

Zhang

et al.

RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance. J Neurosurg 2017; 126: 1106–1113.

275.

Bang

Chung

Cha

et al.

A polymorphism in RNF213 is a susceptibility gene for intracranial atherosclerosis. PLoS One 2016; 11: e0156607.

276.

Kamada

Aoki

Narisawa

et al.

A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 2011; 56: 34–40.

277.

Smith

Leventer

Mackay

et al.

Identification of a novel RNF213 variant in a family with heterogeneous intracerebral vasculopathy. Int J Stroke 2014; 9: E26–E27.

278.

Jalloul

Szerencsei

Schnetkamp

. Cation dependencies and turnover rates of the human K(+)-dependent Na(+)-Ca(2)(+) exchangers NCKX1, NCKX2, NCKX3 and NCKX4. Cell Calcium 2016; 59: 1–11.

279.

Citterio

Simonini

Zagato

et al.

Genes involved in vasoconstriction and vasodilation system affect salt-sensitive hypertension. PLoS One 2011; 6: e19620.

280.

Hellbach

Weise

Vezzali

et al.

Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome. Hum Mol Genet 2014; 23: 6177–6190.

281.

Choquet

Pawlikowska

Nelson

et al.

Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc Dis 2014; 38: 433–440.

282.

Abbott

Ronnback

Hansson

. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41–53.

Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches

Abstract

Keywords

Introduction

Complexity of neurovascular coupling and CBF

Extrinsic and intrinsic cerebral vasculature: Neurogenic factors and neurotransmitter release

Extrinsic perivascular nerves in the cerebral circulation and dura mater

Advances in our understanding of the neuronal innervation of the extraparenchymal cerebral vasculature

Vasoconstrictive agents

Vasodilating agents

The effect of exogenous administration of vasoactive peptides

Plasma–protein extravasation

Integration of vasoconstrictors and vasodilators

Possible importance of the endothelium

Inflammation and BBB integrity and permeability

Internal and external factors and genetic predisposition in primary headaches

Neuronal hyperexcitability and vascular regulation

Primary headaches and sensitization

Chronification of pain in primary headaches

Episodic to chronic headache: Neurogenic inflammation and chronification

Summary

Footnotes

Funding

Declaration of conflicting interests

References