Rozprawy doktorskie na temat „Migraines”

Migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a painful neurovascular disease, affecting approximately 16% of the general population. It is characterised by a wide variety of symptoms including headache, nausea and vomiting, and photo- and phonophobia. The disorder is complex involving not only multiple genes, but also specific environmental factors, which can induce attacks in genetically predisposed individuals. Hyperhomocysteinaemia is a known risk factor for cerebrovascular, peripheral vascular and coronary heart disease. The Methylenetetrahydrofolate Reductase (MTHFR) enzyme is involved in homocysteine metabolism. Furthermore, it has been reported that a homozygous mutation (677C to T; Ala to Val) in the 5,10-MTHFR gene is associated with an elevation in plasma homocysteine levels (Frosst et al., 1995). This common mutation in the MTHFR gene has recently been associated with migraine with aura in a Japanese cohort (Kowa et al., 2000). The present study was designed to determine the prevalence of the MTHFR C677T mutation in Australian patients with migraine and to determine whether this mutation is associated with the disease in Caucasians. A large case-control study, consisting of 270 patients with migraine (167 with aura and 103 without aura), and 270 normal matched controls was investigated. Genotypic results indicated that the prevalence of the homozygous (T/T) genotype in migraine sufferers (15%) was higher than that of controls (9%) (P = 0.084). Furthermore, the frequency of the mutant (T/T) genotype in individuals with MA (19%) was significantly higher than in controls (9%) (P = 0.006). Interestingly, the risk of MA was ~2.5-fold higher in suffers possessing the homozygous variant (OR = 2.52, CI: 1.42 - 4.47, P = 0.0012). To confirm the MTHFR allelic association with MA, family-based tests were performed in an independent pedigrees group, where only those with MA were considered affected. Results from both the Pedigree Disequilibrium Test (PDT) and Family-Based Association Test (FBAT) analysis revealed slight, although not significant (PDT test, P = 132; and FBAT test, P = 0.390), over-transmission of the mutant allele (T) from parents to affected offspring. However, despite the MTHFR variant having a high heterozygosity (0.48), there were a limited number of informative transmissions for the MTHFR variant in the pedigree group resulting in reduced power for these tests. In conclusion, our results support the trends reported in the Japanese migraine study and suggest that the homozygous 677T gene variant causing mild hyperhomocysteinaemia, is a genetic risk factor for migraine, and indicate that further studies investigating the role of this gene are warranted. Mutations in various ion channel genes are responsible for neurovascular and other neurological disorders. Inherited ion channel mutations or "channelopathies" are increasingly found to be the cause of various neurological disorders in humans. Wittekindt and colleagues (1998) reported that the calcium-activated potassium channel (hKCa3) gene is a good candidate for schizophrenia and bipolar disorder (BD), as well as for other neurological disorders such as migraine. The hKCa3 gene is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. The hKCa3 gene encodes a protein of 731 amino acids containing two adjacent polyglutamine sequences in its N-terminal domain separated by 25 amino acids. The C-terminal polyglutamine sequence is highly polymorphic in length (Austin et al., 1999). hKCa3 plays a critical role in determining the firing pattern of neurons via the generation of slow after-polarization pulses and the regulation of intracellular calcium channels (Kohler et al., 1996). Three distinct mutations in the a1 calcium channel gene have been shown to cause SCA-6, episodic ataxia-2 and familial hemiplegic migraine (FHM) (Ophoff et al., 1996). The hKCa3 gene contains a highly polymorphic CAG repeat that was initially mapped (Chandy et al., 1997) to a schizophrenia locus on chromosome 22 (Pulver et al., 1994). Recently Austin et al (1999) re-mapped hKCa3 and found it to reside on chromosome 1q21, a region that has been linked to FHM (Austin et al., 1999), a rare subtype of MA (Ducros et al., 1997; Gardner et al., 1998), and a region recently showing genetic linkage to typical migraine (Lea et al., 2002). The hKCa3 polymorphism results in small variations in polyglutamine number, similar to those that occur in the calcium channel a1a subunit gene (CACNA1A), which is encoded by CAG expansions and thought to cause Spinocerebellar Ataxia Type 6 via loss of channel function (Austin et al., 1999). Given the recent linkage of FHM to the region of chromosome 1q21, to which hKCa3 resides, and also linkage of typical migraine to this region, a large case-control study investigating this hKCa3 CAG marker and consisting of 270 migraine and 270 stringently matched healthy controls was undertaken. Our results indicated that there was no statistically significant difference in allele distributions for this marker between migraine and non-migraine patients (P >0.05). No significant difference in the allelic distribution was observed in the MA or MO groups when compared to controls (P >0.05) and there was no significant difference in CAG repeat length distribution between the migraine group and controls (P = 0.92), or between the MA and MO groups (P = 0.72) collectively. Hence, the CAG repeat in this gene does not show expansion in migraine. Overall, our results provide no genetic evidence to suggest that the hKCa3 CAG repeat polymorphism is involved in migraine aetiology in Australian Caucasians. Thus the involvement of the hKCa3 gene in migraine is not likely, although the hKCa3 gene remains an important candidate for other neurological disorders that may be linked to the 1q21.3 chromosomal region.

Migraine, comprised of migraine with aura (MA) and migraine without aura (MO), is a painful neurovascular disease, affecting approximately 16% of the general population. It is characterised by a wide variety of symptoms including headache, nausea and vomiting, and photo- and phonophobia. The disorder is complex involving not only multiple genes, but also specific environmental factors, which can induce attacks in genetically predisposed individuals. Hyperhomocysteinaemia is a known risk factor for cerebrovascular, peripheral vascular and coronary heart disease. The Methylenetetrahydrofolate Reductase (MTHFR) enzyme is involved in homocysteine metabolism. Furthermore, it has been reported that a homozygous mutation (677C to T; Ala to Val) in the 5,10-MTHFR gene is associated with an elevation in plasma homocysteine levels (Frosst et al., 1995). This common mutation in the MTHFR gene has recently been associated with migraine with aura in a Japanese cohort (Kowa et al., 2000). The present study was designed to determine the prevalence of the MTHFR C677T mutation in Australian patients with migraine and to determine whether this mutation is associated with the disease in Caucasians. A large case-control study, consisting of 270 patients with migraine (167 with aura and 103 without aura), and 270 normal matched controls was investigated. Genotypic results indicated that the prevalence of the homozygous (T/T) genotype in migraine sufferers (15%) was higher than that of controls (9%) (P = 0.084). Furthermore, the frequency of the mutant (T/T) genotype in individuals with MA (19%) was significantly higher than in controls (9%) (P = 0.006). Interestingly, the risk of MA was ~2.5-fold higher in suffers possessing the homozygous variant (OR = 2.52, CI: 1.42 - 4.47, P = 0.0012). To confirm the MTHFR allelic association with MA, family-based tests were performed in an independent pedigrees group, where only those with MA were considered affected. Results from both the Pedigree Disequilibrium Test (PDT) and Family-Based Association Test (FBAT) analysis revealed slight, although not significant (PDT test, P = 132; and FBAT test, P = 0.390), over-transmission of the mutant allele (T) from parents to affected offspring. However, despite the MTHFR variant having a high heterozygosity (0.48), there were a limited number of informative transmissions for the MTHFR variant in the pedigree group resulting in reduced power for these tests. In conclusion, our results support the trends reported in the Japanese migraine study and suggest that the homozygous 677T gene variant causing mild hyperhomocysteinaemia, is a genetic risk factor for migraine, and indicate that further studies investigating the role of this gene are warranted. Mutations in various ion channel genes are responsible for neurovascular and other neurological disorders. Inherited ion channel mutations or "channelopathies" are increasingly found to be the cause of various neurological disorders in humans. Wittekindt and colleagues (1998) reported that the calcium-activated potassium channel (hKCa3) gene is a good candidate for schizophrenia and bipolar disorder (BD), as well as for other neurological disorders such as migraine. The hKCa3 gene is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. The hKCa3 gene encodes a protein of 731 amino acids containing two adjacent polyglutamine sequences in its N-terminal domain separated by 25 amino acids. The C-terminal polyglutamine sequence is highly polymorphic in length (Austin et al., 1999). hKCa3 plays a critical role in determining the firing pattern of neurons via the generation of slow after-polarization pulses and the regulation of intracellular calcium channels (Kohler et al., 1996). Three distinct mutations in the a1 calcium channel gene have been shown to cause SCA-6, episodic ataxia-2 and familial hemiplegic migraine (FHM) (Ophoff et al., 1996). The hKCa3 gene contains a highly polymorphic CAG repeat that was initially mapped (Chandy et al., 1997) to a schizophrenia locus on chromosome 22 (Pulver et al., 1994). Recently Austin et al (1999) re-mapped hKCa3 and found it to reside on chromosome 1q21, a region that has been linked to FHM (Austin et al., 1999), a rare subtype of MA (Ducros et al., 1997; Gardner et al., 1998), and a region recently showing genetic linkage to typical migraine (Lea et al., 2002). The hKCa3 polymorphism results in small variations in polyglutamine number, similar to those that occur in the calcium channel a1a subunit gene (CACNA1A), which is encoded by CAG expansions and thought to cause Spinocerebellar Ataxia Type 6 via loss of channel function (Austin et al., 1999). Given the recent linkage of FHM to the region of chromosome 1q21, to which hKCa3 resides, and also linkage of typical migraine to this region, a large case-control study investigating this hKCa3 CAG marker and consisting of 270 migraine and 270 stringently matched healthy controls was undertaken. Our results indicated that there was no statistically significant difference in allele distributions for this marker between migraine and non-migraine patients (P >0.05). No significant difference in the allelic distribution was observed in the MA or MO groups when compared to controls (P >0.05) and there was no significant difference in CAG repeat length distribution between the migraine group and controls (P = 0.92), or between the MA and MO groups (P = 0.72) collectively. Hence, the CAG repeat in this gene does not show expansion in migraine. Overall, our results provide no genetic evidence to suggest that the hKCa3 CAG repeat polymorphism is involved in migraine aetiology in Australian Caucasians. Thus the involvement of the hKCa3 gene in migraine is not likely, although the hKCa3 gene remains an important candidate for other neurological disorders that may be linked to the 1q21.3 chromosomal region.
Thesis (Masters)
Master of Philosophy (MPhil)
School of Health Sciences
Full Text

This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.
Bachelors
Nursing
Nursing

This study was completed to better understand and treat couples wherein one partner suffers from chronic migraines. I interviewed eight couples about their experiences in dealing with migraines as a patient, as a partner, and together. The interviews were transcribed and analyzed by a team of seven researchers. We developed a theory that can be used to understand how patients and their partners adapt to chronic migraines. The theory was grounded in the experiences of the patients and partners who were interviewed. We found that patients and partners alike dealt with burdens and costs associated with chronic migraines. Coping, healthcare, couple experience, and identity were found to be the means through which patients and partners adapted to their burdens. These concepts are broken down and discussed in greater detail. A model is provided that can be used to create a visual representation of how well a couple deals with migraines. Suggestions for couples who are dealing with chronic migraines, and for medical providers and therapists who work with couples affected by chronic migraines, are provided.

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.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Sciences
Full Text

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.

EEG biofeedback training, known as neurofeedback, has been explored as a nonpharmacologic prophylaxis for migraines. Based on the conceptual model of disregulation of central arousal function, the Othmers proposed a protocol in migraine prophylaxis by raising the sensory motor rhythm (SMR, 12- 15 Hz), accompanied by an inhibition of theta ( 4- 7 Hz) frequency. Relaxation with music, on the other hand, is another type of nonpharmacologic prophylaxis for migraines and is used to reduce perceived psychological and/or physiological stress and pain. Studies showed that an effective relaxation with music program is one that integrates certain relaxing musical characteristics and personal factors. Six female participants (29 to 57 years of age) previously diagnosed with migraines participated in this single-subject design study. This study employed two independent variables- the SMR/theta training and music therapy, and the dependent variables were the SMR and theta recording registration. Each participant first participated in the EEG Base-rate recording session, and was then randomly assigned to the following treatment conditions: SMR/Theta training only, music therapy only, and SMR/Theta training and music therapy." Counterbalancing of the treatment conditions was applied across participants, two sessions weekly for a total of 13 sessions, 30 minutes each session. In SMR/Theta training only, participants were instructed to raise their SMR while inhibiting theta. In music therapy only, participants were instructed to select their relaxation CD music to be played during the sessions. The SMR and theta data were graphed for each participant and implications were discussed. Graph analysis indicated that two participants were responsive to SMR/Theta training and music therapy and SMR/Theta training only respectively. Overall, all participants acquired relaxation skills and seemed better at adapting themselves to a stressful environment.

L'objet de la recherche a ete d'etudier l'efficacite d'une psychotherapie hypnotique pour des personnes souffrant de migraines ou de cephalees de tension. Ces deux types de cephalees se presentent comme des problemes psychosomatiques. Ainsi, un traitement psychologique constitue une approche therapeutique appropriee pour ces patients. Parmi les differentes psychotherapies disponibles, nous avons choisi l'hypnotherapie. L'hypnose representatn un etat modifie de conscience, l'hypnotherapie consiste a l'utiliser dans le cadre d'une psychotherapie de courte duree. Apres la presentation de l'histoire et des theories de l'hypnose, nous avons decrit les phenomenes hypnotiques et les differentes formes d'hypnotherapie. Ensuite, nous avons presente les travaux accomplis dans l'hypnotherapie des cephalalgiques. Nous avons egalement expose notre demarche pour le traitement hypnotique des cephalalgiques. Il s'agit d'une psychotherapie ou l'hypnose est associe a une approche psychanalytique (hypno-analyse) et a des techniques comportementales et cognitives. La pratique de l'autohypnose en tant que traitement de fond et traitement de crise constitue un aspect important de notre therapie. L'hypnotherapie concue de cette facon a ete appliquee chez une population de treize sujets migraineux et de neuf sujets souffrant de cephalees de tension. Le traitement s'est deroule a raison d'une seance (d'environ une heure) par semaine pendant dix seances. L'evaluation des sujets avant le traitement, a l'issue du traitement et lors du suivi un an apres la derniere seance nous permet de constater l'efficacite de l'hypnotherapie pour les cas de migraine. Dans les cas de cephalees de tension, l'amelioration variable obtenue a l'issue du traitement hypnotique ne se maintient que chez les patients qu ont continue la pratique de l'autohypnose
The aim of the research was to study the effectiveness of a hypnotic psychotherapy for persons suffering from migraines or tension headaches. These two types of headaches appear like psychosomatic problems. Thus a psychological treatment constitutes an appropriate therapeutic approach for these persons. Among the different psychotherapies available, we have chosen hypnotherapy. Hypnosis representing an altered state of consciousness, hypnotherapy consists in using it within the framework of a short-term psychotherapy. After presenting the history and the theories of hypnosis, we have described the hypnotic phenomena and the different forms of hypnotherapy. Then, we have presented a review of the literature on hypnotherapy of headache patients. We have also explained our procedure for the hypnotic treatment of headaches patients. It is a psychotherapy where hypnosis is associated with a psychoanalytic approach (hypnoanalysis). Behaviour therapy and cognitive therapy. The practice of self-hypnosis constitutes an important aspect of our therapy. Tension headaches patients. The treatment was conducted at the rate of one session (of about an hour) per hypnotherapy conceived in this manner was applied to a population of thirteen migraine patients and nine week for ten sessions. The evaluation of the subjects before the treatment, at the end of the treatment and at the follow-up one after the last session proves the efficacy of hypnotherapy in the case of migraines. As for the tension headaches, the varied improvements obtained at the end of the hypnotic treatment are maintained only for patients who have continued the practice of self-hypnosis

A vast amount of research shows that migraines affect many people around the world. It has been suggested that stress, caffeine and artificial sweeteners are three of the many factors that can cause migraines. Caffeine, ironically, has been shown to be both a trigger and a treatment. Pre-med students have been shown to be prone to migraines as their future goals require high/successful involvement in both the community and academics. This study provides insight into whether consumption of diet drinks, caffeinated drinks and/or stress is/are correlated with the intensity or frequency of migraines by surveying pre-med students near beginning and towards the end of their undergraduate career. While there was no correlation with consumption of either artificially sweetened or caffeinated beverages, stress was found to be the most common migraine trigger for this population. Rigor of major and post-graduation plans were among the highest sources of stress. Considering the influence stress had on migraine experience and these sources of stress, learning and utilizing stress reduction methods such as Cognitive Behavioral Therapy (CBT), Stress Inoculation Therapy (SIT), and Mindfulness Based Stress Reduction (MBSR) might be the most effective way to reduce intensity/frequency of migraines.

The development of neural stimulations devices may help treat many patients who suffer from migraines and chronic headaches via an electrical stimulation to the patient’s nerve. The electrical stimulation will mask the pain associated with these diseases. The system is subcutaneously implanted into the back of the neck and recharged via inductive coupling. Discussed is the transmission of signals in nerve fibers and the testing involved with neural stimulation implantable devices. Research was performed for preliminary testing on the charging rates, tests to analyze the heat dissipated during recharging, ergonomic factors to be considered, developing a model to simulate an in vivo environment.

La céphalée migraineuse est une pathologie invalidante qui représente un véritable problème de santé publique. Cette maladie chronique se déroule en crises récurrentes de 4 à 72 heures. Les douleurs observées résultent de la mise en jeu du système trigémino-vasculaire formé par les vaisseaux sanguins cérébraux et méningés et les fibres nerveuses nociceptives trigéminales. Ces fibres nociceptives expriment une large gamme de protéines (canaux ioniques) spécialisées dans la détection et la propagation du message douloureux. Parmi eux, le canal ionique Nav1.9 revêt un intérêt particulier en raison de son expression restreinte aux neurones nociceptifs et de son rôle prépondérant dans l'activité des nocicepteurs. Les résultats obtenus dans notre laboratoire montrent que le canal Nav1.9 est un acteur majeur de la céphalée migraineuse et doit être considéré comme une cible thérapeutique prometteuse dans le traitement de la migraine. Nous cherchons maintenant à comprendre quel est le rôle du système immunitaire, et en particulier des mastocytes, dans la céphalée migraineuse. Les mastocytes sont localisés à proximité des vaisseaux sanguins méningés, en étroite apposition avec les fibres nociceptives. Les mastocytes sont connus pour libérer un grand nombre de médiateurs de l'inflammation par un processus de dégranulation. Nous pensons que ces facteurs sécrétés agissent sur le canal Nav1.9 et contribuent à amplifier l’inflammation neurogène et la céphalée. Nos travaux visent donc à évaluer le poids de la dégranulation mastocytaire dans la phase de céphalée migraineuse, à en comprendre les mécanismes intimes et à développer de nouveaux médicaments sur la base de ces mécanismes
Résumé vulgarisé en anglaisMigraine is a common neurological disorder that affects a large portion of the population. This chronic disease occurs in attacks or episodes that can cause significant pain (4 to 72 hours) accompanied by light (photophobia) and sound (phonophobia) sensitivity and cutaneous hypersensitivity. Current treatments have many side effects and remain ineffective in chronic conditions.Migraine pain results from the activation of nociceptive pathways (fibers of pain) at the level of meningeal vessels. These nociceptive fibers express a wide range of proteins (ion channels) specialized in the detection and spread of the pain message. Among them, the ion channel Nav1.9 is particular interest because of its restricted expression to nociceptive neurons and its preponderant role in the activity of nociceptors. We developed a model of migraine headache in mice that has all migraine symptoms. These symptoms disappear when the gene encoding the Nav1.9 channel has been invalidated. We have shown that activation of the Nav1.9 channel is responsible for pain during a migraine attack and that it is involved in sterile neurogenic inflammation of the meninges.The results obtained show that the Nav1.9 channel is a critical determinant of migraine attack and emerges as a promising target for migraine therapeutics

Migraine is a common and painful neurological disorder, with genetic and environmental components. The prevalence of migraine varies between different racial groups, being higher in Caucasian populations (12%). Several conditions have been shown to be comorbid with migraine. One heart disorder that has been associated with migraine is a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO), resulting from an incomplete anatomic fusion of the atrial septum primum and secundum. Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). Samples were genotyped for the single nucleotide polymorphism (SNP) using FACSArray flow cytometer and frequencies for this variant compared in migraine cases and age, sex and ethnicity matched controls...
Thesis (Masters)
Master of Philosophy (MPhil)
School of Medical Science
Griffith Health
Full Text

Personer som lider av migrän har i de flesta fall någon gång funderat över vad som är den utlösande faktorn. Ibland vet de svaret, ibland är svaret inte lika tydligt. Att ha kunskap och förståelse över sin migrän kan öka chanserna till självhjälp och ökad empowerment. Patienterna har tillräcklig kunskap för att kunna ta beslut som bidra till en bättre hälsa för individen. Patienten hjälper således sig själv till ett bättre välmående utifrån den kunskap som patienten har om sig själv och sin sjukdom. För att skapa en förståelse och större kunskap för sin sjukdom kan det underlätta att dokumentera sina migränanfall. Dokumentationen kan sedan användas för att hitta en gemensam nämnare till anfallen. Att dokumentera migränanfall kan också kallas för att föra en migrändagbok. Migrändagböcker kan ordineras ut av hälso- och sjukvård i form av enklare dokumentation på pappersark. Det finns också digitala lösningar där personer som lider av migrän kan dokumentera in mer utförliga uppgifter om sin migränattack via olika migränappar som finns att ladda ner. En digital lösning ger större möjlighet till en rikare information om personens sjukdom, men saknar ofta anpassning för migränpatienters särskilda behov och upplevda problematik. Personer som lider av migrän kan uppleva problematik med att interagera med digitala skärmar. Att interagera med skärmar kan vara en bidragande orsak till ett sämre mående, vilket framkom i denna undersökning. Syftet med denna studie var att undersöka hur ett gränssnitt för en mobil hälsoapplikation för migränpatienter kunde utformas med fokus på empowerment och god användarupplevelse. För att ta reda på detta, genomfördes 7 stycken semistrukturerade intervjuer. Informanterna fick berätta om sina upplevelse av migrän, deras egen kunskap om sin sjukdom, samt tekniska aspekter om hur de vill interagera med mobilappar under tiden som de har migrän. Den data som uppkom utifrån intervjuerna analyserades sedan med hjälp av kvalitativ kodning som resulterade i fyra olika teman. Behovet visar att dokumentation av migränanfall genom mobilapplikationer ska ske med så lite interaktionstid med skärmen som möjligt. Dokumentation av migränanfall kan med fördel ske med hjälp av tal och ljud. Själva gränssnittet ska vara enkelt och simpelt med avskalade ikoner som tydligt ska gå att identifiera. Det ska finnas möjlighet att manuellt eller med automatiska inställningar dämpa ljuset på skärmen. Resultatet av undersökningen mynnade sedan ut i lämpliga gränssnittsförslag i form av mockuper. För framtida forskning rekommenderas att utföra användartester med utökade prototyper, för att undersöka huruvida de designförslag som tagits fram i denna studie upplevs som en god användarupplevelse och bidrar till empowerment.
People who suffer from migraines have probably at some point thought about what the triggering factor is. Sometimes the answer is clear, and sometimes it’s not that obvious. To have understanding and knowledge of their migraine can increase the chances of self-help and also higher levels of empowerment. With self-help, the patient can make better decisions based on the knowledge of the disease, which can lead to a better well-being. In order to establish an understanding and more knowledge about their illness, it can be helpful to document the migraine attacks. The documentation can then be used to find a possible cause of the attacks. This is also called a migraine journal. Migraine journals can be prescribed by the health services, where you get a template with less words and with simple instructions of the tasks on them. There are also digital solutions, like mobile applications, that supports more detailed documentation. A digital solution provides more opportunities for more detailed information about the person's illness, but mobile apps often lacks adaption for the patient's specific needs and problems. Persons who suffers from a migraine attack, can experience difficulties when documenting a large amount of information on applications. The interaction with digital screens may worsen the symptom. This is one of the findings of this study. The purpose of this study was to examine how a user interface for a mobile health application, could be designed with focus of empowerment and a good user experience. To find out, 7 semi structured interviews were conducted. The informants were asked to tell about their experiences, their knowledge about their illness and some technical aspects of how they want to interact with mobile applications while they are suffering from an attack. The data that was obtained from the interviews were then analyzed using qualitative coding that resulted in four different themes. The study showed that the potential users wish to interact as little as possible with the screen. Documentation of migraine attacks can be done with the help of speech and sound. The interface itself should be easy with simple icons which are easy to identify. It should be possible to manually or automatically adjust the light on the screen. The result of the study contributed to suggestions for how to design a suitable interface for migraine patients. The interface is visualised in this report in the form of mockups. For future research , it is recommended to perform user tests with extended prototypes to investigate whether the design principles and design suggestions developed in this study are perceived as a good user experience and contribute to empowerment.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. Functional brain imaging in acute migraine has proved challenging due to the logistic problems associated with an episodic condition although it has provided us with important insights into the pathophysiology of the condition. Since the seminal observation of brainstem activation in migraine there has only been a single case substantiating this finding. Our objectives were, first, to test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomical localisation with higher resolution positron emission tomography (PET) and more advanced analysis techniques. Secondly, we wanted to explore the glyceryl trinitrate (GTN) model of migraine further to determine reliability and reproducibility. Finally, using this model we wished to explore the issue of laterality in migraine and, in particular, how it relates to brainstem activation. H2150-labelled PET was used to study acute migraine attacks occurring spontaneously in five migraineurs. Using GTN-triggered migraine twenty-four migraineurs (divided into three groups according to the site of their headache: right/ left/ bilateral) and eight controls were scanned. The data was analysed using statistical parametric mapping (SPM99). Significant brainstem activation was seen in the dorsolateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state in both spontaneous and induced migraine groups. When the induced group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Looking at the GTN model, thirty-three of the forty-four patients administered GTN had a migraine attack fulfilling International Headache Society criteria. Twelve patients described typical premonitory symptoms, which have not been previously documented with GTN-induced migraine. A repeat attack was triggered in all subjects but one and laterality was also remarkably reproducible. In one case a visual aura was also triggered both times. Our study shows that GTN-induced triggering is common in our patients, and remarkably reproducible. Overall, our findings provide clear evidence for dorsal pontine activation in migraine, and reinforce the view that migraine is a subcortical disorder involving modulation of afferent neural traffic. The results also suggest that lateralisation of pain in migraine is due to lateralised brain dysfunction.

Introduction: Bipolar Disorder (BD) is a chronic mental illness associated with functional decline, mortality, and significant health care costs; furthermore, specific general medical conditions have been found to occur disproportionately within BD patient populations, among them, migraine is one of the most studied. Migraine has a global prevalence of 10%, and it is a disorder with elevated direct and indirect costs, the later mostly derived from its association with mood and anxiety disorders. Specifically, the reported prevalence of migraine in the BD population ranges from 24.8% to 39.8%, rates that are considerable higher than those found in the general population.
Objective: To explore the prevalence and clinical characteristics of BD patients with and without migraine (Study 1), and to examine the psychiatric comorbidity in patients suffering from migraine (Study 2).
Methods: 323 BD patients were studied, using SADS-L and SCID as diagnostic interviews, and ill-Migraine questionnaire to assess the presence of migraine. Statistical analyses were conducted using parametric analysis and the development of log-linear models. Additionally, 102 migraine patients were interviewed using SADS-L, and the descriptive characteristics of the sample were analyzed.
Results: For Study 1, we found that 24.5% of BD patients suffer from migraine, and it is significantly associated with BD 2, suicidal behaviour, and a variety of anxiety disorders. As well, over 70% of migraine patients showed a lifetime psychiatric diagnosis, mainly within the spheres of mood and anxiety disorders; specifically, the prevalence of BD among migraine patients was 12.7%.
Conclusions: Our study highlights the high prevalence of migraine among BD patients, and the elevated prevalence of psychiatric comorbidity among migraine sufferers. The study of this comorbidity will deepen our understanding of the mechanisms that underlie both disorders and provide a better framework for the developing of molecular techniques to further analyze the molecular physiopathology of Bipolar Disorder.

Migraine can be conceptualised as a disorder of sensory processing, manifest by such symptoms as headache (pain), phonophobia and photophobia. Current models of migraine pathophysiology incorporate a significant role for the brainstem. Vestibular migraine (VM) is a subtype of the disorder in which significant brainstem dysfunction has been documented. The condition is known to have a significant effect on mental health. This study was designed to investigate disturbances in audiovestibular brainstem function in vestibular migraine in a four part study: 1. Otoacoustic emission suppression by contralateral noise, a test of auditory efferent pathway function, was measured in a group of 33 VM patients and compared with 31 healthy controls. Regression analysis showed a higher rate of abnormality amongst the VM group (p=0.03). 2. Vestibular evoked myogenic potentials were recorded in a group of 30 VM patients and compared with 35 healthy controls. Recordings showed a higher rate of abnormal responses in the VM group than amongst controls (p=0.008). 3. The potential for vestibular stimuli to act as migraine triggers was investigated by observing the effect of vestibular testing or a control condition on 148 individuals. Vestibular stimulation was associated with a significant increase in the probability of developing a migraine attack over the following 24 hour period (p=0.01). 4. Psychological symptoms of depression and anxiety were assessed using questionnaires 39 patients with VM and compared with a control group of 44 patients with dizziness of other causes. Although the VM group had a significantly higher load of symptoms of depression and anxiety, regression modelling showed that this effect was largely accounted for by an excess of dizziness symptoms. In conclusion, this study documents a number of audiovestibular sensory processing abnormalities using a variety of techniques. Vestibular migraine has a significant effect on psychological wellbeing, largely via the associated balance symptoms.

Migraine is a common, episodic neurological disorder that includes headache, nausea and hypersensitivity to sensory stimuli. During the headache phase of migraine, migraine patients can be especially hypersensitive to thermal stimuli. The unpredictable and episodic nature of migraine makes it difficult to treat and much of the mechanism of migraine has yet to be elucidated. A T44A substitution in casein kinase 1δ is inherited with migraine with aura. A transgenic mouse model suggests that animals with this mutation exhibit increased sensitivity to thermal stimuli after injection with nitroglycerin (NTG). We performed behavior assays that measure animal responses to thermal stimuli, after injection with NTG, a known migraine-inducer in human migraine patients. Female animals with the CK1δ-T44A mutation are more sensitive than wildtype littermates, suggesting a sex difference emerges in pain sensitivity in animals that express the CK1δ-T44A but not in wildtype siblings. Female CK1δ-T44A animals are more sensitive to the effects of NTG on pain than male CK1δ-T44A mice. This indicates a potential sex hormone related pain response. Since estrogen is implicated in both migraine and pain response, we test the thermal sensitivity of heterozygous ERβKO/+ and CK1δ-T44A; ERβKO/+ mice compared to wildtype and CK1δ-T44A mice. Overall thermal sensitivity is decreased before stress of injection in both male and female ERβKO/+ and CK1δ-T44A: ERβKO/+ mice. This demonstrates that ERβ is necessary for thermal nociception in untreated mice. However, after injection with saline or NTG, animals of all genotypes responded to thermal stimuli similarly. This suggests that estrogen signaling through ERβ is likely not part of the pathway of NTG-induced thermal sensitivity or that one copy of ERβ is sufficient for NTG-induced thermal sensitivity. Since ERβ is fully functional in CK1δ-T44A mice and CK1δ-T44A mice have wildtype thermal sensitivity at baseline, we can conclude that CK1δ-T44A does not modulate ERβ to affect thermal sensitivity in untreated animals.

This research was conducted to expand the understanding of the role of the X chromosome in common and familial typical migraine. The primary objective of this study was to identify new X chromosomal genetic targets that cause migraine. Overall this research has identified nine genetic targets of interest. Various obstacles were encountered throughout this study, but the knowledge gained for overcoming these obstacles are invaluable for implementation and improvement of future genetic studies investigating the X chromosome.

Migraine is a serious neurological disorder that affects the central nervous system causing painful attacks of headache. Attacks of head pain vary widely in intensity, frequency and duration lasting from anywhere between 4-72 hours and are often accompanied by further symptoms of nausea, vomiting, photo- and phonophobia. In 1988, a group of world leaders in the diagnosis of migraine formed the International Headache Society (IHS) and compiled and published a consensus set of diagnostic criteria known as International Classification of Headache Disorders, ICHD-I 1988. This was the first classification system and was subsequently updated in 2004, ICHD-II 2004 and more recently a 3rd Edition beta version has been released (ICHD-3rd Ed Beta Version) and is the gold standard for diagnosing headache disorders. Migraine displays two main subtypes termed migraine with or without aura (MA and MO respectively). The two forms are distinguished from each other based on the development of aura, a period of variable and diverse neurological symptoms that precede the headache phase.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Science, Environment, Engineering and Technology
Full Text

Nella tesi è descritto un modello matematico per l'aura emicranica e, più precisamente, per lo scotoma scintillante (schema di fortificazione) e per la Cortical Spreading Depression, il fenomeno neuropatofisiologico alla base dell'aura. In particolare è spiegato un modello cinematico per l'evoluzione della CSD nella corteccia visiva primaria, considerata un mezzo debolmente eccitabile, la mappa retino-corticale e il modello, tramite fibrato, dei Pinwheels di V1.

Research into the association between migraine and menstruation has been hampered by lack of an agreed definition for 'menstrual' migraine. This thesis presents evidence for increased risk of migraine without aura on or between the two days before menstruation and the first three days of bleeding. Within individual women menstrual attacks differ from attacks at other times of the cycle, being longer and more severe. These findings led to the development of definitions for 'pure menstrual migraine' and 'menstrually-related migraine', which have subsequently been adopted by the International Headache Society. Further research identified an inverse relationship between oestrogen and migraine incidence. The follicular phase oestrogen rise was associated with reduced risk of migraine late luteal oestrogen 'withdrawal' at menstruation was associated with increased risk of migraine. In order to counteract the luteal phase oestrogen drop and prevent menstrual attacks, oestrogen supplements were used from the luteal phase oestrogen peak (day-6) through to the early follicular rise of endogenous oestrogen (day +2). Identification of ovulation using a fertility monitor enabled prediction of menstruation and accurate timing of oestrogen supplements, despite a wide inter- and intra-individual range in cycle length. The results showed that use of oestrogen supplements was associated with a significant reduction in migraine days compared to placebo. However, the benefits were offset by delayed oestrogen 'withdrawal' migraine. In women with migraine in the pill-free interval of combined hormonal contraceptives, there was a trend for oestrogen supplements to prevent 'menstrual' attacks, although the dose used was suboptimal. These findings support the hypotheses that menstrual migraine is a discrete clinical entity and is associated with oestrogen 'withdrawal'. Further, oestrogen 'withdrawal' migraine can be independent of menstruation and independent of ovulation. Oestrogen 'withdrawal' migraine can be prevented with oestrogen supplements, although the optimal regime has yet to be established.