2,995 research outputs found

    Computational techniques to interpret the neural code underlying complex cognitive processes

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    Advances in large-scale neural recording technology have significantly improved the capacity to further elucidate the neural code underlying complex cognitive processes. This thesis aimed to investigate two research questions in rodent models. First, what is the role of the hippocampus in memory and specifically what is the underlying neural code that contributes to spatial memory and navigational decision-making. Second, how is social cognition represented in the medial prefrontal cortex at the level of individual neurons. To start, the thesis begins by investigating memory and social cognition in the context of healthy and diseased states that use non-invasive methods (i.e. fMRI and animal behavioural studies). The main body of the thesis then shifts to developing our fundamental understanding of the neural mechanisms underpinning these cognitive processes by applying computational techniques to ana lyse stable large-scale neural recordings. To achieve this, tailored calcium imaging and behaviour preprocessing computational pipelines were developed and optimised for use in social interaction and spatial navigation experimental analysis. In parallel, a review was conducted on methods for multivariate/neural population analysis. A comparison of multiple neural manifold learning (NML) algorithms identified that non linear algorithms such as UMAP are more adaptable across datasets of varying noise and behavioural complexity. Furthermore, the review visualises how NML can be applied to disease states in the brain and introduces the secondary analyses that can be used to enhance or characterise a neural manifold. Lastly, the preprocessing and analytical pipelines were combined to investigate the neural mechanisms in volved in social cognition and spatial memory. The social cognition study explored how neural firing in the medial Prefrontal cortex changed as a function of the social dominance paradigm, the "Tube Test". The univariate analysis identified an ensemble of behavioural-tuned neurons that fire preferentially during specific behaviours such as "pushing" or "retreating" for the animal’s own behaviour and/or the competitor’s behaviour. Furthermore, in dominant animals, the neural population exhibited greater average firing than that of subordinate animals. Next, to investigate spatial memory, a spatial recency task was used, where rats learnt to navigate towards one of three reward locations and then recall the rewarded location of the session. During the task, over 1000 neurons were recorded from the hippocampal CA1 region for five rats over multiple sessions. Multivariate analysis revealed that the sequence of neurons encoding an animal’s spatial position leading up to a rewarded location was also active in the decision period before the animal navigates to the rewarded location. The result posits that prospective replay of neural sequences in the hippocampal CA1 region could provide a mechanism by which decision-making is supported

    Advanced glycation end products and age-related diseases in the general population

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    In this thesis, epidemiological, nutritional, and gut microbiome related studies are presented to illustrate the relation of advanced glycation end products (AGEs) with age-related diseases. The studies are embedded in the Rotterdam Study, a cohort of the Dutch general population of middle-aged and elderly adults. The amount of skin AGEs measured as SAF was used as a representative of the long-term AGE burden. Chapter 1 gives an overview of the whole thesis (Section 1.1) and gives a brief introduction to AGEs and their implications in disease pathophysiology. Chapter 2 focuses on the interplay of AGEs in the skin and clinical and lifestyle factors, and Chapter 3 concerns the link of skin and dietary AGEs with age-related diseases. Chapter 4 discusses the interpretations and implications of the findings, major methodological considerations, and pressing questions for future research

    Addiction in context

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    The dissertation provides a comprehensive exploration of the interplay between social and cultural factors in substance use, specifically focusing on alcohol use disorder (AUD) and cannabis use disorder (CUD). It begins by introducing the concept of social plasticity, which posits that adolescents' susceptibility to AUD is influenced by their heightened sensitivity to their social environment, but this sensitivity increases the potential for recovery in the transition to adulthood.A series of studies delves into how social cues impact alcohol craving and consumption. One study using functional magnetic resonance imaging (fMRI) investigated social alcohol cue reactivity and its relationship to social drinking behavior, revealing increased craving but no significant change in brain activity in response to alcohol cues. Another fMRI study compared social processes in alcohol cue reactivity between adults and adolescents, showing age-related differences in how social attunement affects drinking behavior. Shifting focus to cannabis, this dissertation discusses how cultural factors, including norms, legal policies, and attitudes, influence cannabis use and processes underlying CUD. The research presented examined various facets of cannabis use, including how cannabinoid concentrations in hair correlate with self-reported use, the effects of cannabis and cigarette co-use on brain reactivity, and cross-cultural differences in CUD between Amsterdam and Texas. Furthermore, the evidence for the relationship between cannabis use, CUD, and mood disorders is reviewed, suggesting a bidirectional relationship, with cannabis use potentially preceding the onset of bipolar disorder and contributing to the development and worse prognosis of mood disorders and mood disorders leading to more cannabis use

    Clinical, immunological and genetic features of histiocytic disorders

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    Advanced glycation end products and age-related diseases in the general population

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    In this thesis, epidemiological, nutritional, and gut microbiome related studies are presented to illustrate the relation of advanced glycation end products (AGEs) with age-related diseases. The studies are embedded in the Rotterdam Study, a cohort of the Dutch general population of middle-aged and elderly adults. The amount of skin AGEs measured as SAF was used as a representative of the long-term AGE burden. Chapter 1 gives an overview of the whole thesis (Section 1.1) and gives a brief introduction to AGEs and their implications in disease pathophysiology. Chapter 2 focuses on the interplay of AGEs in the skin and clinical and lifestyle factors, and Chapter 3 concerns the link of skin and dietary AGEs with age-related diseases. Chapter 4 discusses the interpretations and implications of the findings, major methodological considerations, and pressing questions for future research

    Clinical, immunological and genetic features of histiocytic disorders

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    Weak-Instrument and Pleiotropy-Robust Methods for Mendelian randomisation, with Applications to Mental Health

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    This PhD dissertation focused on developing and applying new methods for Mendelian Randomisation (MR), a technique that uses genetic variants as instrumental variables in order to assess causal effects of exposures on health outcomes. The major focus of the applied research is psychiatric research and mental health, with a range of analyses that address the topic of causal risk factors for depression with the use of these genetics-informed methods. The first contribution of this dissertation is the development of new methods for pleiotropy-robust MR by leveraging sex specificity of phenotypes. These methods allow for more accurate and robust estimation of causal effects by cancelling out potential pleiotropic effects of genetic instruments. The second contribution is a new method for appraising high-dimensional correlated variables in multivariable MR. This method allows for the inclusion of multiple correlated variables as exposures in MR analyses, through a transformation to groups of exposures that have attractive statistical properties and biological meaning. Finally, the dissertation provides an applied analysis of how inflammation and BMI affect a range of depression phenotypes with cutting-edge methods. This analysis replicates previous results on the harmful effects of overweight on mood and challenges the independent effect of inflammation as proxied by CRP. The introduction of the dissertation is divided into two parts. The first part provides a walkthrough of the epidemiological concepts of bias, randomisation, and causal inference with observational data. The second part is a specific introduction to MR, including its underlying assumptions and limitations, as well as detailed discussion of developments that make it more robust. Overall, this dissertation contributes new methods and applied analyses to the field of MR, with potential implications for researchers and practitioners

    Investigating the role of complement in the pathogenesis of pre-eclampsia in previously healthy pregnant women, and in high-risk groups.

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    Pre-eclampsia (PE) is a leading cause of obstetric morbidity and mortality. Certain groups of women, including those with chronic kidney disease (CKD) and those of sub-Saharan African (SSA) ethnicity, are at particularly high risk. There remains no definitive treatment other than expedited delivery of baby and placenta. Previous studies suggest a role for complement dysregulation in the pathogenesis of PE, but results are often conflicting, and it remains unclear whether changes in circulating complement concentrations reflect a general heightened inflammatory state in PE or are directly associated with placental complement-mediated injury. This thesis tested the hypothesis that PE is associated with excessive complement activation within placental tissue, with concurrent complement activation within the maternal and fetal circulation, and that groups with a high prevalence of PE, and of PE with severe features (women with CKD and women of SSA ethnicity) would exhibit a greater degree of systemic complement activation. Three arms of research were conducted, and I report: • In a cohort of previously healthy women, PE was associated with significant placental complement deposition, associated with concurrent changes in maternal and fetal circulating complement markers (reduced maternal properdin and C4, and elevated maternal and fetal Ba). Placental C4d deposition was strongly correlated with maternal properdin and C4, suggesting that those patients with the most excessive changes in circulating markers of complement activation also have the greatest extent of placental complement-mediated damage. • There was no evidence of excessive complement activation in the maternal circulation in superimposed PE in a cohort of women with CKD. However, raised Ba levels were associated with adverse pregnancy outcomes in women with CKD. • There was no evidence of excessive complement activation in PE in a Ghanaian cohort of women of SSA ethnicity when compared to healthy pregnant controls. However, pregnant women of SSA ethnicity did have significantly elevated levels of C5b-9, serum free light chains, and immunoglobulin G, when compared to the UK-recruited cohorts; suggestive of a baseline elevated inflammatory state. The results suggest that inhibition of complement activation is a potential therapeutic target for certain groups of women with PE. However, PE is a heterogenous syndrome and additional pathophysiological mechanisms may contribute to the development of disease in women with CKD and women of SSA ethnicity

    Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea

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    ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK

    Differences in well-being:the biological and environmental causes, related phenotypes, and real-time assessment

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    Well-being is a complex, and multifaceted construct that includes feeling good and functioning well. There is a growing global recognition of well-being as an important research topic and public policy goal. Well-being is related to less behavioral and emotional problems, and is associated with many positive aspects of daily life, including longevity, higher educational achievement, happier marriage, and more productivity at work. People differ in their levels of well-being, i.e., some people are in general happier or more satisfied with their lives than others. These individual differences in well-being can arise from many different factors, including biological (genetic) influences and environmental influences. To enhance the development of future mental health prevention and intervention strategies to increase well-being, more knowledge about these determinants and factors underlying well-being is needed. In this dissertation, I aimed to increase the understanding of the etiology in a series of studies using different methods, including systematic reviews, meta-analyses, twin designs, and molecular genetic designs. In part I, we brought together all published studies on the neural and physiological factors underlying well-being. This overview allowed us to critically investigate the claims made about the biology involved in well-being. The number of studies on the neural and physiological factors underlying well-being is increasing and the results point towards potential correlates of well-being. However, samples are often still small, and studies focus mostly on a single biomarker. Therefore, more well-powered, data-driven, and integrative studies across biological categories are needed to better understand the neural and physiological pathways that play a role in well-being. In part II, we investigated the overlap between well-being and a range of other phenotypes to learn more about the etiology of well-being. We report a large overlap with phenotypes including optimism, resilience, and depressive symptoms. Furthermore, when removing the genetic overlap between well-being and depressive symptoms, we showed that well-being has unique genetic associations with a range of phenotypes, independently from depressive symptoms. These results can be helpful in designing more effective interventions to increase well-being, taking into account the overlap and possible causality with other phenotypes. In part III, we used the extreme environmental change during the COVID-19 pandemic to investigate individual differences in the effects of such environmental changes on well-being. On average, we found a negative effect of the pandemic on different aspects of well-being, especially further into the pandemic. Whereas most previous studies only looked at this average negative effect of the pandemic on well-being, we focused on the individual differences as well. We reported large individual differences in the effects of the pandemic on well-being in both chapters. This indicates that one-size-fits-all preventions or interventions to maintain or increase well-being during the pandemic or lockdowns will not be successful for the whole population. Further research is needed for the identification of protective factors and resilience mechanisms to prevent further inequality during extreme environmental situations. In part IV, we looked at the real-time assessment of well-being, investigating the feasibility and results of previous studies. The real-time assessment of well-being, related variables, and the environment can lead to new insights about well-being, i.e., results that we cannot capture with traditional survey research. The real-time assessment of well-being is therefore a promising area for future research to unravel the dynamic nature of well-being fluctuations and the interaction with the environment in daily life. Integrating all results in this dissertation confirmed that well-being is a complex human trait that is influenced by many interrelated and interacting factors. Future directions to understand individual differences in well-being will be a data-driven approach to investigate the complex interplay of neural, physiological, genetic, and environmental factors in well-being
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