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Objective The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. Methods This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review. Results Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. Conclusions The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

Background Calcitonin gene-related peptide plasma levels have frequently been determined as a biomarker for primary headaches. However, published data is often inconsistent resulting from different methods that are not precisely described in most studies. Methods We applied a well-proven enzyme-linked immunosorbent assay to measure calcitonin gene-related peptide concentrations in human blood plasma, we modified parameters of plasma preparation and protein purification and used calcitonin gene-related peptide-free plasma for standard solutions, which are described in detail. Results Calcitonin gene-related peptide levels are stable in plasma with peptidase inhibitors and after deep-freezing. Calcitonin gene-related peptide standard solutions based on synthetic intercellular fluid or pooled plasma with pre-absorbed calcitonin gene-related peptide influenced the measurements but yielded both comprehensible results. In a sample of 56 healthy subjects the calcitonin gene-related peptide plasma levels varied considerably from low (500 pg/mL) values. After a 12-hour exposure of these subjects to normobaric hypoxia the individual calcitonin gene-related peptide levels remained stable. Conclusion Buffering with peptidase inhibitors and immediate freezing or processing of plasma samples is essential to achieve reliable measurements. Individuals show considerable differences and partly high calcitonin gene-related peptide plasma levels without detectable pathological reason. Thus plasma measurements are suited particularly to follow calcitonin gene-related peptide levels in longitudinal studies. The use of data for this study was approved by the Ethics Committee of the Medical University of Innsbruck ( https://www.i-med.ac.at/ethikkommission/ ; EK Nr: 1242/2017).

Background Migraine shows a cyclic pattern with an inter-ictal-, a pre-ictal, an ictal- and a post-ictal phase. We aimed to examine changes in psychophysical parameters during the migraine cycle. Methods The perception of nociceptive and non-nociceptive stimuli and an electrically induced axon-reflex-erythema were assessed in 20 healthy controls and 14 migraine patients on five consecutive days according to different phases of the migraine cycle. Pain was rated three times during a 10-second electrical stimulus. The size of the axon-reflex-erythema was determined using laser-Doppler-imaging. Intensity and hedonic estimates of odours presented by Sniffin’ Sticks were rated. Results In healthy controls, no significant changes over the test days were observed. In migraine patients pain thresholds at the head decreased with an ictal minimum. Less habituation after five seconds of stimulation at the head was found pre-ictally, whereas reduced habituation to 10-second electrical stimulation was present in all phases. The axon-reflex-erythema size showed an inter-ictal-specific minimum at the head. odours were perceived ictally as more unpleasant and intense. Conclusions Somatosensory functions, pain thresholds and habituation as predominantly central parameters, axon-reflex-erythema as a peripheral function of trigeminal neurons and odour perception as a predominantly extra-thalamic sensation change specifically over the migraine cycle indicating complex variations of neuronal signal processing.

BackgroundThe pathophysiology of headaches associated with rhinosinusitis is poorly known. Since the generation of headaches is thought to be linked to the activation of intracranial afferents, we used an animal model to characterise spinal trigeminal neurons with nociceptive input from the dura mater and paranasal sinuses.MethodsIn isoflurane anaesthetised rats, extracellular recordings were made from neurons in the spinal trigeminal nucleus with afferent input from the exposed frontal dura mater. Dural and facial receptive fields were mapped and the paranasal cavities below the thinned nasal bone were stimulated by sequential application of synthetic interstitial fluid, 40 mM potassium chloride, 100 µM bradykinin, 1% ethanol (vehicle) and 100 µm capsaicin.ResultsTwenty-five neurons with input from the frontal dura mater and responses to chemical stimulation of the paranasal cavities were identified. Some of these neurons had additional receptive fields in the parietal dura, most of them in the face. The administration of synthetic interstitial fluid, potassium chloride and ethanol was not followed by significant changes in activity, but bradykinin provoked a cluster of action potentials in 20 and capsaicin in 23 neurons.ConclusionSpecific spinal trigeminal neurons with afferent input from the cranial dura mater respond to stimulation of paranasal cavities with noxious agents like bradykinin and capsaicin. This pattern of activation may be due to convergent input of trigeminal afferents that innervate dura mater and nasal cavities and project to spinal trigeminal neurons, which could explain the genesis of headaches due to disorders of paranasal sinuses.

Background For future experimental studies or the development of targeted pharmaceutical agents, a deeper insight into the pathophysiology of migraine is of utmost interest. Reliable methods to trigger migraine attacks including aura are desirable to study this complex disease in vivo. Methods To investigate hypoxia as a trigger for migraine and aura, we exposed volunteers diagnosed with migraine, with (n = 16) and without aura (n = 14), to hypoxia utilizing a hypoxic chamber adjusted to a FiO2 of 12.6%. The occurrence of headache, migraine, aura, and accompanying symptoms were registered and vital signs were collected for 6 hours under hypoxia and 2 hours of follow-up. A binary logistic regression analysis examined the probability of triggering headaches, migraines, aura, photo- and phonophobia. Findings Of 30 participants, 24 (80.0%) developed headaches and 19 (63.3%) migraine, five (16.7%) reported aura. Two patients that developed aura never experienced aura symptoms before in their life. The increase of mean heart frequency was higher in patients developing headaches or migraine. Mean SpO2 during hypoxia was 83.39%. Conclusion Hypoxia was able to trigger migraine attacks and aura independently of any pharmacological agent.

Das „calcitonin gene-related peptide“ (CGRP) wird bei Migrane- und Clusterkopfschmerzanfallen aus trigeminalen Afferenzen freigesetzt. Die Infusion von CGRP kann Kopfschmerzanfalle bei Patienten mit Migrane und Clusterkopfschmerz auslosen. Die Hemmung des CGRP-Systems ist bei Migrane und Clusterkopfschmerz therapeutisch wirksam. CGRP ist ein potenter Dilatator intrakranialer Arterien, hat aber keine direkte Wirkung auf die Aktivitat des trigeminalen Schmerzsystems. CGRP steuert wahrscheinlich Signalvorgange zwischen Zellen im Ganglion trigeminale und verstarkt die Neurotransmission im Trigeminuskern. Durch periphere Hemmung des CGRP-Signalsystems werden diese Wirkungen vermindert. Auserhalb des trigeminovaskularen Systems ist CGRP wichtig fur die Durchblutung vieler Organe in kritischen Situationen, fordert Wachstums- und Reparaturvorgange und hat immunmodulatorische Funktionen. Diese Wirkungen sollten bei einer lang dauernden Unterdruckung des CGRP-Signalsystems beachtet werden.

The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood–brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.

Clinical publications show consistently that headache is a common symptom in the coronavirus disease of 2019 (COVID-19). Several studies specifically investigated headache symptomatology and associated features in patients with COVID-19. The headache is frequently debilitating with manifold characters including migraine-like characteristics. Studies suggested that COVID-19 patients with headache vs. those without headache are more likely to have anosmia. We present a pathophysiological hypothesis which may explain this phenomenon, discuss current hypotheses about how the coronavirus SARS-CoV-2 enters the central nervous system and suggest that activation of the trigeminal nerve may contribute to both headache and anosmia in COVID-19.

The mechanisms underlying headaches attributed to hypoxia are poorly known. The activation of spinal trigeminal neurons with meningeal afferent input is believed to be responsible for the generation of headaches. In the caudal spinal trigeminal nucleus of anaesthetized and ventilated rats, the spontaneous firing of neurons with input from the exposed parietal dura mater and the activity evoked by mechanical stimuli to the dura and the adjacent periosteum were recorded, whereas the O2 fraction of the ventilation gas was stepwise reduced by omitting O2 and adding nitrogen. The expiratory CO2 level, the arterial pressure, the pulse rate, and the peripheral O2 saturation (SpO2) were registered. The meningeal blood flow was recorded using laser Doppler flowmetry; video imaging was used to measure the diameter of dural and medullary arteries. Lowering O2 in the ventilation gas from hyperoxic to normoxic and finally hypoxic conditions was followed by an increase in spontaneous activity up to 300% of the initial activity in most neurons, whereas the activity in a minor fraction of neurons ceased. The mechanical threshold was reduced under hypoxia. Arterial pressure, pulse rate, and SpO2 fell during stepwise lowering of the O2 concentration, whereas the arteries of the dura mater and the medulla dilated. Increased neuronal activity in the spinal trigeminal nucleus following lowering of the inhaled O2 goes along with variations in cardiovascular parameters. The experiments may partly model the conditions of high altitudes and other hypoxic states as risk factors for headache generation.

Calcitonin gene-related peptide (CGRP) is released from trigeminal afferents during migraine and cluster headache attacks and can be detected in the jugular plasma. Infusion of CGRP can induce headache attacks in migraine and cluster patients. Inhibition of the CGRP signal system is therapeutic in migraine and cluster headache. CGRP is a potent dilator of intracranial arteries but does not immediately activate the trigeminal pain system. CGRP may act as a signal molecule between different cells in the trigeminal ganglion and enhances nociceptive transmission in the spinal trigeminal nucleus. Peripheral inhibition of the CGRP system reduces these actions. Outside the trigeminovascular system, CGRP is important for maintaining the perfusion of organs in critical situations, promotes growth and repair functions and is an immunomodulatory factor. These actions should be considered when the CGRP system is suppressed for a long time.Das „calcitonin gene-related peptide“ (CGRP) wird bei Migräne- und Clusterkopfschmerzanfällen aus trigeminalen Afferenzen freigesetzt. Die Infusion von CGRP kann Kopfschmerzanfälle bei Patienten mit Migräne und Clusterkopfschmerz auslösen. Die Hemmung des CGRP-Systems ist bei Migräne und Clusterkopfschmerz therapeutisch wirksam. CGRP ist ein potenter Dilatator intrakranialer Arterien, hat aber keine direkte Wirkung auf die Aktivität des trigeminalen Schmerzsystems. CGRP steuert wahrscheinlich Signalvorgänge zwischen Zellen im Ganglion trigeminale und verstärkt die Neurotransmission im Trigeminuskern. Durch periphere Hemmung des CGRP-Signalsystems werden diese Wirkungen vermindert. Außerhalb des trigeminovaskulären Systems ist CGRP wichtig für die Durchblutung vieler Organe in kritischen Situationen, fördert Wachstums- und Reparaturvorgänge und hat immunmodulatorische Funktionen. Diese Wirkungen sollten bei einer lang dauernden Unterdrückung des CGRP-Signalsystems beachtet werden.

Background The α1 -adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side-effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system. Methods Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena. Results Phenylephrine above 10 mM dose-dependently released calcitonin gene-related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, whereas hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine-evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1-deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre-application of the CGRP receptor antagonist CGRP8-37 or the TRPV1 antagonist BCTC. Conclusions Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine. Significance Phenylephrine is used at high concentrations as a mydriaticum and for treating nasal congestion. As adverse side-effects burning sensations and headaches have been described. Phenylephrine at high concentrations causes calcium transients in trigeminal afferents, CGRP release and increased meningeal blood flow upon activation of TRPV1 receptor channels, which is likely underlying the reported pain phenomena.

Cutaneous afferent nerves convey sensory information from the external, visceral nerves from the internal environment. The saphenous nerve arising from lumbar dorsal root ganglia and the vagus nerve originating in the nodosum ganglia are prototypic examples of such cutaneous and visceral nerves. Despite a common sensory role, these two nerves have distinct embryonic origin and vary in neuropeptide expression. Because of their distinct physiological roles, it is plausible that they differ also in conductive properties. We have tested calcitonin gene-related peptide (CGRP) release in these nerves in response to electrical and chemical stimulation. Electrical stimulation at 3, 6, and 9 Hz increased the release in saphenous but not vagus nerves, with 6 Hz being the most potent stimulus. Similarly, both capsaicin and a depolarizing solution of 60 mM KCl evoked CGRP release in saphenous but not vagus nerves. Simultaneous recording of the superimposed (compound) action potentials of these nerves revealed that only saphenous nerves exhibit a progressive and marked activity-dependent slowing of conduction velocity in response to electrical stimulation at 3, 6, and 9 Hz (30%, 44%, and 50%, respectively). Capsaicin caused an unexpected decrease in conduction latency (i.e., speeding) in contrast to the slowing seen in other nerves. Exposure of axons to 1 µM TTX rapidly blocked conduction in all nerves. Together our results demonstrate that vagus and saphenous primary afferents reveal different activation and conductive properties, presumably correlating their particular physiological roles in transmitting sensory signals. © 2018 Wiley Periodicals, Inc.

Primary headaches may be accompanied by increased intracranial blood flow induced by the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from activated meningeal afferents. We aimed to record meningeal and medullary blood flow simultaneously and to localize the sites of CGRP release in rodent preparations in vivo and ex vivo. Blood flow in the exposed rat parietal dura mater and the medulla oblongata was recorded by laser Doppler flowmetry, while the dura was stimulated by topical application of 60mM potassium chloride (KCl). Samples of jugular venous plasma and cerebrospinal fluid (CSF) collected from the cisterna magna were analysed for CGRP concentrations using an enzyme immunoassay. In a hemisected rat skull preparation lined with dura mater the CGRP releasing effect of KCl superfusion was examined. Superfusion of the dura mater with KCl decreased meningeal blood flow unless alpha-adrenoceptors were blocked by phentolamine, whereas the medullary blood flow was increased. The same treatment caused increased CGRP concentrations in jugular plasma and CSF and induced significant CGRP release in the hemisected rat skull preparation. Anaesthesia of the trigeminal ganglion by injection of lidocaine reduced increases in medullary blood flow and CGRP concentration in the CSF upon meningeal KCl application. CGRP release evoked by depolarisation of meningeal afferents is accompanied by increased blood flow in the medulla oblongata but not the dura mater. This discrepancy can be explained by the smooth muscle depolarising effect of KCl and the activation of sympathetic vasoconstrictor mechanisms. The medullary blood flow response is most likely mediated by CGRP released from activated central terminals of trigeminal afferents. Increased blood supply of the medulla oblongata and CGRP release into the CSF may also occur in headaches accompanying vigorous activation of meningeal afferents.

Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we explored the influence of olfactory and trigeminal signaling in the nasal cavity. A forced choice water consumption paradigm was used to ascertain whether trigeminal and olfactory stimuli could influence behaviour in mice. Mice avoided water sources surrounded by both volatile TRPV1 (cyclohexanone) and TRPA1 (allyl isothiocyanate) irritants and the aversion to cyclohexanone was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioural effect we recorded from single trigeminal sensory axons innervating the nasal respiratory and olfactory epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in mice expressing channel-rhodopsin (ChR2) under the olfactory marker protein (OMP) promoter. Photoactivation of olfactory sensory neurons produced no modulation of axonal action potential conduction in individual trigeminal axons. Similarly, no evidence was found for collateral branching of trigeminal axon that might serve as a conduit for cross-talk between the olfactory and respiratory epithelium and olfactory dura mater. Using direct assessment of action potential activity in trigeminal axons we observed neither paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the rodent nasal cavity. Our current results suggest that olfactory sensory neurons exert minimal influence on trigeminal signals within the nasal cavity.

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (T(max)) at 2 hours increases from 2 to 4 hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand‐searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti‐inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene–related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (E(max)). E(max) was compared with known T(max) from pharmacokinetic studies to estimate the delay to pain‐free. The delay in therapeutic gain varied from 1–2 hours for zolmitriptan 5 mg to 7 hours for naproxen 500 mg. An increase in effect from 2 to 4 hours was observed after eletriptan 40 mg, frovatriptan 2.5 mg and lasmiditan 200 mg, and after rizatriptan 10 mg (T(max) = 1 h) from 1 to 2 hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino‐vascular system did not yield a simple explanation for the delay. In addition, E(max) for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.

Die Dura mater encephali und grose zerebrale Arterien gelten als die entscheidenden Strukturen, von denen Kopfschmerzen ausgehen, da ihre Reizung ausschlieslich Kopfschmerzempfindungen hervorruft. Inwieweit auch extrakraniale Strukturen wie die Kopf- und Halsmuskulatur mit ihren Triggerpunkten daran beteiligt sind, wird immer wieder kritisch diskutiert. Als Erklarung fur den Einfluss der extrakranialen nozizeptiven Vorgange auf das Kopfschmerzgeschehen wird vor allem die konvergente afferente Innervation auf der Ebene der sekundaren Neurone im trigemino-zervikalen Hirnstammkomplex genannt. Neue strukturelle und funktionelle Untersuchungen, insbesondere sogenannte Tracingexperimente bei Nagern und am Menschen, weisen aber deutlich darauf hin, dass Nervenfasern der Dura mater mit kollateralen Verzweigungen durch Suturen und Venenkanale den Schadelknochen verlassen und Teile des auseren Periost sowie tiefe Schichten der Kopfmuskulatur innervieren konnen. Bei noxischer Stimulation dieser extrakranialen Strukturen wird die Erregung auch in die meningealen Aste der afferenten Fasern fortgeleitet, wodurch Neuropeptide freigesetzt und die Hirnhautdurchblutung gesteigert werden konnen. Der Nachweis solcher extrakranialen Kollateralen meningealer Nervenfasern fuhrt zu einer veranderten Sicht auf Vorgange, die der Auslosung von Kopfschmerzen und ihrer therapeutischen Beeinflussung durch extrakraniale Manipulationen zu Grunde liegen.

Objective In this review we attempt to characterize the acute and chronic role of 5-HT2B receptors with regard to meningeal nociception in animal experiments and clinical data targeting migraine therapy. Background Migraine is a common disabling neurovascular primary headache disease, the pathomechanism of which is still unclear. Serotonin (5-HT) and its receptors might play an important role in some aspects of migraine pathogenesis. The ability of the unselective 5-HT2B receptor agonist m-chlorophenylpiperazine to induce migraine attacks in migraine sufferers, the high affinity of prophylactic antimigraine drugs to this receptor and its expression in migraine-relevant structures like the dura mater argue for a role of 5-HT2B receptors in the pathogenesis of migraine attacks. Methods For this review, the relevant databases such as PubMed, MEDLINE®, Cochrane Library and EMBASE, respectively, were searched to December 2015 using the keywords “migraine, 5-HT2, trigeminal, neurogenic inflammation, nitric oxide, nitroxyl, vasodilatation, plasma protein extravasation” and combinations thereof. Conclusion Our literature review suggests an important role of 5-HT2B receptor activation in meningeal nociception and the generation of migraine pain.

Activity within the CNS can be quantified by a variety of methods. Here, we present an indirect method utilizing the neuro-vascular coupling via a continuous measurement of the vessel diameter. In anaesthetized rats, induced neuronal activity in the trigeminal system could be detected via arterial diameter measurements at the back of the medullary brainstem. Building upon the previously described diameter plugin, in images aligned to compensate for ventilation and heart-rate associated movement, automated processing allowed an evaluation immediately after acquisition. Electrical stimulation of facial trigeminal areas or the cranial dura mater caused vasodilatation of arteries in the dorsal medullary brainstem, which was abolished after application of the CGRP receptor antagonist olcegepant. No change in diameter was observed in corresponding veins. Intravenous infusion of sodium sulfide, which induces nitroxyl formation, also induced vasodilatation of brainstem-supplying arteries. Both experiments show a functional role of CGRP in the trigeminal nuclear brainstem complex. The presented method allows estimating central activity at the spinal level by vascular responses.

Introduction Migraine is characterized by cycling phases (interictal, preictal, ictal and postictal) with differing symptoms, while in chronic tension type headache pain phases are fluctuating. The question we asked is whether these phases are associated with changes in parameters of somatosensation and axon-reflex erythema. Methods Patients with episodic migraine and chronic tension type headache were examined psychophysically in the interictal, preictal and ictal phase and healthy subjects on five different test days. Thresholds and suprathreshold ratings of pressure and electrical pain were assessed on three different regions of the head. In migraine patients and in healthy controls, electrically induced axon-reflex erythema was measured in the area of the first trigeminal branch. All migraine patients filled out questionnaires about prodromal symptoms at every visit. Results The axon-reflex erythema was always larger in patients with migraine in contrast to healthy subjects. The pressure pain threshold was lower in migraine patients and chronic tension type headache in comparison to healthy subjects. Electrical pain thresholds did not differ between headache patients and healthy subjects and showed no changes between the phases. However, suprathreshold pain ratings showed less habituation solely in the preictal phase of migraine. The number of prodromal symptoms in migraine patients was increased in the preictal and ictal phase. Discussion Reduced habituation was the unique sign of the preictal phase in migraine patients, independently of prodromal symptoms, whereas a larger axon-reflex erythema and higher pressure pain sensitivity are constitutional and non-phase dependent properties of migraine. Reduced inhibitory mechanisms in the preictal phase may contribute to trigger headache attacks in migraine.

Background Meningiomas are generally slowly growing intracranial tumors. They are often incidentally diagnosed, given that symptoms may be absent even in cases of an enormous tumor size. Headache is a frequent but not consistent symptom. Therefore, we examined the association between structural, biochemical and histochemical tumor parameters with preoperative as well as postoperative occurrence of headache. Methods In our study, we prospectively investigated 69 consecutive patients enrolled for meningioma neurosurgery. Anatomical, histological and biochemical parameters were acquired, and headache parameters were registered from the clinical report and from a questionnaire filled by the patients before neurosurgery. The headache was re-evaluated one year after neurosurgery. The study was designed to exploratively investigate whether there is an association of acquired clinical and biological parameters with the occurrence of preoperative and postoperative headache. Results Edema diameter and the proliferation marker MIB-1 were negatively associated with the incidence and intensity of preoperative headache, while the content of prostaglandin E2 in the tumor tissue was positively associated with preoperative headache intensity. Headache was more prevalent when the meningioma was located in the area supplied by the ophthalmic trigeminal branch. Compared to preoperative headache levels, an overall reduction was observed one year postoperative, and patients with a larger tumor had a higher headache remission. In parietal and occipital meningiomas and in those with a larger edema, the percentage of the headache remission rate was higher compared to other locations or smaller edema. Multivariable analyses showed an involvement of substance P and prostaglandin E2 in preoperative headache. Conclusions The study demonstrates new associations between meningiomas and headache. The postoperative headache outcome in the presented patient sample is encouraging for the performed neurosurgical intervention. These results should be tested in a prospective study that incorporates all patients with meningiomas.

Introduction The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches. Methods An online search based on PubMed was made using the keyword “trigeminal ganglion” in combination with “anatomy”, “headache”, “migraine”, “neuropeptides”, “receptors” and “signaling”. From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation. Results The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1–V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non-calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells. Conclusions The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood-brain barrier should therefore be taken into account.

Turkey red is a traditional pigment for textile dyeing and its use has been proven for various cultures within the last three millennia. The pigment is a dye-mordant complex consisting of Al and an extract from R. tinctorum that contains mainly the anthraquinone derivative alizarin. The chemical structure of the complex has been analyzed by various spectroscopic and crystallographic techniques for extractions from textiles or directly in solution. We present an in-situ study of Turkey red by means of μ-XRF mapping and NEXAFS spectroscopy on textile fibres dyed according to a traditional process to gain insight into the coordination chemistry of the pigment in realistic matrix. We find an octahedral coordination of Al that corresponds well to the commonly accepted structure of the Al alizarin complex derived from ex-situ studies.