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I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.

In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.

Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences.

While statins are routinely prescribed to prevent cardiovascular diseases, their effects on brain alterations remain largely unknown. Very few studies have examined the differences in brain volumes between statin users and non-users, and existing research has yielded inconsistent results. This cross-sectional study aims to investigate the association between statin use at baseline and global and specific brain volumes measured 9 years later in a large population-based sample of middle-aged and older adults. Participants from the UK Biobank without neurological and psychiatric disorders consisted of 3285 statin users (mean 60 years and 69% males) and 36 229 non-users (mean 55 years and 46% males). We used linear models to estimate the mean volumetric differences between statin users and non-users while adjusting for UK Biobank assessment centre, age, sex, ethnicity, education, apolipoprotein E ɛ4 status, Townsend deprivation index, antidepressant use, intracranial volume, lifestyle factors (alcohol intake frequency, smoking and physical activity) and health-related conditions (body mass index, blood pressure, diabetes, coronary heart disease, stroke, head injury, depression and insomnia). Moreover, mediation analysis was performed to evaluate whether the association between statin use and global brain volumes was mediated by total serum cholesterol concentration. Statin use was associated with lower grey matter volume [β = −1575 mm³ (−2358, −791)], with 20% of this association mediated by total serum cholesterol concentration. Statin use was also associated with lower peripheral cortical grey matter volumes [β = −1448 mm³ (−2227, −668)] and higher white matter hyperintensity [β = 0.11 mm³ (0.07, 0.15)]. However, white matter volume did not differ significantly between statin users and non-users. Further analyses revealed that volumes of thalamus, pallidum, hippocampus, nucleus accumbens and other regions of the temporal lobe were smaller among statin users compared with non-users. This study showed that statin use is associated with higher white matter hyperintensity volumes and lower total and peripheral cortical grey matter volumes 9 years later, indicative of the brain’s ageing process. Moreover, the observed grey matter alterations were partially explained by statin-induced total serum cholesterol reduction. This study emphasizes the potential direct and indirect effects of statins on brain volume.

Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.

Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random- effects empirical Bayes model.

Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of - 8.94 points (CI [ - 10.04,- 7.84], p < 0.01) in the BDI scale, of - 5.90 points (CI [ - 9.92,- 1.88], p < 0.01) in the BDI-II scale and of - 6.19 points (CI [ - 9.52,- 2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of - 4.10 (CI [ - 7.31,- 0.89], p = 0.01) points in the HIT6 scale, - 32.05 (CI [ - 55.96,- 8.14], p = 0.01) in the MIDAS scale, - 1.7 (CI [ - 3.27,- 0.13], p = 0.03) points in the VAS scale and of - 6.27 (CI [ - 8.48,- 4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.

Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.

Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.