Coming dissertations at Uppsala university
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Beating of hammers
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-526438
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.
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Aromatase, sex hormones and the young adult brain
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-526315
The enzyme aromatase coded by the gene CYP19A1/Cyp19a1 (humans/animals) catalyses the conversion of androgens into oestrogens, which play an important role in brain function from development through adulthood. Together with the sex hormones, aromatase seems to influence behaviour and cognition by affecting neurogenesis, differentiation, neuroplasticity, and neuroprotection. It is highly expressed in the limbic brain, suggesting a link to sex differences in mental health, including nicotine addiction, gambling disorder and resilience to early life stress (ELS) as well as structural properties of the brain. However, the underlying molecular mechanisms remain unclear. The studies of the present dissertation explored the distribution and influence of aromatase and sex hormones in rat and human brains, using different molecular biological methods, cognitive testing, as well as multimodal neuroimaging. Using fluorescence in-situ hybridization in the rat brain, Cyp19a1 expression was observed in the limbic regions and found to be higher in males compared to females, with the highest expression in the medial amygdala and the bed nucleus of the stria terminalis. Most Cyp19a1-expressing cells were GABAergic, some glutamatergic, and a small population of astrocytes expressing the gene was found. Furthermore, the expression of Cyp19a1 was observed to be lower in the medial prefrontal cortex (mPFC) of male rats exposed to ELS compared to controls, and a relationship between ELS and DNA methylation in the Cyp19a1 gene was detected. Using magnetic resonance imaging combined with [11C]cetrozole positron emission tomography in young adult women, aromatase availability (AA) was observed in the thalamus, the amygdala and the hypothalamus. A positive correlation with grey matter volume in those regions was found, together with a relationship between AA and the volume and cortical thickness of the mPFC and the volume and microstructure of the fornix. Additionally, an acute dose of nicotine was able to reduce AA in the thalamus. Experimental testing in young women showed an effect of menstrual cycle phase on reward-based decision-making and suggested a possible interaction between oestradiol and nicotine. In conclusion, these findings show for the first time in rats that aromatase is sex-, region- and cell type-specifically expressed and is affected by ELS. Moreover, in women aromatase is shown to be related to brain morphology and can be inhibited by nicotine, while fluctuating oestradiol influences cognition both alone and possibly in an interplay with nicotine. These findings advance our knowledge on the role of aromatase in the brain and the theoretical framework of psychoneuroendocrinology.
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Defining generalised joint hypermobility : Aspects of reliability, validity and the association to pregnancy induced pain
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524426
The aim of this thesis was to evaluate the definition of joint hypermobility and generalised joint hypermobility with aspects of reliability, validity and the association between generalised joint hypermobility and pregnancy-induced pain. Generalised joint hypermobility is used to reflect hereditary systematic connective tissue fragility. In study I, the inter-rater and intra-rater reliability, were evaluated in 49 women and men through 12 joint mobility tests included in three instruments for defining generalised joint hypermobility. In study II, the criterion validity was evaluated in 339 women in early pregnancy between the self-reported five-part questionnaire to identify generalised joint hypermobility, with the Beighton score. In study III, 255 women in early pregnancy were included to evaluate if a subset of joint mobility tests could define generalised joint hypermobility and establish limits for joint hypermobility. In study IV, 99 women pain-free before pregnancy were included to investigate the first onset of self-reported pain during pregnancy comparing women with and without generalised joint hypermobility, by parity and pain location. The reliability was good-to-excellent for both inter- and intra-rater reliability, for the majority of the joint mobility tests. The five-part questionnaire to identify generalised joint hypermobility with a cut-off level of ≥ 2 entailed the highest clinimetric values. However, the odds of having generalised joint hypermobility with a positive self-reported five-part questionnaire were low and yielding a false positive rate of 38%. No subset of joint mobility tests could define generalised joint hypermobility. Different combinations of joint mobility tests in upper- and lower limbs and the axial skeleton were compiled and evaluated for different standard deviation levels, where plus two standard deviations were most difficult to achieve. Women with generalised joint hypermobility and multiparous women experienced substantial earlier onset of self-reported pain during pregnancy, mainly in the lower back region. Thoroughly measured joint mobility and defining generalised joint hypermobility through different combinations of joint mobility tests, probably increased the precision of defining generalised joint hypermobility. Generalised joint hypermobility seems to be important for early development of pain during pregnancy. To identify women with generalised joint hypermobility in early pregnancy might be important in order to offer proper information, advice and rehabilitation.