This dissertation will present the four manuscripts I published or am ready to publish on the study of the pathophysiology of migraine headache. The first chapter will discuss the background of the current understanding of migraine pathophysiology. Chapter 2 is focused on studying how Transient receptor potential vanilloid 4 (TRPV4) might play a role in migraine headache. Chapter 3 is the study of a novel cell type: dural fibroblasts might also play an active role in migraine headache. Chapter 4 is discussing Norepinephrine's role in headache pathophysiology. Chapter 5 is studying the combined effect of Acid and ATP in the pathophysiology of migraine headache. The dissertation will end in a conclusion in Chapter 6.

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.

Purpose: To determine if patients with migraine show clinically apparent visual field deficits in the peripheral visual field compared to healthy controls. Methods: Normal observers (n=25; mean age 41 y, range 15-67 y) and patients with migraine (n=12, mean age 48 y, range 21-55 y) were examined with a fully automated kinetic perimetry program (Octopus 900, Haag-Streit, Switzerland) on two separate study visits within two weeks. The program examined 3 isopters (I4e, I2e, I1e) at stimulus velocities of 5°, 4°, and 3°/s respectively. For every isopter, 12 stimulus vectors were presented at meridians spaced 30° apart, in random order, and each isopter was measured 3 times. Patients with migraine had been diagnosed by a neuro-opthalmologist according to criteria of the International Headache Society. Results: Differences in mean isopter radius between migraine observers and healthy controls were small (< 1.3°) and not statistically significant (P>0.05, Mann-Whitney U). No learning or practice effects were observed between study visits, and AKP showed reasonable repeatability for all three isopters. Conclusion: Patients with migraine did not demonstrate decreased peripheral visual fields in comparison to controls. This study had sufficient power (90%) to detect a group difference in mean isopter radius of approximately 2°.

No description available.

Thesis (M.A.)--Northern Kentucky University, 2008. / Made available through ProQuest. Publication number: AAT 1450372. ProQuest document ID: 1490083611. Includes bibliographical references (p. 44-46)

Thesis (Ph.D.)--Duquesne University, 2005. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p.238-245) and index.

BACKGROUND: Migraine is a primary headache disorder that has a high prevalence and burden of disease throughout the world. Migraine symptoms include throbbing head pain, nausea, hypersensitivity to light, sound, and smell, and autonomic, cognitive, emotional, and motor disturbances. About a third of migraineurs have aura symptoms which are transient neurological symptoms with gradual onset before the migraine attack, visual disturbances, sensory loss, and/or communication impairment. The trigeminovascular system, central descending modulation, and brainstem descending modulation have been implicated in the pathophysiology of migraine. However, the exact neurovascular mechanism for migraine has not been determined. Several imaging techniques have been used to find structural and functional brain changes in migraineurs. OBJECTIVE: In order to further existing knowledge of migraine pathophysiology, structural brain differences were investigated using imaging between migraineurs and healthy individuals and differences within migraineurs. METHODS: Thirty-two patients with migraine (25 females) and 32 healthy control subjects (25 females) age-, ethnicity-, and gender-matched participated in our study. Magnetic resonance imaging (MRI) scans were collected from each participant. Then, voxel-based morphometry (VBM) was utilized to find any gray matter (GM) volume differences between migraine patients and controls. Also, VBM was performed in specific regions-of-interest (ROIs) to compare 11 migraine patients with aura (MA) and 11 migraine patients without aura (MO). RESULTS: A significant increase in regional gray matter volume difference was observed for migraine patients compared to control subjects in the intracalcarine gyrus of the visual cortex (corrected, p<0.05). In the VBM analysis of ROIs, the similarities between the MO and MA subjects included increases in the anterior cingulate cortex (ACC), hippocampus, insula, and intracalcarine cortex, along with decreases in the ACC and insula (uncorrected, p<0.05). MO subjects had decreases in the amygdala, hippocampus, intracalcarine cortex, and thalamus, but not in the MA subjects (uncorrected, p<0.05). The MA patients had increases in the amygdala and thalamus, but not in the MO patients (uncorrected, p<0.05). DISCUSSION: It can be concluded that the visual cortex is involved in the migraine mechanism since a large increase in GM volume difference was found in migraine, MO, and MA cohorts, as well as results from previous studies. Numerous GM volume changes in MO and MA cohorts reinforce evidence that particular brain regions are a part of migraine pathophysiology, but there were some regions that do not. Further research using imaging analysis and with larger study populations should be conducted to enhance our understanding of the migraine mechanism and differences that arise between migraine groups, so that diagnosis and treatment administration can be improved.

6 1. ABSTRACT Background: This study is primarily aimed at describing migraine illnesses, the existing patient care algorithm with this diagnosis and to estimate the direct costs of treatment of migraine from the point of view of the health care system in the Czech Republic. In the theoretical part, the basic concepts and procedures of health economics and the health technologies assessment are examined, especially the cost-of-illness of the analysis that is conducted in the practical part, namely just on the illness of migraine. Methods: The cost of drugs used to treat migraine is determined using FNHK (Fakultni nemocnice Hradec Kralove) prescription data. Further, using the data on health care (both ambulatory and inpatient care), these services are being appraised and this way the cost of treatment of a patient with the disease estimated from the point of view of the health system in the Czech Republic. Results: The average annual cost of treatment of one patient with episodic migraine was assessed at CZK 1,182 for outpatient care, CZK 786 for hospitalization and CZK 2,707 for medication. For chronic migraines, the average cost is higher and estimated at CZK 3,321 for outpatient care, CZK 2,745 for hospitalization and CZK 7,415 for medication. Conclusions: The total direct annual cost of the patient was...

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Estuda atravÃs de ensaio duplo cego, controlado, randomizado o efeito da Toxina BotulÃnica do tipo A na profilaxia de crises de migrÃnea sem aura. A migrÃnea à um tipo comum de cefalÃia primÃria, benigna, episÃdica, e recorrente que se caracteriza por dor geralmente hemicrÃnica e pulsÃtil, e que à agravada pela atividade fÃsica. Existem outros sintomas associados como nÃuseas, fotofobia, fonofobia, ou irritabilidade. Na migrÃnea com aura podem tambÃm ocorrer alteraÃÃes neurolÃgicas motoras, sensitivas, ou visuais denominadas de aura. A migrÃnea, cuja fisiopatologia ainda nÃo à perfeitamente compreendida, seria o resultado de um processo patolÃgico complexo que envolveria o tronco cerebral e levaria à inflamaÃÃo local de vasos sangÃÃneos cranianos atravÃs da liberaÃÃo de neuropeptÃdeos vasoativos como SubstÃncia P (SP), Neurocinina A (NA), e PeptÃdio Relacionado ao Gene da Calcitonina (PRGC). Apesar das vÃrias opÃÃes terapÃuticas (analgÃsicos simples, antiinflamatÃrios hormonais e nÃo hormonais, triptanos, antipsicÃticos, derivados ergotamÃnicos, e opiÃides) para tratamento da crise ou para tratamento preventivo, somente cerca de um terÃo dos pacientes fica satisfeito com o tratamento. Foi observado que pacientes utilizando toxina botulÃnica para tratamento estÃtico de rugas da face ou distonias apresentavam uma reduÃÃo na quantidade de crises de migrÃnea. A toxina botulÃnica à uma potente neurotoxina produzida pela bactÃria Clostridium botulinum. A aÃÃo da toxina à impedir a liberaÃÃo de acetilcolina nos terminais nervosos. Ela tambÃm age inibindo a liberaÃÃo de neuropeptÃdeos vasoativos. O uso da toxina botulÃnica nos faria agir exatamente no cerne do processo fisiopatolÃgico da doenÃa. Com o objetivo de testar esse possÃvel efeito analgÃsico nos pacientes portadores de migrÃnea sem aura, realizou-se um estudo duplo-cego, controlado, e randomizado. Mediu-se o nÃvel de dor atravÃs de escalas para quantificar a intensidade e o nÃmero de dias com dor na semana antes e apÃs a injeÃÃo de Toxina BotulÃnica em mÃsculos da face. O grupo controle recebeu SF como placebo. Os pacientes foram seguidos durante trÃs meses. Ao final concluiu-se que nÃo houve diferenÃa estatÃstica na intensidade nem na freqÃÃncia da dor de cabeÃa nos pacientes que usaram a toxina botulÃnica em relaÃÃo aos que usaram placebo (SF) / A randomized, double-blind, placebo-controlled study of the use of botulinum toxin type A in the prophylactic treatment of Migraine is presented. Migraine is a common type of primary, benign, episodic headache. It is characterized by pain usually unilateral and throbbing. Other associated symptoms are nausea, sensitivity to light and sound, or irritability. The pain is usually worsened by physical activity. There are also motor, sensitive, or visual neurological alterations, denominated aura. The physiopathology of migraine is not still perfectly understood but it could involve liberation of vasoactive neuropeptides as Substance P, Neurokinine A, and Calcitonin gene-related peptide, promoting an inflammation. Migraine, then, would be the result of a complex process that would involve the brainstem and induce local inflammation of cranial blood vessels. In spite of the therapeutic options (analgesics, steroidal and non-steroidal anti-inflammatory, triptans, neuroleptics, ergot derivatives, and opioids) only about one third of patients is satisfied with the treatment. The preventive treatment is appropriate for those that have frequent crises. It was observed that the patients using botulinum toxin for aesthetic treatment of wrinkles of the face, or dystonia presented a reduction in the amount of migraine crises. The botulinum toxin is a potent neurotoxin produced by the bacterium Clostridium botulinum. The action of the toxin is to inhibit the acetylcholin liberation from the nerve terminal. It acts also inhibiting the liberation of vasoactive neuropeptides. Therefore, Botulinum Toxin would act exactly in the core of the physiopathologic process of the disease. With the objective of testing possible analgesic effects of botulinum toxin in migraine without aura bearers, we performed a double-blind, controlled, and randomized study. The pain level was measured by scales and by the amount, and number of days of pain in a week, before and after botulinum toxinâs injection in muscles of the face. The placebo group received saline injection. The patients were followed for three months. At the end it was concluded that there was not statistic difference in intensity nor in frequency of the headache of the patients that used botulinum toxin in relation to the people that used placebo (saline)

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