BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.

Objetivos: O objetivo deste estudo foi avaliar o limiar de dor a pressão (LDP) em crianças com migrânea, o impacto da cefaleia e a qualidade de vida relacionada a saúde. Métodos: Compuseram a amostra 50 crianças com migrânea sem aura de ambos os gêneros de 6 a 12 anos de idade que estavam em atendimento no Ambulatório de Cefaleia Infantil e 50 crianças sem diagnóstico de migrânea ou outro tipo de cefaleia há pelo menos 3 meses que estavam em acompanhamento no Ambulatório de Problemas de Crescimento e Desenvolvimento do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, em 2010 e 2011. O LDP foi avaliado com a utilização de um algômetro digital em 9 pontos anatômicos bilaterais (total 18), determinados pelo Colégio Americano de Reumatologia. Para verificação do impacto da cefaleia na vida destas crianças foi aplicado o questionário PedMIDAS (Pediatric Migraine Disability Score) e para qualidade de vida relacionada a saúde foi aplicado o questionário PedsQL4.0 (Pediatric Quality of Life InventoryTM) nas crianças e nos pais. Na análise estatística foi utilizado o modelo linear de efeitos mistos (efeitos aleatórios e fixos) e o coeficiente de correlação de Sperman (?). Resultados: Os resultados mostram que em se somando todas as regiões corporais avaliadas, não foi possível detectar diferença do LDP entre as crianças com migrânea e as do grupo controle. Entretanto quando os grupos foram descriminados pelo gênero, tanto as garotas quanto os garotos com migrânea apresentam LDP baixo em pelo menos uma região avaliada, do que os garotos e garotas sem cefaleia. O LDP foi baixo em um ponto cefálico (musculatura suboccipital) e um ponto extracefálico (aspecto anterior de C5-C7) nas crianças com migrânea. O ponto cefálico obteve LDP baixo em relação aos pontos extracefálicos, em ambos os grupos, exceto a região de segundo espaço intercostal. A cefaleia interfere nas atividades diárias, principalmente escolar, das crianças com migrânea, independente do gênero. E a qualidade de vida relacionada à saúde não se apresentou pior em crianças com migrânea comparadas com as sem cefaleia, pela percepção das crianças. Mas pela percepção dos pais, a qualidade de vida relacionada á saúde é pior em crianças com migrânea. Nenhuma correlação foi encontrada entre: LDP e dias perdidos devido à cefaleia, LDP e qualidade de vida. Conclusões: Este estudo demonstrou que a migrânea não está associada com dor muscular generalizada, mas que interfere nas atividades diárias, principalmente na escolar, independentemente do gênero. Pela percepção dos pais a qualidade de vida relacionada á saúde é pior em crianças com migrânea que nos controles. / Objectives: The objective of the present study was to assess the pressure pain threshold (PPT) of children with headache and the impact of headache on healthrelated quality of life. Methods: The sample consisted of 50 children of both genders aged 6 to 12 years with migraine without aura, who were being followed up at the Childhood Headache Outpatient Clinic and 50 children without a diagnosis of migraine or other headache for at least 3 months who were being followed up at the Growth and Dveleopment Problems Outpatient Clinic of the University Hospital, Faculty of Medicine of Ribeirão Preto, in 2010 and 2011. The PPT was evaluated using a digital algometer at 9 bilateral points (a total of 18) determined by the American College of Rheumatology. The Pediatric Migraine Disability Score (PedMIDAS) questionnaire was applied to determine the impact of headache on the life of these children and the Pediatric Quality of Life InventoryTM (PedsQL4.0) questionnaire was applied to determine the quality of life related to health in children and parents. The statistical analysis used the linear mixed effects (random and fixed effects) and the Spearman correlation coefficient (?). Results: The results showed that, when all the body regions evaluated were summed, it was not possible to detect a difference in PPT between children with migraine and controls. However, when the groups were discriminated by gender, both the girls and the boys with migraine presented a lower PPT in at least one of the regions evaluated than boys and girls without headache. The PPT was lower in a cephalic point (suboccipital musculature) and in an extracephalic point (anterior aspect of C5-C7) in children with migraine. The PPT was lower in the cephalic point compared to the extracephalic points in both groups, except for the region of the second intercostal space. Headache interferes with the daily activities, mainly school ones, of children with migraine regardless of gender. And, according to the perception of the children, the health-related quality of life was not worse in children with migraine compared to children without it. However, compared to the perception of the parentes, the health-related quality of life is worse in children with migraine. No correlation was detected between PPT and days lost due to headache, or between PPT and quality of life. Conclusions: The present study demonstrated that migraine was not associated with generalized muscle pain but interfered with daily activities, mainly school ones, regardless of gender. According to the perception of the parents, health-related quality of life is worse in children with migraine than in controls.

Objetivo: verificar a razão extensores/flexores dos músculos cervicais no âmbito de força muscular e atividade eletromiográfica durante a mensuração da força na contração isométrica voluntária máxima (CIVM) e teste de flexão craniocervical (TFCC) em pacientes com migrânea e em indivíduos sem cefaleia. Além de verificar o desempenho muscular, avaliado pelo TFCC, em ambos os grupos. Materiais e métodos: foram incluídas 52 mulheres com diagnóstico de migrânea segundo a Classificação Internacional de Cefaleias e 52 mulheres sem histórico de cefaleia ou dor cervical com idade entre 18 e 55 anos. No grupo migrânea os questionários Neck Disability Index, Migraine Disability Assessment e 12-item Allodynia Symptom Checklist foram aplicados. Em ambos os grupos a força dos músculos flexores e extensores cervicais foi avaliada utilizando-se um dinamômetro manual (Lafayette Instrument Company®, Lafayette, IN, USA). A CIVM foi mantida por 3 segundos e foram realizadas 3 repetições. Além do teste de força, o TFCC também foi realizado para os dois grupos utilizando-se o dispositivo de pressão Stabilizer Pressure Biofeedback® (Chatanooga, Hixson, TN, USA). O dispositivo, incialmente, foi inflado a 20 mmHg e a participante deveria aumentar 2 mmHg a cada estágio, totalizando cinco estágios (30 mmHg), e manter a pressão por 10 segundos. Em ambos os testes, para os dois grupos, a atividade eletromiográfica dos músculos cervicais foi avaliada por meio de sensores de superfície sem fio (TrignoTM Wireless System, Delsys Inc. Boston, MA). Resultados: observamos que o grupo migrânea apresenta uma redução na força dos músculos flexores em comparação ao grupo controle e consequentemente, uma maior razão de força dos músculos extensores/flexores além de uma reduzida razão eletromiográfica dos músculos extensores/flexores durante a CIVM em flexão. Nossos resultados demonstraram ainda uma pior performance no TFCC no grupo migrânea e consequente aumento da razão eletromiográfica dos músculos extensores/flexores cervicais no último estágio do teste. Conclusão: de acordo com os nossos resultados podemos concluir que mulheres com migrânea apresentam um notável desequilíbrio dos músculos flexores e extensores cervicais em comparação a controles não apenas na produção de força, mas também na atividade muscular. / Objective: To verify the extensor/flexor ratio of neck muscle strength and electromyographic activity at maximal voluntary isometric contraction (MVIC) and at the craniocervical flexion test (CCFT) of patients with migraine and of individuals with no history of headache. In addition, we aimed to assess the performance of both groups at the CCFT. Materials and methods: Fifty-two women with a diagnosis of migraine according to the International Classification of Headache Disorders and 52 women without history of migraine or cervical pain with ages between 18 and 55 years were included. The Neck Disability Index, Migraine Disability Assessment and 12-item Allodynia Symptom Checklist questionnaires were applied to the migraine group. In both groups, cervical muscle strength was assessed during a MVIC using a hand-held dynamometer (Lafayette Instrument Company®, Lafayette, IN, USA). The MVCI was maintained for 3 seconds and 3 repetitions were performed. The CCFT was also performed by the two groups using the Stabilizer Pressure Biofeedback® (Chatanooga, Hixson, TN, USA). The device was initially inflated to 20 mmHg and the participant had to increase 2 mmHg at each stage, achieving five stages (30 mmHg), and maintaining the pressure for 10 seconds. In both tests, the electromyographic activity of the cervical muscles was evaluated using wireless surface sensors (TrignoTM Wireless System, Delsys Inc. Boston, MA). Results: migraine group has a reduction in flexor muscle strength compared to the control group and consequently a greater muscle strength ratio of extensor/flexor and a reduced electromyographic ratio of the extensor/flexor muscles during MVIC in flexion. Our results also demonstrated a worse performance in the CCFT in the migraine group and consequent increase in the electromyographic ratio of the extensor/flexor neck muscles in the last stage of the test. Conclusion: women with migraine present a remarkable imbalance of the flexor and extensors cervical muscles compared to controls not only in the production of strength but also in muscle activity.

Objetivo: verificar a razão extensores/flexores dos músculos cervicais no âmbito de força muscular e atividade eletromiográfica durante a mensuração da força na contração isométrica voluntária máxima (CIVM) e teste de flexão craniocervical (TFCC) em pacientes com migrânea e em indivíduos sem cefaleia. Além de verificar o desempenho muscular, avaliado pelo TFCC, em ambos os grupos. Materiais e métodos: foram incluídas 52 mulheres com diagnóstico de migrânea segundo a Classificação Internacional de Cefaleias e 52 mulheres sem histórico de cefaleia ou dor cervical com idade entre 18 e 55 anos. No grupo migrânea os questionários Neck Disability Index, Migraine Disability Assessment e 12-item Allodynia Symptom Checklist foram aplicados. Em ambos os grupos a força dos músculos flexores e extensores cervicais foi avaliada utilizando-se um dinamômetro manual (Lafayette Instrument Company®, Lafayette, IN, USA). A CIVM foi mantida por 3 segundos e foram realizadas 3 repetições. Além do teste de força, o TFCC também foi realizado para os dois grupos utilizando-se o dispositivo de pressão Stabilizer Pressure Biofeedback® (Chatanooga, Hixson, TN, USA). O dispositivo, incialmente, foi inflado a 20 mmHg e a participante deveria aumentar 2 mmHg a cada estágio, totalizando cinco estágios (30 mmHg), e manter a pressão por 10 segundos. Em ambos os testes, para os dois grupos, a atividade eletromiográfica dos músculos cervicais foi avaliada por meio de sensores de superfície sem fio (TrignoTM Wireless System, Delsys Inc. Boston, MA). Resultados: observamos que o grupo migrânea apresenta uma redução na força dos músculos flexores em comparação ao grupo controle e consequentemente, uma maior razão de força dos músculos extensores/flexores além de uma reduzida razão eletromiográfica dos músculos extensores/flexores durante a CIVM em flexão. Nossos resultados demonstraram ainda uma pior performance no TFCC no grupo migrânea e consequente aumento da razão eletromiográfica dos músculos extensores/flexores cervicais no último estágio do teste. Conclusão: de acordo com os nossos resultados podemos concluir que mulheres com migrânea apresentam um notável desequilíbrio dos músculos flexores e extensores cervicais em comparação a controles não apenas na produção de força, mas também na atividade muscular. / Objective: To verify the extensor/flexor ratio of neck muscle strength and electromyographic activity at maximal voluntary isometric contraction (MVIC) and at the craniocervical flexion test (CCFT) of patients with migraine and of individuals with no history of headache. In addition, we aimed to assess the performance of both groups at the CCFT. Materials and methods: Fifty-two women with a diagnosis of migraine according to the International Classification of Headache Disorders and 52 women without history of migraine or cervical pain with ages between 18 and 55 years were included. The Neck Disability Index, Migraine Disability Assessment and 12-item Allodynia Symptom Checklist questionnaires were applied to the migraine group. In both groups, cervical muscle strength was assessed during a MVIC using a hand-held dynamometer (Lafayette Instrument Company®, Lafayette, IN, USA). The MVCI was maintained for 3 seconds and 3 repetitions were performed. The CCFT was also performed by the two groups using the Stabilizer Pressure Biofeedback® (Chatanooga, Hixson, TN, USA). The device was initially inflated to 20 mmHg and the participant had to increase 2 mmHg at each stage, achieving five stages (30 mmHg), and maintaining the pressure for 10 seconds. In both tests, the electromyographic activity of the cervical muscles was evaluated using wireless surface sensors (TrignoTM Wireless System, Delsys Inc. Boston, MA). Results: migraine group has a reduction in flexor muscle strength compared to the control group and consequently a greater muscle strength ratio of extensor/flexor and a reduced electromyographic ratio of the extensor/flexor muscles during MVIC in flexion. Our results also demonstrated a worse performance in the CCFT in the migraine group and consequent increase in the electromyographic ratio of the extensor/flexor neck muscles in the last stage of the test. Conclusion: women with migraine present a remarkable imbalance of the flexor and extensors cervical muscles compared to controls not only in the production of strength but also in muscle activity.

Migraine is a complex neurological disorder that affects approximately 38 million Americans. For over 25 years, the neuropeptide calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. In fact, several pharmaceutical companies are tailoring treatments to antagonize CGRP actions. However, due to the complexity of migraine, exactly how and where CGRP acts to contribute to migraine have remained controversial: whereas several studies suggest that CGRP acts in the central nervous system (CNS) in this context, others have indicated a role in the periphery. Central nervous system sites of action include the trigeminal nucleus and several higher brain regions, and peripheral sites include the vasculature and dural mast cells in the meninges. Among the sites of CGRP action, the trigeminal nerve, which is the major somatosensory structure of the face, is of particular interest because it bridges the CNS and the periphery. Migraine is generally thought to involve abnormal signaling in the trigeminovascular system, and about 50% of trigeminal neurons have CGRP immunoreactivity. Although the notion that CGRP has a central site of action in relation to migraine had gained ground over the past decade, the recent discovery that monoclonal antibodies against CGRP can prevent migraine attacks has resurrected the possibility that a peripheral site of action is involved as well. Clarification of the sites of CGRP action in migraine will be crucial to developing an understanding of mechanisms that underlie migraine so that future treatments can be rationally designed. One diagnostic criterion for migraine is photophobia, a painful and often debilitating response to non-noxious levels of light. Our laboratory previously developed a preclinical model of migraine in which the light-aversive behavior of mice is used as a surrogate of photophobia. Specifically, mice were sensitized to CGRP by introducing a nestin/hRAMP1 transgene. In these mice versus control littermates, light aversion in response to central (intracerebroventricular, ICV) injection of CGRP was enhanced in dim light. In wild-type mice, CGRP (ICV) also elicited aversion to very bright light; this did not occur in vehicle-treated mice. Additionally, I have shown that CGRP injected peripherally (intraperitoneal, IP) can induce significant light aversion in wild-type mice. I have begun to identify the sites of action outside of the central nervous system, using four lines of transgenic mice with different patterns of overexpression of CGRP receptors: global hRAMP1 mice (expression in all tissues), nestin/hRAMP1 mice (expression only in nervous tissue), tagln/hRAMP1 (expression only in smooth muscle cells), and tek2/hRAMP1 (expression in endothelial cells). As predicted, in the global hRAMP mice light aversion, in response, to IP-injected CGRP was enhanced. However, in nestin/hRAMP1 mice, only ICV-injected, and not IP-injected, CGRP induced enhanced light aversion. This finding suggests that peripheral CGRP activates neural pathways involved in light aversion, but by an indirect mechanism. To determine where in the periphery CGRP is acting, a pharmacological and genetic approach was taken. Since CGRP is one of the most potent vasodilators in the body, it is well positioned to have vascular effects that induce light aversive behavior. This hypothesis was based on findings that 1) intravenous administration of CGRP in human subjects can cause migraine pain, and 2) perivascular CGRP can sensitize the trigeminal nerve, which could alter synaptic transmission to the central nervous system and 3) CGRP monoclonal antibodies are effective in clinical trial and likely do not cross the blood brain barrier. Thus, there is a mechanism by which CGRP in the periphery can sensitize the trigeminal nerve and alter sensory perception, leading to photophobia. The role of the vasculature in migraine, specifically vasodilation, has been controversial and now the consensus is that it is neither necessary nor sufficient. First, I wanted to test the role of vasodilation in this model. I pharmacologically inhibited CGRP-induced vasodilation using two vasoconstrictors, phenylephrine and endothelin-1. Blocking CGRP-induced vasodilation partially attenuates the light aversive response. Moreover, mice that overexpress the CGRP receptor in smooth muscle, but not endothelial, cells exhibit enhanced light aversion indicating a role for vascular actions of CGRP in this preclinical model of migraine. These results present clear evidence that CGRP has actions on the vasculature to induce light aversion. Additionally, the inability of blocking vasodilation to completely rescue the light aversion suggests that the vasculature may not be the only peripheral target of CGRP in migraine pathophysiology. This work improves the understanding of peripheral CGRP actions in migraine and raises awareness that contribution of the vasculature in migraine should not be ignored. The identification of sites of CGRP action in regions inside and outside of the CNS could lead to improved and more successful therapeutics for migraine.

Calcitonin gene-related peptide (CGRP) has been strongly implicated in the pathophysiology of migraine. CGRP levels are elevated during a migraine attack. Injection of CGRP can trigger a delayed migraine-like headache in migraineurs. Finally, CGRP receptor antagonists are effective antimigraine therapeutics. Consequently, a CGRP-sensitized mouse, nestin/hRAMP1 was genetically engineered to conditionally express a subunit of the CGRP receptor, hRAMP1, in neurons and glia. In response to CGRP, nestin/hRAMP1 mice demonstrated a significant decrease in time in the light zone of a dim light-dark box compared to vehicle-treated nestin/hRAMP1 mice and CGRP-treated control mice. This reflects photophobia-like behavior. Photophobia is a common symptom of migraine, where light exacerbates the headache pain. Furthermore, CGRP decreased motility in the dark zone, which may reflect exacerbation of pain by movement that is often experienced during a migraine. Wildtype mice have also demonstrated this CGRP-induced behavior, but required bright light and habituation to the chamber. While there is a difference in sensitivity in this assay between wildtype and nestin/hRAMP1 mice, it demonstrates that endogenous CGRP receptors are sufficient to convey this behavior. A common antimigraine drug, rizatriptan, attenuated the CGRP-induced behaviors in wildtype mice validating the assay as a migraine model. To explore the relative contributions of CGRP receptors on neurons versus glia, synapsin/hRAMP1 transgenic mice were genetically engineered to express hRAMP1 in neurons only. In contrast to the nestin/hRAMP1 mice, the synapsin/hRAMP1 mice did not show CGRP-induced light aversion upon naïve exposure to a dim chamber. This suggests that neuronal overexpression of hRAMP1 is insufficient to convey a heighted sensitivity to CGRP in the light aversion assay. As a first step to understanding the mechanism underlying CGRP-induced light aversion, a non-behavioral assay was developed to measure photic blink reflexes by measuring orbicularis oculi EMG responses in mice. Bright light increased orbicularis oculi activity, and an air puff induced a blink response. Interestingly. CGRP and bright light increased the duration of squinting following the air puff-induced blink. This pilot suggests that the trigeminal system plays a key role in mediating CGRP-induced light sensitivity. Overall, these studies propose a potential model for the mechanisms involved in migraine and photophobia in which CGRP likely acts through endogenous CGRP receptors on neurons and glia in the trigeminal system to trigger light sensitivity.

Typical migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a chronic, painful and debilitating neurovascular disease which is generally characterised by recurrent attacks of severe headache usually accompanied by nausea, vomiting, photo and phonophobia. Migraine has been shown to affect a large proportion of Caucasian populations with a recent comprehensive study indicating that around 25% of women and 8% of men suffer from the disease. Strong familial aggregation of typical migraine and an increased concordance for the disease in MZ twins over DZ twins, suggests that it has a significant genetic component. Heritability estimates are calculated to be between 40% and 60%, indicating that disease variation, in part, is explained by environmental determinants. The mode of transmission of typical migraine is not clear but is most likely multifactorial. Although the MA and MO subtypes exhibit some clinical heterogeneity, segregation analysis has suggested that there may be a common genetic aetiology for MA and MO, and a major gene contributing to typical migraine pathogenesis. This idea is substantiated by the fact that both subtypes of migraine can occur within the same family and even within the same individual, with up to 33% of sufferers experiencing both types of the disease. In addition, migraine prophylactics have been shown to result in similar effects in patients treated for both types of migraine. However, whether the two subtypes are truly separate entities or not remains unclear. At present, the type and number of genes involved in typical migraine is not known. Despite this, several studies into Familial Hemiplegic Migraine (FHM), a very severe subtype of MA, have led to the discovery that mutations in a brain specific calcium channel subunit gene (CACNA1A) located on chromosome 19, cause FHM in about 50% of affected families. FHM is a rare disease and is distinguished from typical migraine by its association with hemiparesis and clear autosomal dominant mode of inheritance. However, certain clinical features are common to both FHM and typical migraine including similarities in headache characteristics and triggers. Hence, FHM genetic studies provide a valuable model for investigating the genes involved in the more prevalent types of migraine with and without aura. For this reason the Genomics Research Centre has been conducting linkage studies utilising large Australian migraine pedigrees with a focus on the known FHM (CACNA1A) gene region on chromosome 19p13. Our results to date have indicated suggestive linkage to the FHM region on 19p13 in a large multigenerational pedigree (MF1) affected with typical migraine, with a maximum parametric LOD score of 1.92 (P = 0.001) obtained for a triplet repeat polymorphism situated in exon 47 of the CACNA1A gene. Expansion of this repeat was not observed, but is possible that mutations elsewhere in the CACNA1A gene may be responsible for migraine in this pedigree. To investigate this possibility, the current research involved sequencing two patients carrying the critical susceptibility haplotype surrounding the CACNA1A gene. The results of this mutation screen revealed no disease causing mutations or polymorphisms in any of the 47 exons screened. To determine whether the CACNA1A genomic region was implicated in typical migraine susceptibility in the general Caucasian population, 82 independent pedigrees and a large case-control group were also analysed using highly polymorphic microsatellite markers. There was no linkage or association detected in these groups and thus, it was concluded that if CACNA1A plays a role in typical migraine it does not confer a major effect on the disease. However, subsequent case-control studies of SNPs in the INSR gene, which is located ~15cM telomeric from CACNA1A, provided evidence of association to typical migraine. Thus, the INSR gene may now emerge as the new migraine susceptibility gene in this genomic region on chromosome 19. Family linkage studies conducted by Gardner et al have implicated an additional FHM susceptibility region on chromsome 1q31. Furthermore, independent research carried out by Ducros et al. has indicated a second FHM locus at 1q21-23, which is ~ 30cM centromeric to the region reported by Gardner et al. At this stage it is not clear whether there is a single locus, or two distinct loci, on the chromosome 1q region. This research also involved a family-based linkage and association approach to investigating the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned ~18cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782, P = 0.00004. Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P = 0.008). Utilising the independent sample of 82 pedigrees we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 (global c2(5) of 15.00, P = 0.010) in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers, but overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. The serotonergic system has long been implicated in the pathophysiology of migraine. Researchers have therefore focused on the serotonin receptors and the genes that code for them when investigating this disease. Although serotonin receptor agonists have proven to be effective in the treatment of migraine, there has been little evidence of a serotonin receptor gene being associated with the disorder. However, in 1998, Ogilvie et al reported that a VNTR in the serotonin transporter gene (SERT) showed altered allelic distributions in a Danish migraine population. In addition to serotonin, there has been renewed interest in the involvement of the dopaminergic pathways in migraine. This interest has gained impetus since the study of Peroutka et al who reported an allelic association between the dopamine receptor gene DRD2 and migraine with aura. Another dopamine related gene, the dopamine beta-hydroxylase gene (DBH), has been localised to Chr 9q34 and codes for the enzyme that catalyses the conversion of dopamine to norepinephrine. It therefore plays an important role in dopaminergic and noradrenergic neurotransmission. Serum levels of DbH enzyme have been reported to be elevated in migrainous patients during the headache phase of an attack. Also, significantly increased DbH enzyme activity has been observed in migraine patients during the headache-free interval. Thus, the DBH gene is another good candidate for involvement in migraine pathophysiology and, to our knowledge, has not been previously implicated in this disease. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. This research also involved a linkage and association approach to investigating neurotransmitter related migraine candidate genes. Specifically, polymorphisms within the serotonin transporter gene (SERT), the dopamine receptor gene (DRD2) and the dopamine beta-hydroxylase (DBH) gene were tested in unrelated Caucasian migraineurs and non-migraine control individuals. In addition, an independent sample of 82 families affected with migraine were examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (c2 = 16.53, P = 0.019). Furthermore, the transmission/disequilibrium test (TDT) which was implemented on the family data also indicated distortion of allele transmission for the same DBH marker (c2 = 4.44, P = 0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's Combined P-value = 0.006) and indicate that further research into the role of the DBH gene in migraine aetiology is warranted. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since nitric oxide synthase (NOS) enzymes catalyse the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This research involved investigating the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine aetiology. A large group of migraine affected individuals were genotyped and compared to an age and sex matched group of unaffected controls. Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (c2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis. In summary, this research involved linkage and association analysis of migraine candidate genes and genomic susceptibility regions. Whilst, the known FHM gene (CACNA1A) was excluded for significant involvement in typical migraine the adjacent INSR gene has been associated. Migraine is genetically heterogeneous and the results of this research also provide good evidence that the DBH gene is involved in disease predisposition, whilst the DRD2, SERT and INOS gene were not shown to be implicated. An additional susceptibility region for typical migraine is also likely to localise to chromosome 1q31. Overall, the results presented in this thesis have contributed valuable data to the understanding of the molecular genetics of migraine with and without aura. Future research into the molecular pathophysiological mechanisms of migraine will greatly facilitate the development of more effective diagnosis and treatment strategies.

This thesis presents the results of three studies examining the management of migraine in children. First we conducted a systematic review of all clinical trials conducted in children and adolescents of the acute migraine therapy. A meta-analysis of the 26 randomized controlled trials is presented. A single trial with a focus on Emergency Department (ED) management was identified. As such, we then examined current ED practice in two retrospective practice variation studies. The first compared four regional hospital EDs where practice patterns were significantly different between mixed population EDs (both adult and pediatric patients) and the tertiary pediatric ED. The second examined practice variation among ten tertiary pediatric EDs in Canada where significant differences were again observed. Factors that influenced the choice of medications included increasing patient age and the physicians diagnosis of migraine. Important areas of future investigation include: (1) the effectiveness of intravenous fluids alone; and (2) the use of combined medications. / Clinical Epidemiology

Bakgrund: Migrän räknas till en av våra vanligaste folksjukdomar och förekommer hos cirka 10% av befolkningen. Patienter som provade akupunkturbehandling hade oftast positiva upplevelser och erhöll god smärtlindrande effekt. De upplevde en känsla av att återfå kontrollen över sitt liv. Syfte: Att belysa migränpatientens upplevelse av akupunkturbehandling vid migrän. Metod: Litteraturstudien baserades på totalt tio vetenskapliga kvantitativa och kvalitativa studier. Resultat: Två olika kategorier utkristalliserades, upplevelser av effekter vid akupunktur samt upplevelser under och av akupunkturbehandlingen. Patienterna beskrev färre och kortare migränattacker och för en del upphörde de helt. Den psykiska hälsan förbättrades. Det var svårt för patienterna att skilja på riktig akupunktur eller om de fick sham vid behandlingstillfällena och det visade sig att även sham akupunktur hade positiv effekt. Diskussion: Det behövs fler och bättre studier för att säkerställa akupunkturens vetenskapliga effekt och upplevelse av smärtlindring vid migrän. Akupunktur bör övervägas som behandling för de patienter som önskar eftersom goda effekter och upplevelser av smärtlindring finns. Slutsats: Flertalet patienter hade positiva upplevelser och var positiva till akupunktur som komplementär behandling. / Background: Migraine is considered one of our most common diseases and affects approximately 10% of the population. Patients who tried the acupuncture treatment had mostly positive experiences, and experienced good analgesic effect. Purpose: To highlight the migraine patient's experience of acupuncture treatment for migraine. Method: The study is based on totally ten scientific studies. Results: Two categories emerged, experiences the effects of acupuncture and experiences of acupuncture treatment. The patients described fewer and shorter migraine attacks and for some they ceased entirely. Mental health improved. It was difficult for patients to distinguish between real acupuncture or if they received the sham treatment sessions and it turned out that even sham acupuncture had a positive effect. Discussion: We need more and better studies to ensure acupuncture scientific impact and experience of pain in migraine. Acupuncture should be considered as a treatment for patients since good quality effects and experiences of pain relief are present. Conclusion: Most patients had positive experiences and were in favor of acupuncture as complementary treatment.

Ph.D.