The present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and... Show moreThe present dissertation investigated adolescents’ overall stress and perceived stressors, the effectiveness of a universal psychoeducational program about stress, the Stress Lessons, and adolescents’ self-referral to a targeted school-based intervention. Another aim was to examine whether adolescents from different demographic groupings vary in their experience of stressors and the effect of psychoeducation. A large and heterogeneous sample was recruited from schools with variation in educational tracks and self-perceived ethnic backgrounds. The sample consisted of 1613 predominantly young adolescents with an average age of 13 years old. Most adolescents have to maneuver through a world of stressors, mostly related to the school environment, their health, and future uncertainty, while adolescents experience less stress from social pressure and financial pressure. Furthermore, our results indicate that the Stress Lessons were effective regarding improving adolescents’ knowledge about stress, but not in terms of stress levels. Finally, we found that adolescents who reported higher levels of test anxiety were generally more likely to show interest in an intervention targeting reduction of performance anxiety after the Stress Lessons. However, we did not find that adolescents with lower levels of social skills were more interested in an intervention targeting improvement of social skills. Show less
This book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of... Show moreThis book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of breathing. In the respiratory vagal nerve stimulation model of contemplative practices (rVNS) specific respiratory patterns lead to changes in autonomic nervous system functioning that in turn produce changes in the central nervous system, which can be observed in a healthier cognitive and emotional balance. Second, there are two empirical chapters that show null-results on cognition with meditative movement (Tai Chi Chuan) and breathing interventions. The possible reasons for these lack of results are extensively discussed in this dissertation and put into a wider perspective within the scientific field. Show less
What we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The... Show moreWhat we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The stress response is for an important part dependent on glucocorticoid hormones. By and large, the acute response to glucocorticoids is beneficial, but chronic exposure often becomes maladaptive. To improve prevention and treatment of disorders we can develop due to stress, it is important to better understand the effects and working mechanisms of glucocorticoids. While we already possess extensive knowledge regarding glucocorticoids and glucocorticoid receptor signaling, we introduced and studied five “aspects of context”, which we felt address important current misconceptions or gaps of knowledge. Corticosterone was at the center of all the studies we performed, yet the eventual outcome of glucocorticoid receptor activation differed extensively in all experiments. Thus, the context in which corticosterone exerts its effects matters, and it is to researcher to be aware of this when designing new studies and interpreting available data. Whilst our research merely addressed some specific processes, the lessons learned from these experiments can be applied much broader to the biology of glucocorticoid signaling and other nuclear family members. Show less
From an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment.... Show moreFrom an evolutionary perspective, stress is an adaptive system that is necessary togenerate appropriate responses to stochastic and unpredictable events, and copeaccordingly with the environment. The physiological response to stress has beenremarkably conserved in vertebrate evolution. However, the threats to ourinternal “equilibrium” have changed between our ancestral environments and ourcurrent modern societies, and the demands for survival have evolved. Theglucocorticoid receptor (GR) is a timeless component of stress adaptation, as it is atthe intersection between the environmental stressors (i.e., physical, or psychosocial)and the genome. Therefore, the GR represents a valuable therapeutic target instress- and glucocorticoid-related disorders. This thesis provides new insightsinto the molecular mechanisms underlying GR signaling in metabolic diseases andbrain function and highlights the promise and importance of selectivity in novel GRtargeting treatments. Show less
This thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress... Show moreThis thesis addresses the pathophysiology of stress related diseases, taking two rare diseases, in which the hypothalamic-pituitary-adrenal axis and cortisol play a key role, as a model for stress vulnerability of the brain and the eye. The second aim of this thesis is to describe the organization of thromboprophylaxis management, and the outcome evaluation and quality of care for patients treated for Cushing’s syndrome. For more informatie, please refer tot he summary in the pdf of the thesis. Show less
More than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation... Show moreMore than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation of the structurally comparable mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can lead to very different, or even opposite effects. It also remained unclear how the consequence of activation of a single receptor, GR, can differ from cell to cell and from situation to situation. In this thesis we have investigated two aspects of transcriptional regulation in response to glucocorticoids: the cause of MR/GR specificity, and the role of crosstalk with other transcription factors. Within the hippocampus, we found NeuroD factors to drive the specificity in corticosteroid receptor DNA binding and subsequent gene regulation, i.e. by stimulating MR signaling. We identified Jun dimerization protein 2 (Jdp2) as a stress-responsive MR-specific target gene. In a stress hormone relevant memory task, GR was suggested to act context-dependently and several novel GR target genes were detected. Further elucidation of distinct MR/GR downstream pathways will enable us to better understand the stress physiology and more specifically target aspects of glucocorticoid signaling for treatment of stress-related disorders. Show less
Neurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks... Show moreNeurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks of neurodegeneration are still not fully understood. In this thesis, we make use of bioinformatics approaches to analyze a high-resolution spatial gene expression atlas of the healthy human brain generated by the Allen Institute of Brain Science. Spatial transcriptomics allows examining the molecular and functional organization of the human brain and can be combined with neuroimaging data to identify brain regions and anatomical structures that are vulnerable to cell loss in neurodegenerative diseases. By combining both data modalities, we examined healthy molecular functions in brain regions associated with disease vulnerability based on neuroimaging features, namely gray matter loss within brain networks in individuals with Parkinson’s disease, Huntington’s disease, and individuals at risk of schizophrenia. With this thesis, we have shown that by applying data-driven computational methods we can explore the whole genome and find gene expression patterns informative of regional brain vulnerability in neurodegenerative diseases. Our methods can similarly be applied to unravel the molecular mechanisms in other neurodegenerative diseases, and potentially even reveal shared mechanisms between neurological disorders. Show less
The locus coeruleus, a small brainstem nucleus, is the main source of the chemical norepineprine in the brain and is involved in a number of cognitive functions as well as several neurological and... Show moreThe locus coeruleus, a small brainstem nucleus, is the main source of the chemical norepineprine in the brain and is involved in a number of cognitive functions as well as several neurological and psychiatric disorders. In this dissertation we study the human LC-NE system, the anatomy of this tiny brainstem nucleus and the involvement of the LC-NE system in stress, arousal, cognitive flexibility and physiology (hormones & pupil responses). To date, the LC-NE system has been studied in animals or ex vivo (dead donors). This dissertation is among the first ones to study and visualize the LC-NE system in humans in vivo (alive volunteers) and to approach the human cognition and the study of the LC-NE system in a holistic manner: from central neuromodulators to hormones that are secreted in the body, from anatomy to physiology and cognition. To this end, all chapters were written by taking into consideration theoretical knowledge about the LC-NE system with regard to brain anatomy, cognitive functions, neuromodulation, physiological responses, and clinical applications. Chapters 2 and 3 deal mainly with the anatomy of the LC, while Chapters 4, 5 and 6 concentrate on cognition and human physiology. Additionally Chapters 5 and 6 take also a clinical approach. Show less
It is common in life to not perform at the very top of our cognitive abilities. This phenomenon usually exacerbates when we are under high levels of stress and in people with psychiatric disorders.... Show moreIt is common in life to not perform at the very top of our cognitive abilities. This phenomenon usually exacerbates when we are under high levels of stress and in people with psychiatric disorders. Attention to negative information is considered to play a crucial role in the development and maintenance of these disorders, especially anxiety-related disorders. Attention to negative information is not necessarily bad as it is an evolutionary function to protect us from dangerous situations. However, it can be destructive when it occurs constantly or when we need to focus on an important task. There are many situations where we have to perform difficult cognitive tasks and we worry about our performance or other people’s evaluation. Trait cognitive control, the ability to control attention and maintain a goal-relevant behaviour, is suggested to play a key role in the relationships between anxiety/stress, attention to negative information, and cognitive performance. Yet, the evidence is limited and further investigation is needed. In the current thesis, the relations between anxiety/stress, attention to emotional information, and cognitive performance will be investigated in a multidisciplinary approach, synthesizing clinical and cognitive factors and neurobiological underpinnings, while focusing on the role of trait cognitive control. Show less
With this thesis the PhD-candidate aims to enrich the body of evidence concerning the relation between stress and health, and the mediating role of (un)conscious perseverative cognitions (which is... Show moreWith this thesis the PhD-candidate aims to enrich the body of evidence concerning the relation between stress and health, and the mediating role of (un)conscious perseverative cognitions (which is captured in the extended perseverative cognition hypothesis). The main aim of this thesis was to find direct evidence for the extended PC hypothesis in real life. She examined whether reducing (un)conscious perseverative cognitions, or worry, improved stress-related physiological activity and subjective health complaints. Show less
The human body is inherently designed to be able to adapt to challenging situations. However, some experiences are so severe that they can lead to substantial and longerlasting disturbances in an... Show moreThe human body is inherently designed to be able to adapt to challenging situations. However, some experiences are so severe that they can lead to substantial and longerlasting disturbances in an individuals’ behavioral, psychological and physiological functioning. Importantly, there is a degree of inter-individual variation, as not all individuals show similar reactions to severe stress. Neuroimaging techniques can help to unravel the brain characteristics related to vulnerability and resilience to severe stress. In the research for this dissertation several neuroimaging modalities were used to further explore the brain characteristics related to (dys)function after exposure to severe stress and after exposure to hypercortisolism, such as voxel-based morphometry and diffusion tensor imaging to study the structure of gray and white matter in the brain, and resting-state fMRI to study functional connectivity patterns. We studied brain characteristics in several groups consisting of: patients in long-term remission of Cushing’s disease, and individuals with a history of childhood emotional maltreatment to examine the effects of hypercortisolism and severe stress on the brain. In addition, we studied a group of police officers and a group of individuals with a history of childhood maltreatment to investigate the brain characteristics related to resilience to stress. Show less
During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory... Show more During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory processes. To investigate this further we aimed to answer the question:""What are the primary genomic binding sites of the by stress and thus cortisol stimulated protein receptors MR and GR in the hippocampus?" To answer this question, new methods have been applied to determine where exactly MR and GR bind to the DNA, to find out which genes are potentially involved during stress management. As a result we have identified thousands of GR-binding sites at the DNA of which we have analyzed a selection in further detail. One of the identified pathways that have been found to be sensitive for activated GR and corticosteroids is the mTOR pathway. This pathway is involved in neuronal plasticity, which is the fundament for resilience. We have found that expression of the mTOR protein is decreased after exposure to acute stress when the organism has a history of chronic stress. Our results indicate that the reduced resilience after experiencing chronic stress is likely to be mediated by mTOR. Show less
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. Show less
The overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study,... Show moreThe overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study, was to expand our knowledge of homeostatic mechanisms at old age, thus trying to unravel underlying mechanisms of healthy human longevity. The focus of this thesis will be on analysis of the HPT-axis and HPA-axis in participants who have the propensity to reach old age in good health compared to age-matched controls. In humans, we are able to assess the 'function' of the HPT- and HPA- axes by measuring the key hormones involved as well as physiological parameters that are affected by these systems (heart rate, metabolism) under different conditions (in rest and during stress). Show less
The aim of this thesis was to identify the neural mechanisms that enable a person to adaptively respond to, and recover from stress, which was studied in healthy controls, in people with increased... Show moreThe aim of this thesis was to identify the neural mechanisms that enable a person to adaptively respond to, and recover from stress, which was studied in healthy controls, in people with increased vulnerability or resilience to stress-related disorders, and in people with depression or PTSD, using magnetic resonance imaging (MRI). In most of the studies, a specific MRI method was employed, with which it is possible to assess how different brain regions communicate with each other (i.e., functional connectivity) when the brain is initiating or regulating stress responses. Structure, activity, and connectivity of the amygdala, a small brain region important for stress reactivity, was of main interest. The results show how stress influences information processing, and causes changes in the communication between brain areas, even long after the stressful event ended. Furthermore, personality dimensions associated with increased vulnerability or resilience to affective disorders were associated with changes in brain networks involved in emotion processing and regulation. Finally, smaller amygdala volumes were found in women with PTSD, while reduced integrity of affective brain networks was demonstrated in depression. Together, these results open important new avenues for future research into the short and long term effects of stress on the brain. Show less
In this thesis I aimed to explore further finesses in the cellular dynamics of the two corticosteroid receptors, the MR and the GR, in both their membrane-associated and their nuclear... Show moreIn this thesis I aimed to explore further finesses in the cellular dynamics of the two corticosteroid receptors, the MR and the GR, in both their membrane-associated and their nuclear subpopulations. Amongst others I quantified the dynamics of the receptors at the membrane (only MR) and at the chromatin Show less
In this thesis studies are reported aimed to modulate the function of the GR by targeting GR-coregulator interactions. To achieve this goal, we used two different approaches. Firstly, we... Show moreIn this thesis studies are reported aimed to modulate the function of the GR by targeting GR-coregulator interactions. To achieve this goal, we used two different approaches. Firstly, we manipulated the splicing of SRC-1 with antisense oligonucleotides (AONs) administered in the CeA to change the relative expression of the two SRC-1 splice variants. Secondly, we used two novel GR ligands that allowed certain GR-coregulator interactions while preventing others, thus resulting in a mixed GR-coregulator interaction profile, which exhibited a spectrum of both agonist and antagonist activities Show less
Confidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the... Show moreConfidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the neurotrophin hypothesis. And where expected associations were established (e.g., abnormally low serum BDNF concentrations in the depressed state), the meaning often was not that clear (e.g., reverse causation). I therefore conclude, whilst taking limitations into account and acknowledging that the results are contingent upon imperfect and peripheral measurement, that the most reliable evidence in humans does not corroborate the neurotrophin hypothesis. So, given the data, the final words of this thesis are that solid work over novelty shows that the neurotrophin hypothesis should no longer be credited in its original form. All that glitters is not gold - back to the drawing table Show less
When a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood... Show moreWhen a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood emotional maltreatment (CEM). CEM is the most common form of child abuse, however, CEM is also the most hidden, underreported and least studied form of child abuse. An important reason for this may be because that the consequences of CEM are underestimated (e.g. __Sticks and Stones may break bones, but words will never hurt me__). However, this thesis shows that CEM is related with a persistent negative impact on cognition and the brain. We discovered that individuals that report CEM show differential structure and function of a brain area (the medial prefrontal cortex) that is crucial for role in responding to stress and thinking about yourself. Individuals with CEM also showed more activity in an area that signals threat (the amygdala) which may represent a persistent vigilance towards the detection of threat from others. These brain changes may underlie our other findings that individuals with CEM think more negatively about themselves and others. Negative thoughts can evoke negative thoughts and in new situations, which reinforces more negative memories. Due to this process, emotionally abused individuals may be more vulnerable to develop a depressive and/or anxiety disorder. Our findings warrant scientific and policital investments to increase societal awareness about the detrimental impact of CEM on cognition and the brain. Increased societal knowledge will hopefully lead to better awareness, reports, and subsequent interventions for individuals with CEM. Show less
Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new... Show moreChronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that would express anhedonia, induced by chronic stress. Mice were repeatedly exposed to the non-physical presence of a rat. Alterations in stress system activity were measured. Anhedonia was assessed by studying the behavioral response to positive stimuli. As a potential therapeutical approach we assessed reward expectation, and studied the effect of repeated administration of mifepristone (glucocorticoid receptor antagonist), directly targeting stress system regulation. Our model induced changes in the sensitivity of the reward system that contributed to cognitive impairments underlying anhedonia. The effects could partially be restored by additional reward. Mifepristone in na_ve mice suppressed stress system activity, which could indicate a similar direction of effects in stressed mice if provided. Concluding, our chronic stress mouse model induces anhedonia. The new methodology to reduce stress by either providing additional positive stimuli or mifepristone, increases the well being of the mice and may prove a new drug target to treat depression in humans. Show less
