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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.

Introduction: Experimental animal studies have revealed mechanisms that link cortical spreading depression (CSD) to the trigeminal activation mediating lateralized headache. However, conventional CSD as seen in lissencephalic brain is insufficient to explain some clinical features of aura and migraine headache. Areas covered: The importance of CSD in headache development including dysfunction of the thalamocortical network, neuroinflammation, calcitonin gene-related peptide, transgenic models, and the role of CSD in migraine triggers, treatment options, neuromodulation, and future directions are reviewed. Expert opinion: The conventional understanding of CSD marching across the hemisphere is invalid in gyrencephalic brains. Thalamocortical dysfunction and interruption of functional cortical network systems by CSD may provide alternative explanations for clinical manifestations of migraine phases including aura. Not all drugs showing CSD blocking properties in lissencephalic brains have efficacy in migraine headache and monoclonal antibodies against CGRP ligand/receptors which are effective in migraine treatment, have no impact on aura in humans or CSD properties in rodents. Functional networks and molecular mechanisms mediating and amplifying the effects of limited CSD in migraine brain remain to be investigated to define new targets.

Background: To examine the impact of the lockdown period of the pandemic on COVID-19 phobia and post-traumatic stress disorder in migraine patients.Methods: A total of 73 patients, including 39 migraine and 34 controls, completed the study during the lockdown period. The patients were evaluated by using Structured Headache Questionnaire, PCL-5 and COVID -19 Phobia Scale via the telephone-based telemedicine method.Results: Migraine patients had significantly lower scores in all subgroups of the COVID-19 Phobia Scale (mean = 42.33 ± 12.67) than those in the healthy control group (mean = 52.88 ± 13.18). PCL-5 scale scores in migraine patients were significantly lower (mean = 27.18 ± 14.34) compared to the healthy controls (Mean = 34.03 ± 14.36). Migraine attack frequency decreased or did not change in 67% of the patients during the lockdown period.Conclusion: Acute stress response to an extraordinary situation such as a pandemic may be more controlled in migraine patients, yet specific phobia and post-traumatic stress disorder have been reported more frequently in patients with migraine under normal life conditions. We interpreted that the life- long headache associated stress may generate tendency to a resilience and resistance to extraordinary traumatic events in migraine patients.

Migraine is a multifaceted brain disorder where multisensory disturbances are associated with headache. Yet sensory symptoms are conventionally justified by dysfunctions confined to the cerebral cortex, a perspective through the complex interplay of thalamocortical network would provide the entire picture, more pertinent to the central sensory processing. It is important to consider thalamus as a hub that integrates multiple domains via extensive connections among anatomically and functionally separate cortical areas. Accordingly, cortical spreading depression (CSD), implicated in migraine pathophysiology can be seen as a tool to disconnect thalamocortical network by functionally eliminating cerebral cortex. Hence, including thalamic reticular nucleus and higher order thalamic nuclei, which conveys the information transthalamically among visual, somatosensory, language and motor cortical areas, would greatly improve our current understanding of migraine.Key words:Migraine, headache, sensory discrimination, thalamocortical network, sensory integration, CSD

Background Headache is the most common COVID-19-related neurological symptom. We aimed to reveal diagnostic clues of headache for COVID-19 infection and to investigate the course of primary headaches during the pandemic. Methods We developed a detailed web-based questionnaire screening the characteristics and course of headaches besides clinical COVID-19 features. The participants were grouped according to being diagnosed with COVID-19 infection or not, and having previous or new-onset headaches. The COVID-19 related headache features and their associations with other clinical features were investigated. A binary logistic regression model was performed to differentiate the characteristics of headache related to COVID-19. Findings A total of 3458 participants (2341 females;67.7%, 1495 healthcare workers;43.2%) with a mean age of 43.21 ± 11.2 years contributed to the survey. Among them, 262 participants had COVID-19 diagnosis and 126 (48.1%) were male. The rate of males in the group without COVID-19 was 31% (991 out of 3196 participants) showing significant gender difference between groups (p p p p = 0.04 for long duration and p Interpretation Bilateral, long-lasting headaches, resistance to analgesics and having male gender were more frequent in people with COVID-19 in conjunction with anosmia/ageusia and gastrointestinal complaints. These features may be helpful for diagnosing the headache related to COVID-19 during the pandemic.

A well-balanced intracellular iron trafficking in glial cells plays a role in homeostatic processes. Elevated intracellular iron triggers oxidative stress and cell damage in many neurological disorders, including migraine. This study aimed to investigate the effects of glyceryl trinitrate (GTN), on cellular iron homeostasis, matrixmetalloproteinase (MMP)-9, and calcitonin gene related peptide (CGRP) receptor (CRLR/CGRPR1) production in microglia, astrocyte, and meningeal cell cultures. Primary glial and meningeal cells in culture were exposed to GTN for 24 h. Messenger RNA expression was assessed using qPCR. Iron accumulation was visualized via modified Perl’s histochemistry. MMP-9 levels in cell culture supernatants were measured using ELISA. Ferritin and CRLR/CGRPR1 proteins were visualized via immunofluorescence staining. Nitric oxide production increased significantly with GTN in meningeal and glial cells. GTN significantly increased the expression of the storage protein ferritin for all three cell types, but ferritin-L for meningeal cells and microglia. Iron trafficking associated with the efflux protein ferroportin and influx protein divalent metal transporter (DMT)1 was affected differently in all three cell types. MMP-9 expression was increased in astrocytes. GTN stimulation increased both CRLR/CGRPR1 expression, and immunostaining was apparent in microglia and meningeal cells. This study showed for the first time that GTN modulates intracellular iron trafficking regulated by storage and transport proteins expressed in meningeal cells and glia. CRLR/CGRPR1 expression might be related to altered iron homeostasis and they both may stimulate nociceptive pathways activated in migraine. These molecules expressed differently in glial and meningeal cells in response to GTN may bring not only new targets forward in treatment but also prevention in migraine.

Headache was reported in up to one-third of the hospitalized patients; yet, the clinical characteristics of headache associated with coronavirus disease 2019 (COVID-19) have not been defined. This observational case study included patients who were consulted to headache unit due to headache and had COVID-19 illness. Headache features in 13 PCR-confirmed COVID-19 patients with mild symptoms were reported. Headache was the isolated symptom of the COVID-19 in 3 patients and emerged as an early symptom during the disease course in all patients. Patients specified severe, rapid onset, unrelenting headache with migraine-like features, as well as unusual sensory symptoms such as anosmia, and gastrointestinal symptoms such as diarrhea and loss of appetite and weight. Headache lasted up to 3 days in 70% of the patients and resolved in all patients within 2 weeks. Despite the fact that most of the patients were female and headache characteristics were suggestive of migraine, majority of patients were not suffering from primary headaches. It was concluded that headache could be an isolated symptom of COVID-19, which might possibly be ignored in asymptomatic patients. Headaches associated with COVID-19 included features resembling migraine and/or atypical symptoms including anosmia and diarrhea.

Background and objective The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. Methods CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. Results MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. Conclusion CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

To clarify the causal relationship between migraine and atopic disorders in children and adolescents.Migraine headache and atopic disorders including asthma are both common functional syndromes of childhood in which nature of the relationship is still debated. Attacks may induce in both disorders upon exposure to potential triggers in genetically susceptible individuals. Clinical phenotype manifests by temporary dysfunction of target tissue mediated by inflammation triggered by specific agents. Clinical features also change after puberty because of the partial effect of female sex hormones on the process. Appropriate definition of the syndrome and differentiating from other disorders are necessary not only for correct diagnosis, but also for planning of management strategies in children. Allergic rhinosinusitis needs to be differentiated from migraine even in experienced clinics. Questioning the presence of cranial autonomic symptoms is important clue in the differential diagnosis. Atopic disorder screening is particularly required in the diagnosis of migraine in childhood and adolescents. The link between both disorders of childhood seems to be far from a coincidence and some common inflammatory mechanisms are shared.On the basis of clinical features, laboratory findings and some practical clues in children, accurate diagnosis of migraine and atopic disorders are very critical for physicians, pediatricians and algologists.

bstractObjective.It has been shown that patients with migraine have endothelial dysfunction. Migraine patients with aura, especially, have more clinical manifestations of autonomic nervous system dysfunction. We aimed to evaluate the endothelial and autonomic functions in migraine patients during both migraine headache attack and headache-free periods.Design.This was a cross-sectional, randomized study.Subjects and Methods.A total of 130 participants (67 male and 63 female patients, minimum age1⁄419 years, maximum age1⁄471 years, mean age1⁄438.8612.2 years) were enrolled into the study. For the statistical evaluation of data, we classified the participants of the study as fol- lows: group 1: headache (þ) aura (þ); group 2: headache (þ) aura (􏰀); group 3: headache (􏰀) aura (þ); group 4: head- ache (􏰀) aura (􏰀). Noninvasive evaluation of endothelial function was performed by flow-mediated dilation (FMD) and pulse wave analysis methods. Heart rate variability measurements were used for noninvasive evaluation of au- tonomic functions.Results.Group 1 had a higher FMD ratio than the control group, group 3, or group 4 (P0.001,P0.001, andP1⁄40.003, respectively). Group 4 had lower FMD ratio levels than the other migraine groups and or the control group (P0.001). Group 3 had the highest high-frequency (HF) power levels among all migraine groups (P<0.001). Group 2 had higher low-frequency/HF ratio values than other migraineurs (P<0.001).Conclusions.We concluded that endothelial dysfunction and headache are closely related. Additionally, higher parasympathetic to- nus might be associated with the presence of aura.Key Words:Migraine Disorders; Endothelium; Autonomic Nervous System Diseases

WOS:000583303300001 PubMed ID: 33124044 The coronavirus disease 2019 (COVID-19) pandemic has rapidly transformed the whole world and forced us to look through comorbid diseases and risk factors from a different perspective. COVID-19 shows some inherent risk factors like cardiovascular comorbidities independent from age, gender, and geographic location. One of the most peculiar features of the COVID-19 pandemic is that severe acute respiratory syndrome coronavirus 2 respiratory infections disproportionately impact patients with hypertension, diabetes, and other cardiovascular comorbidities rather than those with allergic respiratory diseases and immune-compromised conditions. Migraine is a complex neuro-vasculo-inflammatory disorder that is also packed frequently with certain medical conditions including vascular disorders, hypertension, allergic diseases such as asthma and systemic inflammatory disorders. Accordingly, 2 different questions arise during the pandemic: (1) Do share comorbidities of cardiovascular diseases and hypertension increase the risk of symptomatic COVID-19 for migraine patients? (2) Do comorbid allergic and atopic diseases, including asthma act as opposite influencers alongside with female gender? This paper focuses on the co-existence of comorbidities of COVID-19, in comparison with migraine, based on a wide clinical dataset and available reports. Discussed mechanisms include potential strategic roles of angiotensin-converting enzyme 2, angiotensin-II, and nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 inflammasome, playing remarkable parts in the pathogenesis of COVID-19 and migraine. There are also some clues about the importance of endothelial and pericyte dysfunction and neuroinflammation in COVID-19 infection, related to complications and survival of the patients. The large epidemiological studies as well as basic research, focusing on migraine patients with COVID-19 will clarify these vital questions during the upcoming periods. Turkish Academy of Sciences (TUBA)Turkish Academy of Sciences; Gazi UniversityGazi University; Istanbul UniversityIstanbul University The authors would like to thank Dr. Didem Derici Yildirim for re-analizing the data and producing Figure 1. The study partially supported by Turkish Academy of Sciences (TUBA), and Gazi University and Istanbul University Research Projects.

Migraine is a complex brain disorder and initiating events for acute attacks still remain unclear. It seems difficult to explain the development of migraine headache with one mechanism and/or a single anatomical location. Cortical spreading depression (CSD) is recognized as the biological substrate of migraine aura and experimental animal studies have provided mechanisms that possibly link CSD to the activation of trigeminal neurons mediating lateralized head pain. However, some CSD features do not match the clinical features of migraine headache and there are gaps in translating CSD to migraine with aura. Clinical features of migraine headache and results from research are critically evaluated; and consistent and inconsistent findings are discussed according to the known basic features of canonical CSD: typical SD limited to the cerebral cortex as it was originally defined. Alternatively, arguments related to the emergence of SD in other brain structures in addition to the cerebral cortex or CSD initiated dysfunction in the thalamocortical network are proposed. Accordingly, including thalamus, particularly reticular nucleus and higher order thalamic nuclei, which functions as a hub connecting the visual, somatosensory, language and motor cortical areas and subjects to modulation by brain stem projections into the CSD theory, would greatly improve our current understanding of migraine.

Background and Objective Migraine attacks disrupt sensory information processing and may also disturb sensorimotor integration. This prospective pilot study aimed to assess the sensorimotor integration and inhibitory circuitry in the sensorimotor cortex using short-latency afferent inhibition (SAI) paradigm in migraine. Methods Twenty-five migraine without aura patients (10 interictal, 5 preictal, 10 ictal) and 16 healthy controls were enrolled. SAI was elicited by combining the right median nerve electrical stimulation and left motor cortical magnetic stimulation at the 21-millisecond interval. Mean motor evoked potential (MEP) amplitude ratio, recorded from right abductor pollicis muscle after single and conditioned stimulations, was calculated as SAI. Results Average MEP inhibition ratio after single and conditioned stimuli in healthy controls was not significantly different from interictal patients (45.1% +/- 20.3% vs 44.5% +/- 14.75% [P = .93]). However, SAI was significantly reduced during preictal/prodromal (-14.6% +/- 42.8% [P = .002]) and ictal/headache (-7.4% +/- 31.1% [P = .0001]) periods of migraine compared to healthy controls. Conclusion Pronounced decrease in SAI during preictal and ictal periods in migraine was shown for the first time. Instead of inhibition to a conditioned stimulus, facilitation in the sensorimotor cortex was detected both ictally and preictally. Preictal SAI results suggest the presence of increased excitability state several hours prior to the headache phase. This phenomenon could be related to the cortical hyperresponsivity to sensory stimuli and cognitive disturbances accompanying migraine attacks as SAI is modulated by cholinergic activity.

Migraine is a common neurological disorder with significantly higher incidence and prevalence in women than men. The presentation of the disease in women is modulated by changes in sex hormones from adolescence to pregnancy and menopause. Yet, the effect of sex influences has often been neglected in both basic and clinical and in clinical management of the disease. In this review, evidence from epidemiological, clinical, animal, and neuroimaging studies on the significance of the sex-related influences in migraine is presented, and the unmet needs in each area are discussed. © 2016 Wiley Periodicals, Inc.

Background and objective Somatosensory temporal discrimination was recently reported as prolonged during migraine attacks, which is consistent with disrupted sensorial perception in migraine. However, knowledge about central sensory processing in tension-type headache is still lacking. This prospective, controlled study aimed to investigate somatosensory temporal discrimination thresholds in tension-type headache. Methods The study included 10 tension-type headache patients, 10 migraine patients and 10 healthy volunteers without headache. Somatosensory temporal discrimination thresholds were evaluated during the headache attacks of tension-type headache and migraine patients. Results Somatosensory temporal discrimination thresholds of tension-type headache patients (39.0 ± 5.5 ms for the right hand and 40.6 ± 4.6 ms for the left hand) were significantly lower than those of episodic migraine patients (137.1 ± 35.8 ms for the right hand and 118.4 ± 34.3 ms for the left hand, p Conclusion Central sensory processing, as tested by somatosensory temporal discrimination, was remarkably disrupted during the headache attacks in migraineurs, whereas it remained intact in the tension-type headache patients.

The functional anatomy of the trigeminal nerve and upper cervical nerves in transmitting head and neck pain is briefly reviewed. The chapter will focus on specific structures that interventional approaches target in headache management. The aim is to provide a general view and an understanding of the mechanisms underlying peripheral nerve interventions in clinical practice.

Animal models have provided a growing body of information about the pathophysiology of headaches and novel therapeutic targets. In recent years, experiments in awake animals have gained attention as more relevant headache models. Pain can be assessed in animals using behavioral alterations, which includes sensory-discriminative, affective-emotional and cognitive aspects. Spontaneous behavioral alterations such as increased grooming, freezing, eye blinking, wet dog shake and head shake and decreased locomotion, rearing, food or water consumption observed during pain episodes are oftentimes easy to translate into clinical outcomes, but are giving little information about the localization and modality of the pain. Evoked pain response such as tactile and thermal hypersensitivity measures are less translatable but gives more insight into mechanisms of action. Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evaporation test and Hargreaves’ test in animal models. Anxiety and depression are the most frequent comorbid diseases in headache disorders. Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or light/dark box tests. Interpretation of the latter test is challenging in migraine models, as presence of photophobia or photosensitivity can also be measured in light/dark boxes. Depressive behavior is assessed with the forced-swim or tail suspension tests. The majority of headache patients complain of cognitive symptoms and migraine is associated with poor cognitive performance in clinic-based studies. Cluster headache and tension type headache patients also exhibit a reversible cognitive dysfunction during the headache attacks. However, only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies. Thus, the headache field has an excellent and growing selection of model systems that are likely to yield exciting advances in the future.

Background Vestibular migraine (VM) is one of the most common underdiagnosed disorders. We aimed to study the clinical characteristics of VM patients who were referred to a neurology-headache unit by otolaryngology after exclusion of peripheral causes of vertigo. Methods One hundred and one patients diagnosed with VM in the headache unit were included. Description of vestibular symptoms, demographic and clinical features, trigger factors, accompanying diseases, and response to vestibular-suppressant medications and prophylactic migraine treatment were evaluated. Results Vestibular symptoms were triggered by daily head and body movements and mainly consisted of brief attacks lasting seconds (60.4% of patients) although the total duration of the vestibular episode lasted hours or days. Other aggravating factors were moving visual stimuli, passive motion, and visually busy environments. Visually induced vestibular symptoms were defined by 71.3% of the patients, and positional motion-induced vestibular symptoms were described by 82.2% of the patients. Vestibular symptoms were mainly defined as feeling the ground slipping from under their feet (40.6%), feeling like there is an earthquake or swaying (27.7%), sensation of rocking on a boat (26.7%), and sensation as if stepping on empty space (24.8%). The majority of the patients (83.2%) previously used vestibular-suppressant drugs, and these drugs were effective temporarily only in 12.9%. Conclusions Chronic recurrent dizziness symptoms, rather than internal or external vertigo, are predominant in our VM patients. Recurrent brief dizziness attacks induced upon routine visual and/or postural motion, longstanding symptoms with limited response to vestibular suppressants, and precipitation by typical migraine triggers are suggestive of VM.

Aim Chronic migraine is a growing and disabling subtype of migraine with different risk factors and clinical features, even in older adults. We sought to define and differentiate clinical features of chronic migraine in older adults. We also aimed to compare major clinical features of chronic migraine in older adults with those in younger people of both sexes. Methods We used electronic dataset (Turkish Headache Database) from 13 tertiary headache centers in Turkey. Electronic dataset included detailed headache-defining features according to ICHD-II criteria based on face-to-face interviews and examination by a headache specialist. Using statistical methods, clinical variables of chronic migraine in older adults were compared with those of younger adults. We included 915 patients with chronic migraine (mean age 43.80 ± 13.95 years); 83.3% were females. In total, 301 patients (32.9%) with chronic migraine aged >50 years were compared with 614 patients aged

Migraine is a serious health problem which impair quality of life. It is the second most common primary headache that affects approximately more than %10 people in general population. Migraine pathophysiology is still unclear. Increasing results of studies suggest to migraine pathophysiology is related with primary neuronal mechanisms. Migraine pain starts in which region of brain and what brain regions are activated in different stages is unenlightened. There is evidences that growing number of studies which using new imaging techniques as positron emission tomography (PET) and functional magnetic resonans imaging (fMRI) show that migraine and cluster headaches are related with neuronal structures and vasodilatation. There are four phases to a migraine. The prodrome phase, aura, the attack, and the postdrome phase. Some datas obtained from last ten years indicate that cortical excitability has increased in interictal phase too. For many years, studies in rodents show trgimenial nerve is activated and it leads to vasodilatation and neurogenic inflammation in the headache phase. Although the majority of patients encountered in clinical practice are migraine without aura or chronic migraine, experimental studies of the migraine pathophysiology are focusing on the aura model which is used cortical spreading depression.

Background/aim Metoclopramide is an effective and commonly used medication in acute migraine treatment but an experimental evidence base is lacking. We aimed to investigate the antimigraine effect of metoclopramide in a migraine model and whether the analgesic effect of metoclopramide was likely to be D2 receptor-mediated. Materials and methods Cortical spreading depression (CSD) was used to model migraine in adult male Wistar rats. Five CSDs were induced by pinprick. Metoclopramide (two different doses), raclopride, or 0.9% saline were administered 30 min before CSD induction. Two hours after the experiments, brain tissues were examined for c-fos activation. Results In metoclopramide groups brain stem c-fos expression was significantly lower than in the CSD side of the saline group (P = 0.002). In the raclopride group, ipsilateral brain stem c-fos expression was also lower than in the saline group (P = 0.002). No difference in c-fos expression in the ipsilateral trigeminal nucleus caudalis between the raclopride and metoclopramide groups was observed (P > 0.05). Conclusion Metoclopramide is shown to suppress trigeminovascular activation for the first time, providing an experimental basis for its role in migraine. The analgesic effect of metoclopramide is likely to be mediated by D2 receptors since raclopride, a selective D2 receptor antagonist, suppresses trigeminovascular activation similarly.

An altered neurovascular coupling has been proposed in migraine. We aimed to investigate neurovascular coupling during a mental task interictally in patients with migraine without aura (MO) by near-infrared spectroscopy (NIRS). Twelve migraineurs and 12 healthy controls were included. Using NIRS, we recorded the magnitude and latency of cortical changes in oxyhaemoglobin (HbO2) and deoxyhaemoglobin (Hb) during the colour-word matching Stroop test via 16 channels covering the forehead. We found no differences in the magnitude of responses between migraineurs and healthy subjects in the incongruent Stroop task subtracted by the neutral Stroop task on either side of the frontal cortex for HbO2 (left, P = 0.984; right, P = 0.406) or Hb (left, P = 0.689; right, P = 0.406) values. No differences in error rate ( P = 0.611) or reaction time ( P = 0.936) were found between healthy subjects and MO patients for incongruent tasks. The present study suggests that vascular reactivity and oxygen supply during a mental task in patients with MO are intact interictally.

Background and Objective Symptoms and signs of sensorial disturbances are characteristic features of a migraine headache. Somatosensory temporal discrimination measures the temporal threshold to perceive two separate somaesthetic stimuli as clearly distinct. This study aimed to evaluate somaesthetic perception in migraine patients by measuring the somatosensory temporal discrimination thresholds. Methods The study included 12 migraine patients without aura and 12 volunteers without headache. Somatosensory temporal discrimination threshold (STDT) values were measured in the face (V3) and hands (C7) during a lateralized headache attack and the headache-free interictal period. The disease duration, pain intensity, phonophobia, photophobia, nausea, vomiting, and brush allodynia were also recorded during the migraine attack. Results STDT values were within normal limits and not different between the control group and the interictal period in migraine patients. Compared to the headache-free period, STDT values during the attack were significantly prolonged in the contralateral hand (C7) (155.7 ± 84.2 vs 40.6 ± 16.1 ms [P

Background and aims Migraine headache is one of the most common primary headache disorders and is three times more prevalent in women than in men, especially during the reproductive ages. The neurobiological basis of the female dominance has been partly established. The present study aimed to investigate the effect of gender on the headache manifestations in migraine patients. Methods The study group consisted of 2082 adult patients from five different hospitals’ tertiary care-based headache clinics. The relationship between headache characteristics and gender was evaluated in migraine with aura (MwA) and migraine without aura (MwoA). The duration, severity, frequency of headache and associated symptoms were evaluated in both genders and age-dependent variations and analyzed in two subgroups. Results Women with migraine were prone to significantly longer duration and intensity of headache attacks. Nausea, phonophobia and photophobia were more prevalent in women. Median headache duration was also longer in women than in men in MwA ( p = 0.013) and MwoA ( p Conclusion Gender has an influence on the characteristics of the headache as well as on the associated symptoms in migraine patients, and this impact varies across the age groups, particularly in women.

A 38-year-old Caucasian woman suffering from headache attacks that interfered with activities of daily living visited a headache specialist for the first time. The frequency and severity of her headache attacks had increased over the previous 4 months, and she was suffering one or two attacks every week. Her attacks were throbbing and mostly one-sided, either on the right or the left side of her head. The pain would start from the neck and spread to the forehead in some attacks, but in most it would start from the temple on one side and spread behind the ipsilateral eye. During headache attacks, any movement of her head would increase the intensity of headache, and light and noise would disturb her. Severe attacks were associated with nausea without vomiting. She experienced increased sensitivity to touch on her scalp, predominantly on the headache side and particularly during severe headache attacks. Just before an attack, she would yawn repeatedly. She had never experienced any visual, sensory, or speech problem or any transient neurological dysfunction preceding the headache. In the absence of taking any painkiller such as ibuprofen or another nonsteroidal anti-inflammatory drug, the headaches could last up to 3 days. The intensity of her headache attacks was generally severe. She was a manager in public relations in a large company. If she had a severe headache she was unable to perform any work activities and sometimes had to go home when she could not successfully treat the pain. Five months earlier, her position in the company had changed and she was given additional responsibilities. She was married with two daughters, 13 and 5 years old. Her headache attacks had started nearly 1 year after her first delivery. The frequency of attacks was one or two times a month up to the second pregnancy. For 2 years after the first delivery she was taking oral contraceptive pills (OCPs), but had to stop taking them because of a marked increase in the frequency of headache attacks. During the second pregnancy she had almost no headache attacks, but 1 week after the delivery her attacks returned, with pain more severe than before.

This study investigated the effect of repetitive cortical spreading depression (CSD) on behaviour and the anatomical and physiological patterns of cellular activation of cortical and subcortical areas in awake, moving rats. Rat behaviours in response to repetitive CSD events evoked by the application of KCl were quantified with electrophysiological recording. Immunohistochemistry was used to quantify anatomical regions of cellular activation. The effects of acute valproic acid administration on the behavioural parameters and cellular activation were evaluated. CSD significantly decreased locomotor activity and induced freezing in awake, moving rats, and stimulated c-Fos expression in the cortex, trigeminal nucleus caudalis (TNC), and amygdala. CSD also resulted in a prominent increase in c-Fos expression in the ipsilateral thalamic reticular nucleus (TRN) visual sector. Electrophysiological recordings revealed propagation of CSD into the TRN. Valproic acid pretreatment decreased the duration of CSD-induced freezing episodes and reversed the CSD-induced reduction in locomotor activity. Acute valproic acid administration also significantly blocked CSD-induced c-Fos expression in the TNC and TRN. These findings show that CSD events cause consistent behavioural responses and activate specific brain regions in awake, freely moving rats. Selective activation of TRN by CSD and the suppression of this activation by valproic acid suggest that this brain region may play an important role in migraine pathogenesis and may represent a novel target for migraine therapy.

Migraine headache is generated by the complex interaction of various players such as genetic predisposition, environmental triggers and intrinsic factors. The initial mechanism of a migraine attack has long been a controversial topic and exploring its origin is a challenging task. The scientific evidences so far indicate neuronal dysfunction in the cerebral cortex and particularly cortical spreading depression waves, as upstream to cascade of events leading to a migraine attack. Neocortex, evolutionary valuable part of the brain, is surrounded by pain sensing system that is finely tuned for detecting noxious signals. Abnormal functioning of more than one cortical area in migraineurs may suggest that hyperexcitable neocortex could be more easily challenged, overreacts and depolarize to repetitive sensorial stimuli and could switch to extreme excitability state where spreading depression waves occur. In this paper, I will review the data supporting the notion that migraine is a neuronal disorder where cortex has prime importance. Despite clear demonstration of cortical participation in migraine, the contribution of brain structures other than cortex to the development of migraine remains unclear.

Trigeminal nerve-mediated pain disorders such as migraine, temporomandibular joint disorder, and classical trigeminal neuralgia are more prevalent in women than in men. Female laboratory animals also show greater responses to various nociceptive stimuli than male animals. However, current knowledge of migraine pathogenesis is based primarily on experimental studies conducted in male animals and lack of migraine research with female animals limits clinical relevance. Migraine is triggered by any alteration in the intrinsic or extrinsic milieu and women at reproductive age are continuously prone to waxing and waning effects of female sex hormones. The experimental approach to this problem is complex because the rodent estrous cycle differs from the human cycle, and because exogenous hormone replacement in ovariectomized females has its limitations. The existence of multiple estrogen receptors in the trigeminal system also presents a challenge. Estrogens do not seem to directly affect calcitonin gene-related peptide or 5-HT(1D) receptors in the trigeminal system. Nonetheless, 2 estrogen receptors activate MAPK/ERK signaling pathway that mediates nociceptive processing in trigeminal nucleus caudalis. In addition, estrogen enhances susceptibility to cortical spreading depression, the neurobiological event underlying migraine aura, which may be independent of the estrous cycle. Further studies in female animals are required to clarify mechanisms underlying sex differences with respect to fluctuating sex hormones, cortical spreading depression, and excitability of the trigeminovascular system.

Headache treatment has been based primarily on experiences with non-specific drugs such as analgesics, non-steroidal anti-inflammatory drugs, or drugs that were originally developed to treat other diseases, such as beta-blockers and anticonvulsant medications. A better understanding of the basic pathophysiological mechanisms of migraine and other types of headache has led to the development over the past two decades of more target-specific drugs. Since activation of the trigeminovascular system and neurogenic inflammation are thought to play important roles in migraine pathophysiology, experimental studies modeling those events successfully predicted targets for selective development of pharmacological agents to treat migraine. Basically, there are two fundamental strategies for the treatment of migraine, abortive or preventive, based to a large degree on the frequency of attacks. The triptans, which exhibit potency towards selective serotonin (5-hydroxytryptamine, 5-HT) receptors expressed on trigeminal nerves, remain the most effective drugs for the abortive treatment of migraine. However, numerous preventive medications are currently available that modulate the excitability of the nervous system, particularly the cerebral cortex. In this chapter, the pharmacology of commercially available medications as well as drugs in development that prevent or abort headache attacks will be discussed.

Migraine is hypothesized to be a neurovascular coupling disorder where the cerebral vascular reactivity is malfunctioning and measuring hemodynamic changes during migraine without causing more disturbance has always been a challenge. Functional near infrared spectroscopy system (fNIRS) is being proposed as an inexpensive, rapid, safe and accurate alternative to fMRI, transcranial doppler sonography (TCD). We have developed NIROXCOPE 201, a novel device for fNIRS which offers 16 source-detector pairs distributed on a probe that is placed on the forehead. Measuring hemodynamic changes during migraine without causing more disturbance has always been a challenge. Using NIROXCOPE 201, we have attempted to investigate the cerebrovascular reactivity of migraine patients to a breath hold task which produces a metabolic perturbation. Six normals and six migraine patients performed four consecutive breath holding task. We calculated the peak and latencies of the initial dip and recovery phases for [Hb], [HbO(2)], [tHb], and [OXY] signals. [Hb], [tHb], and [OXY] ID and R amplitudes of normals are approximately a magnitude higher than migraine patients (P < 0.01), while latencies showed no significant differences. Data suggests an altered neurovascular coupling in frontal cortex of migraine patients interictally. The application of NIROXCOPE 201 to patients suffering from other primary headache disorders will reveal diagnostic as well as therapeutic implications of the presented study. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Migraine is a disabling neurovascular disorder with a complex pathophysiology. Functional imaging and magneto encephalographic studies strongly suggest that Cortical Spreading Depression (CSD) constitutes the biological basis for the neurologic aura that precedes headache in one fourth of migrainers. It is likely that the aura is the generator of the headache since experimentally, CSD triggers the activation of the trigeminovascular system, possibly through matrix metalloproteases activation which is associated with an increase in vascular permeability. These data may have therapeutic implications: strategies to block trigeminal activation or its downstream consequences are central to treat the acute headache whereas strategies to block events lying upstream of trigeminal activation would be crucial in prophylaxis. © Masson.

Migraine is a complex chronic neurovascular disorder in which the interictal changes in neuronal excitability and vascular reactivity in the cerebral cortex were detected. The extent and direction of the changes in cerebral blood flow that affect cerebral hemodynamics during attacks, however, are still a matter of debate. This may have been due to the logistic and technical problems posed by the different techniques to determine cerebral blood flow during migraine attacks and the different definitions of patient populations. In this study, we have investigated hypercapnia challenges by breath holding task on subjects with and without migraine by using functional near infrared spectroscopy (fNIRS). Measurements of the relative changes in concentration of deoxy-hemoglobin [Hb] and oxy-hemoglobin [HbO2] are performed on four healthy subjects during three breath holdings of 30 seconds (s.) interleaved with 90 s. of normal breathing. We have observed [Hb]increase during breath holding interval in subject without migraine whereas in subject with migraine [Hb] decreases during breath holding interval. The result of our study suggest that hypercapnia effect on cerebral hemodynamic of subject with migraine and without migraine could be due to different vascular reactivity to PCO2 (carbon dioxide partial pressure) in arteries.

Publisher Summary This chapter highlights recent advances in the neurobiology of migraine headache with the hope that a more coherent scientific basis can be achieved. The discovery that mutated P/Q calcium channels underlie a rare migraine headache subtype, raise expectations that identifying genetic mutations and their neurobiological consequences may help to decipher molecular and cellular mechanisms underlying more typical migraine types. Recent magnetic resonance imaging (MRI) studies using high field strength near-continuous recordings suggest a strong relationship between the visual aura and cortical spreading depression (CSD) within the occipital lobe. CSD is a transient phenomenon affecting one hemisphere or cerebral gyrus characterized by slowly propagating excitation followed by a long-lasting depression of neuronal and glial neurophysiological activity. Furthermore, this chapter discusses headache associated with migraine. Perception of headache requires activation of trigeminovascular system. This chapter also presents discussions on triptans and other therapeutic approaches to treat migraine.

Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve.

Cortical spreading depression (CSD) is implicated in migraine. Pain behavior is important for experimental migraine studies.

This study investigates the brain hemodynamic responses of migraine and healthy subjects to breathholding task with ARX model. Analysis has shown that the amplitude of peak response of migraineurs is five folds smaller (p

Chronic migraine is a debilitating disease particularly in women and underlying pathophysiology remains unclear. Clinically relevant migraine models are missing.