Aims: Test the putative contribution of 17-beta-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats. Main Methods: Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-beta-estradiol (180 mu g/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed. Key Findings: A bolus of 17-beta-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-beta-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used. Significance: These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact-rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies.

BACKGROUND: Suicide is a leading cause of maternal death globally, and suicide prevalence rates have been shown to be increased in those with migraine. No previous study has examined the association between migraine and suicidal ideation during pregnancy. OBJECTIVE: To examine the association between migraine and suicidal ideation among a cohort of pregnant women. METHODS: A cross-sectional study was conducted among 3372 pregnant women attending prenatal care clinics in Lima, Peru. Suicidal ideation and depression were assessed using the Patient Health Questionnaire-9 (PHQ-9) scale during early pregnancy. Migraine classification (including migraine and probable migraine) was based on International Classification of Headache Disorders-III beta criteria. Multivariable logistic regression analyses were performed to estimate odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Suicidal ideation was more common among those with migraine (25.6%) as compared to those with probable migraine (22.1%, P < .001) or non-migraineurs (12.3%, P < .001). After adjusting for confounders, including depression, those with migraine or probable migraine had a 78% increased odds of suicidal ideation (OR = 1.78; 95% CI: 1.46-2.17), as compared with non-migraineurs. Women with both migraine and depression had a 4.14-fold increased odds of suicidal ideation (OR = 4.14; 95% CI: 3.17-5.42) compared to those with neither condition. CONCLUSION: Migraine is associated with increased odds of suicidal ideation in pregnant women even when controlling for depression. These findings support the consideration of screening women with comorbid migraine and depression for suicidal behavior during pregnancy. / Revisión por pares

De nombreuses études confirment l'efficacité thérapeutique des traitements non pharmacologiques dans le soulagement des céphalées. Il va sans dire, cependant, que les traitements administrés à la clinique par le thérapeute occasionnent des coûts professionnels considérables. De là, l'intérêt à développer la question de la relation coût-bénéfice. Cette thèse contient deux articles. Le premier est une recension des écrits scientifiques portant sur les différents modes d'administration des traitements non pharmacologiques des céphalées, que sont l'autotraitement, le traitement à domicile avec un contact minimal avec le thérapeute et le traitement en groupe. Le second article fait état d'une étude empirique qui avait pour but de comparer, chez des personnes souffrant de migraines, l'efficacité thérapeutique de la biorétroaction thermique administrée principalement à domicile avec un contact minimal avec le thérapeute à celle de la biorétoaction thermique administrée à la clinique.

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. Allelic candidate gene studies can provide a suitable method for locating genes of small effect that contribute to complex genetic disorders, such as migraine. Family linkage studies are useful for detection of chromosomal susceptibility regions and association studies are powerful when a plausible candidate gene and a sequence variant with potential functional relevance is examined. Mutation screening studies can indicate a direct cause of disorders such as migraine, where possible sequence variants may alter the translation of proteins in genes, causing the disease. The first gene exanted on chromosome 19 was that of the Low Density Lipoprotein Receptor (LDLR) gene. The LDLR gene is a cell surface receptor that plays an important role in cholesterol homeostasis. We investigated the (TA)n polymorphism in exon 18 of the LDLR gene on chromosome l9pl3.2 performing an association analysis in 244 typical migraine affected patients, 151 suffering from migraine with aura, 96 with migraine without aura and 244 unaffected controls. The populations consisted of Caucasians only and controls were age and sex matched. The results showed no significant difference between groups for allele frequency distributions of the (TA)n polymorphism even after separation of the migraine affected individuals into subgroups of MA and MO affected patients. This is in contradiction to Mochi et al, 2003 who found a positive association of this variant with MO. Our study discusses possible differences between the two studies and extends this research by investigating circulating cholesterol levels in a migraine affected genetically-isolated population. Another gene examined on chromosome l9pl3 was the insulin receptor gene (1NSR). The aim of this study was to investigate through direct sequencing the INSR gene in DNA samples from a migraine affected family previously showing linkage to chromosome l9pl3 in an attempt to detect disease associated mutations. The insulin receptor gene (INSR) on chromosome 19pl3.3-13.2 is a gene of interest since a number of SNPs located within the gene have been implicated in migraine with (MA) and without aura (MO). Six DNA samples obtained from non-founding migraine affected members of migraine family one (MF 1) were used in this study. Genomic DNA was sequenced for the 1NSR gene in exons 1-22 and the promoter region. In the six migraine family member samples, previously reported single nucleotide polymorphisms (SNP5) were detected within two exonic DNA coding regions of the INSR gene. These SNPs, in exon 13 and 17, do not alter the normal INSR polypeptide sequence. In addition, intron 7 also revealed a DNA base sequence variation. For the 5' untranslated promoter region of the gene, no mutations were detected. In conclusion, this study detected no INSR mutations in affected members of a chromosome 19 linked migraine pedigree. Hence, migraine linkage to this chromosomal region may involve other candidate genes. The NOTCH3 gene on C19p13.2-p13.l has previously been shown to be a gene involved in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and may also be implicated in migraine as there are some symptom similarities between the two disorders. The TNFSF7 gene localised on Cl9pl3 is homologous to the ligands of the TNF receptor family, including TNF-alpha and TNF-beta, genes that have both been previously associated with migraine. This study investigated the migraine susceptibility locus at Cl9p13 studying two genes that may be involved in the disorder. The NOTCH3 gene was analysed by sequencing all exons with known CADASIL mutations in a family (MF1) that has previously been shown to be linked to Cl9pl3. The sequencing results for affected members of this pedigree proved to be negative for all known sequence variants giving rise to mutation causing amino acid changes for CADASIL. The direct sequencing results displayed that of a normal coding sequence for the NOTCH3 gene F or the TNFSF7 gene, this was investigated through SNP association analysis using a matched case-control migraine diagnosed population. Chi-square results showed non-significant P values across all populations tested against controls except for the MO subgroup which displayed a weak association with the TNFSF7 SNP (genotype, allele analysis P = 0.036, P = 0 017 respectively). Our results suggest that common migraine is not caused by any known CADASIL mutations in the NOTCH3 gene of interest however, the TNFSF7 gene displayed signs of involvement in a MO affected population, but, further studies are needed to confirm these results and to further explore a TNF receptor - migraine potential interaction. A final examination on chromosome 19 involved a case report of an extremely rare and severe form of migraine. As stated earlier Familial Hemiplegic Migraine (FHM) is a severe rare sub-type of migraine and gene mutations on chromosome 19 have been identified in the calcium channel gene CACNA1A (Cl9pl3) fOr FHM. Recently a gene mutation (S218L) for a dramatic syndrome originating from FHM, commonly named 'migraine coma', has implicated exon 5 of the CACNA1A gene. The occurrence of trivial head trauma, in FHM patients, may also be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval. Hemiplegic migraine has also been found to be sporadic in which both forms share a similar spectrum of clinical presentations and genetic heterogeneity. The case report presented in this study enhances the involvement of the S218L CACNA1A mutation in the extremely rare disorder of minor head trauma induced migraine coma. It not only proves to be a powerful diagnostic tool in detecting cases of FHM head trauma induced coma but also for sporadic hemiplegic migraine (SHM) coma subjects. We conclude from this case study that the S218L mutation, in the CACNA1A calcium channel subunit gene, is involved in sporadic hemiplegic migraine (SHM), delayed cerebral edema and coma after minor head trauma. This thesis also involved analysis of chromosome 1 for migraine susceptibility, where FHM studies provided a foundation fOr common migraine research on chromosome 1. Studies have suggested that mutations in the CACNA1A gene on chromosome l9p cause FHM in only approximately 50% of affected pedigrees. The CACNAIA gene has previously been tested, within the Genomics Research Centre, in the common forms of migraine; however no new mutations or the FHM mutations were detected in these MA/MO affected samples. A second FHM susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene have recently been implicated in two Cl-linked FHM pedigrees. As FHM is considered a rare and severe form of MA, it is possible that the chromosome 1q23 locus, and the ATP1A2 gene, may be involved in the common forms of migraine with (MA) and possibly without aura (MO). Also, we have previously reported evidence of linkage to microsatellite markers on chromosome 1q31 in a large pedigree affected predominately with MA, which suggests the possibility that there are two distinct loci for migraine susceptibility on chromosome 1. The objectives of this study were to extend our linkage analysis of chromosome lq microsatellite markers in predominantly migraine with aura pedigrees. Also, our aim was to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (Migraine Family 14; MF 14) showing evidence of linkage of markers to Clq31. This was performed by a chromosome 1 scan (31 markers) in 21 multiplex pedigrees affected mainly with MA. Also, the known FHM-2 ATP1A2 gene mutations were tested, by sequencing, fOr involvement in MA and MO in these pedigrees. Mutation screening by direct sequencing was also performed throughout the coding areas of the ATP1A2 gene in 3 MA individuals fiom MF14. The results of this study detected evidence for linkage in our migraine pedigrees at chromosome 1q23, to microsatellite markers spanning the ATP1A2 (FHM-2) gene. However testing of the known ATP1A2 gene mutations (for FHM) in migraine probands of pedigrees showing excess allele sharing was negative, with no mutations detected in these migraineurs. Sequencing of the entire coding areas of the gene through 3 MA affecteds from MF14, a pedigree showing significant linkage to this region, was also negative for mutations. In conclusion, this study reported that microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The new FHM-2 (ATPIA2 gene) mutations reported by Fusco et al, 2003 do not cause migraine in probands of affected pedigrees showing excess allele sharing to markers in this genomic region. Also no mutations were detected in all exons of the ATP1A2 gene in 3 MA affected individuals from a large pedigree (MF14) showing linkage to this region. Investigation in this thesis continued on chromosome 1, with other genes being examined on C1q23, as well as the C1q31 region for a migraine susceptibility locus or gene. Previously in our laboratory, evidence for linkage was shown to migraine at C1q31 in one family predominantly affected with MA, with microsatellite markers in this region. The initial Cl study (above; ATP1A2 gene) has also provided evidence for linkage to the chromosome 1 locus 1q23, with evidence for excess allele sharing of markers in predominantly MA affected pedigrees. To further investigate both chromosome I loci, an investigation with six candidate genes that lie within the C1q23 and 1q31 regions through association analysis was undertaken. The results from this study reported non-significant chi-square results, showing P values greater than 0.05 across all SNPs (and a CA rpt) tested. An exception was the rs704326 SNP from exon 43 of the CACNA1E gene on C1q31. P values significantly less than 0.001 were obtained in the total migraine population and the MA subgroup, with similar frequency comparisons ascertained in both genotype and allele analysis. Examination through contingency table analysis of the CACNA1E flequency data indicated that the risk allele (A) was over-represented in the migraine group compared to the control group. Further comparison of the genotype data indicated a difference in frequency distributions (P less than 0 0001). Stratified analyses of migraine subtypes indicated that this association was specifically attributed to the MA subtype group. Odds ratios produced an OR of 4.14 with a 95% CI of 2.36 - 7.26 (P less than 0.0001). The positive association results obtained within the CACNA1E gene are interesting in the fact that FHM is considered to be a rare and severe form of migraine with aura (MA) and FHM-1 is caused by mutations contained within the calcium channel gene CACNA1A (localized at Cl9p13). The idea that FHM and specifically an FHM gene in the C1q31 genomic region may also contribute to susceptibility to the more common forms of migraine i e. migraine with aura, strongly supports and reinforces the idea that a common defective gene may be influencing both FHM and typical migraine. In conclusion, this thesis undertook a cross-disciplinary approach to genetic research of a complex disorder. The research involved linkage, association and mutation analysis strategies of migraine. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.

Migrän är en återkommande form av huvudvärk som förmodas bero på hormonella, genetiska och miljörelaterade faktorer. Migrän finns i olika former men detta arbete fokuserar främst på migrän med aura och migrän utan aura. Det utmärkande för migrän med aura är neurologiska störningar som oftast uppstår innan attacken och kan yttra sig i form av tillexempel synstörningar. Det är en komplex sjukdom och uppkomsten är inte helt klarlagd. Smärtan som uppstår i samband med en migränattack förmodas bero på aktivering av det trigeminovaskulära systemet. Migrän anses som den 8:e mest betungande sjukdomen i världen och livskvalitén påverkas ofta negativt hos de individer som lider av migrän. Under en migränattack är det många individer som inte klarar av skol- eller jobbdagen, blir ofta sängliggande och sociala aktiviteter påverkas negativt. Behandlingsformer av migrän delas ofta upp i förebyggande eller anfallskuperande metoder och syftet med behandlingen är att hindra migränattackerna eller häva en pågående attack. Det förekommer både standardbehandling i form av tillexempel NSAID och triptaner. Dessutom finns det hormonell behandling som profylax i mensrelaterad migrän i form av olika hormoner. En stark riskfaktor för att drabbas av migrän är att ha släktingar som är lidande och ärftligheten kan vara så hög som 50%. Kvinnor drabbas oftare än män och bakgrunden till detta kan vara hormonella förändringar i kvinnokroppen, ofta sjunkande halter av östrogen. Denna litteraturstudie granskar sex artiklar, fyra om genetiska variationer vid migrän och två som berör hormonell behandling och migrän. Granskade artiklar visar att det finns en genetisk koppling till migrän, men det behövs fler studier för att få klarare och tydligare resultat. Några gener är länkade till både migrän med och utan aura, medan några är starkare i den ena formen av migrän. Resultat huruvida hormonell behandling kan ha en positiv effekt vid migrän är något klarare. / Migraines are a recurrent form of headache believed to be caused by hormonal, genetic and environmental factors. Migraines exist in different forms, but in this work, focuse is mainly on migraines with aura and migraines without aura. The characteristics of migraines with aura are neurological disorders that usually occur before the attack and can be expressed in the form of visual disturbances. It is a complex disease and the cause is not entirely clear. The pain that occurs in connection to a migraine attack is believed to be due to activation of the trigeminovascular system. Migraines are considered the 8th most burdensome disease in the world and the quality of life is often negatively affected in individuals suffering from migraines. During a migraine attack, many individuals fail to attend to school or to work, get often bedridden and social activities are adversely affected. Means of treatment of migraines are often divided into preventive or emergency methods and the purpose of both methods is to prevent migraine attacks. There are both standard treatments in the form of for example triptans and NSAIDs and there are hormonal treatments in the form of different hormones, such as estrogens. A strong risk factor for migraines is to have relatives who are suffering, the heredity may be as high as 50%. Women suffer more often than men and the background to this can be hormonal changes in the female body, often decreasing levels of estrogen. This literature review examines six articles, four on the link between genetics and migraine and two on hormonal treatment and migraine. Examined articles show that there is a genetic link to migraines, but more research is needed to get clearer results. Some genes are linked to both migraines with and without aura, while some are stronger in one form of migraine. There are some clearer indications that hormonal treatment may have a positive effect on migraines.

Class of 2007 Abstract / Objectives: To compare the cost-effectiveness of amitriptyline, divalproex, propranolol, and topiramate in the prophylactic treatment of migraine headaches based on published data. Methods: A MEDLINE search was done to identify all randomized, controlled clinical trials evaluating the efficacy of amitriptyline, divalproex, propranolol, and topiramate in the prophylactic treatment of migraine headaches. Results from these studies were then combined with drug cost and health care service costs related to treatment failure and adverse events to assess the relative cost-effectiveness of each medication. A decision tree model was created and Monte Carlo simulation was done to determine each products cost-effectiveness. Results: Amitriptyline was both most effective and least costly of the four treatment regimens studied. The mean costs for a 90 day treatment of each of the four respective medications were found to be: amitriptyline $62, divalproex $450, propranolol $91, and topiramate $802. An acceptability curve demonstrated that amitriptyline was most cost-effective 90% of the time, propranolol 10% of the time, and divalproex and topiramate were never the most cost-effective treatment. Conclusions: Among the most common medications used for migraine prophylaxis are amitriptyline, divalproex, propranolol, and topiramate. Based upon this analysis, amitriptyline was found to be the most cost-effective medication. Therefore, it is logical from the perspective of a managed-care organization to recommend amitriptyline as a first-line agent for migraine prophylaxis.

Migraine affects ~15% of the US population (nearly 40 million people), making it one of the most common neurological disorders; however currently available therapeutic options for migraine relief are often ineffective. Moreover, acute and prophylactic drugs are both commonly associated with contraindications and serious side effects, and routine use of acute treatments may result in medication overuse-headaches. Elevated levels of the neuropeptide calcitonin gene-related peptide (CGRP) are known to be a primary factor in migraine pathogenesis, although the mechanisms by which CGRP expression becomes errantly modulated are unclear. CGRP is a product of the trigeminal ganglion and can be released both peripherally onto the dura mater, leading to neurogenic inflammation, and centrally at the spinal trigeminal nucleus, leading to neuromodulation. A great deal of CGRP-relevant migraine research has focused on the trigeminovascular system, but whether the cerebral cortex may have a role in migraine pathophysiology been less well studied. A subset of migraineurs experience a premonitory aura, which often manifests as a disturbance in one visual hemifield. An aberration called cortical spreading depression (CSD) is the likely electrophysiological substrate of the migraine aura, but whether CSD and CGRP are functionally related is not known. CSD is characterized by an initial transient wave of neuronal and glial depolarization, followed by a prolonged period of quiescence that is largely refractory to subsequent stimulation. Converging evidence supports a facilitatory role for cortical spreading depression (CSD) in migraine with and without aura, and CSD propagation has been shown to be dependent on functional CGRP receptors. Moreover, reported effects of CSD overlap with those of CGRP-mediated neurogenic inflammation. The experiments described herein seek to test the hypothesis that induction of CSD in vivo will lead to increased CGRP expression in the rodent cerebral cortex. Preliminary data in rats suggests that 3M KCl-induced CSD can trigger increased CGRP expression in the ipsilateral cortex. Preliminary data in mice has been less conclusive. Presented here are the data obtained from mice and rats, as well as speculation on the cause(s) of the differences in CGRP expression between species and how these findings relate to human studies.

Migraine is a frequent debilitating neurological disorder that is considered to be genetically complex with a multifactorial mode of inheritance. It has a high prevalence with approximately 18% of women and 6% of men suffering from the disorder. Migraine is characterized by severe head pain with associated nausea, emesis, photophobia, phonophobia, and neurological disturbances. The International Headache Society (IHS) has classified various types of migraine according to their clinical features. The two main subtypes of migraine are migraine without aura (MO), occurring in ~70-75% of migraineurs, and migraine with aura (MA) which occurs in ~25% of migraineurs. Some people experience both types of attack in their lives. While the precise pathogenesis of migraine is unknown, it is widely accepted that short-term alterations in neuronal activity occur in relation to the attack, along with temporary changes in the cerebral vasculature. Trigeminal nerve activation is also considered pivotal to progression of a migraine attack. Neurotransmitters, especially serotonin (5-hydroxytryptamine, 5-HT), platelet activation and sympathetic hyperactivity all appear to play a part, whether as part of the primary triggering event, or as a response mechanism. Migraine imparts a significant burden on society, both socially and financially. The World Health Organization has identified migraine among the world's top 20 leading causes of disability, with an impact that extends far beyond individual suffering. There is significant evidence from family and twin studies to indicate a strong genetic component to migraine. The current understanding of migraine is that it is a polygenic multifactorial disorder. It has been postulated that genetic factors set the individual migraine threshold, with environmental influences playing a modulating role. It is likely that many genes may provide an important although moderate contribution to an individual’s migraine susceptibility. The identification of migraine susceptibility genes has been the focus of substantial research to date and could eventually lead to improved treatments and greater understanding of the disorder. Several loci have shown promise, although these need to be followed up by both replication and functional studies to determine a definitive causative role. This research investigated the role of both hormonal and vascular related genes as candidate genes that may play a role in migraine susceptibility due to the well-known role of hormones and vascular changes in some migraineurs. The estrogen receptor (ESR) and progesterone receptor (PGR) genes are potential migraine candidates due to the recognized hormonal influence on migraine susceptibility. Migraines in women frequently occur during the childbearing years and are often influenced by significant hormonal milestones. The fluctuating hormone levels of the menstrual cycle have been implicated in migraine but a definitive role is yet to be established. It has been suggested that factors additional to circulating hormone levels may be at play. This research considered that variation in the ESR 1 and PGR genes may confer an increased migraine risk. To investigate the potential role of these genes in migraine, association studies investigating variants in ESR 1 and PGR were undertaken in two independent casecontrol cohorts. This was followed up by mutation screening and gene expression analysis in an effort to elucidate a functional role for these genes in the pathogenesis of migraine. Vascular genes also represent likely migraine candidates as alterations in both vascular function and cerebral blood flow are well known in migraine. Furthermore, cortical spreading depression (CSD), a depolarization wave that propagates across the brain cortex and has been speculated to cause the neurological symptoms that present in MA, has also been linked to vascular dysfunction. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTRR) genes both play a role in vascular functioning and were thus considered potential migraine candidates for this study. Both are involved in the pathway of homocysteine metabolism. Impaired activity of these enzymes can lead to mild hyperhomocysteinemia which is believed to lead to oxidative arterial damage. This may in turn impact on migraine susceptibility, possibly through the activation of trigeminal fibres. The MTHFR 677T allele results in an amino acid change in the catalytic domain of the enzyme leading to mild hyperhomocysteinemia. This particular variant has been implicated in migraine in four separate studies. One of these studies also suggested a role for the MTHFR 1298C allele in migraine. This allele also results in an amino acid change and reduced enzyme activity. Similarly, the MTRR 66G allele results in an amino acid change and has been associated with reduced activity of MTRR and increased plasma homocysteine concentration. To investigate the role of the ESR 1, PGR, MTHFR and MTRR genes in migraine, samples from two large independent case control cohorts were investigated. Cohort 1 was comprised of 275 migraineur samples and 275 age, sex and ethnicity matched controls while cohort 2 comprised 300 cases and 300 matched controls. All individuals were collected at the Genomics Research Centre with migraine diagnosis undertaken by HIS criteria and migraine affected individuals designated as MO or MA. Results of analysis of ESR 1 indicated a positive association with migraine in the two large independent cohorts for the exon 8 G594A polymorphism (P = 0.003; P = 8x10-6). Similarly, the PGR analysis showed a positive association with migraine for the PROGINS allele (P = 0.02; P = 0.003). Results also showed that individuals with both ESR 1 and PGR susceptibility alleles were 3.2 times more likely to suffer migraine those those with no susceptibility alleles. As the ESR 1 variant is synonymous, a mutation analysis was undertaken in a small sub-sample of individuals carrying the susceptibility allele, but no mutations were detected in these particular samples. Detailed mutation analysis of ESR 1 in a larger study group may be warranted. An ESR 1 and PGR expression analysis by RT-PCR was undertaken to examine if there were any notable expression level changes in migraineurs versus controls and additionally whether the susceptibility genotypes influenced gene expression. Altered expression levels may point to a functional change in the gene. Although results did not show any significant difference in expression levels in the case/control group, nor any influence in gene expression conferred by the specific susceptibility genotypes, ESR 1 expression did appear to be down-regulated in the migraine group and more specifically in the migraine susceptibility genotype subgroup. A larger study group may therefore be warranted to detect any potential genuine changes in gene expression. Overall, these results suggested that these hormonal genes appear to play a role in migraine susceptibility, although further studies are needed to define this. Results of the MTHFR 677 analysis showed that the TT genotype was significantly associated with the MA subgroup in a joint analysis of the two independent cohorts (P = 0.004). Results of analysis of MTHFR 1298, which is tightly linked to the 677 locus, showed a significant association in female migraineurs (P = 0.009). Similarly, results of the MTRR analysis also showed a significant difference between the female case and control groups with the G allele over-represented in female migraineurs (P = 0.022) These results may indicate that a significant gender effect appears in this locus as well as the MTHFR 1298 locus although results may also be due to a larger number of female migraineurs conferring increased statistical power to the gender subgroup. Interaction analysis of the MTHFR 1298 locus and the MTRR locus showed that females who carried both variants under a recessive model were 5 times more likely to suffer migraine those those with no susceptibility genotypes. Overall these results indicated that these vascular genes appear to play a role in migraine susceptibility. The final study focused on 6 genetic variants that had shown a positive association with migraine and/or MA in the same large association population analysed in this research. The aim of this study was to provide preliminary data on the potential role of genetic profiling in migraine. Using the genotypic data to create vascular and hormonal risk profiles based on positive association and interaction of MTHFR 677 T and ACE D alleles, and MTHFR 1298 AA and MTRR GG genotypes as vascular variants; and positive association and interaction of ESR 1 594 A and PGR PROGINS as hormonal variants, this study was able to demonstrate the relevance of genetic risk profiling to migraine. Results showed a significantly higher proportion of individuals with at least one genetic risk profile in the migraine group compared to those in the control group (P = 6 x 10-6). Individuals who possessed either the vascular and/or hormonal genetic risk profile were 8.6 times more likely to suffer from migraine than those who possessed a ‘no risk’ profile. This indicated a greater effect than the individual effect of each of these variants. Furthermore individuals who possessed a vascular or both risk profiles were more likely to suffer nausea, emesis, phonophobia and photophobia, and have a mother who also suffered migraine. Overall, the genetic profiling approach provided interesting preliminary data on migraine susceptibility and indicated that such an approach may prove very useful for migraine diagnosis, particularly when all migraine genes have been identified. In conclusion this study provided the first indication that hormone receptor genes play a role in migraine susceptibility. Hormones have long been considered to play a role in the disorder but this study has provided the first molecular evidence to support this premise. In addition, this study showed that vascular related genes also play a role in migraine susceptibility. Finally, this study has clearly shown that migraine is a complex disorder involving multiple genes. Although a number of studies have implicated neurotransmitter related genes in the disorder, the present study is the first to show that both vascular and hormonal genes also play a role in migraine susceptibility. Thus there now appear to be three classes of genes that affect migraine susceptibility and although this study has implicated new variants, the preliminary genetic profiling study has shown that not all predisposing variants involved in the disorder have been defined.

Migraine affects 8 -16% of population in different countries resulting in significant economic and social impacts. Current pharmacological treatment provides symptomatic relief, but not without side effects. Hence, an increasing proportion of patients prefer complementary therapies including acupuncture for migraine relief. Randomised controlled trials (RCTs) of acupuncture treatment for migraine have produced conflicting evidence due to methodological and reporting deficiencies, including small sample sizes and inappropriate outcome measures. Furthermore, systematic reviews on acupuncture for headache failed to adequately represent non-English studies such as those conducted in China. This project aimed to: (1) systematically review studies of acupuncture for migraine; and (2) conduct a RCT addressing key deficiencies identified from the systematic reviews (SRs). Two SRs were conducted based onfollowing Cochrane review protocols. Major English, Chinese, Japanese and Korean databases were searched. The first SR included 15 English studies and the second SR had 17 Chinese studies. No Japanese or Korean RCTs were identified. Overall, those two SRs supported the value of acupuncture in the treatment and prevention of migraine when compared with western medications. However, conflicting results were found when real acupuncture treatments were compared with sham/placebo procedures. When compared with the studies published in English, Chinese studies had a higher frequency of acupuncture treatment, displayed poor methodological quality, and commonly used pharmacotherapy as a comparator. The SRs revealed that there was limited evaluation of acupuncture for frequent migraine. In the RCT, fifty participants with a minimum of eight migraine days per four weeks were randomly allocated to receive real (RA, n = 26) and sham (SA, n = 24) acupuncture for a total of 16 sessions over 20 weeks in a gradually decreasing treatment frequency. Fixed and supplementary acupoints were used. Participants were followed up for further assessment at three months and one year. Results showed that at the end of the treatment period, the mean (SD) migraine attack days per four weeks decreased from 11.81 (5.76) to 5.17 (5.02) in the RA group and from 12.41 (6.4) to 10.08 (7.11) in SA (group difference: p = .008). Intensity of migraine assessed using a Six-point Likert scale was lower in the RA (2.18 ±1.05) than that in the SA group (2.93 ± 0.61, p = 0.004). The percentile changes of pressure pain threshold (PPTs) detected at the bilateral points of TaiYang (Ex-HN5) were significantly higher in the RA group (RA 228.48% vs. SA -0.66 % on the left and 92.69% vs. -2.52% on the right). However, there was no s tatistically significant difference between the two groups with respect to Migraine Specific Quality of Life (MSQOL). At the end of the three-month follow up, medication consumption was less in the RA group, but not at the one-year follow up. In conclusion, this project demonstrates that acupuncture is a potentially effective and safe option for adult patients with frequent migraine headache with the effects lasting up to three months. Further studies are needed to confirm these therapeutic benefits with adequate sample sizes and the potential mechanism for this action.

Thèse d'exercice : Pharmacie : Université de Nantes : 2004. / Bibliogr. f. 108-120 [115 réf.].