This thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two... Show moreThis thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two major stress systems (i.e. the ANS and the HPA-axis), and their relation with psychological and psychiatric characteristics. Show less
Center-based child care settings are a common form of non-parental child care for many families worldwide. However, according to earlier studies, children can experience stress when they attend... Show moreCenter-based child care settings are a common form of non-parental child care for many families worldwide. However, according to earlier studies, children can experience stress when they attend child care. The aim of the current dissertation was to elucidate the correlates of physiological and behavioral stress (especially around transitions) for young children (aged 0 – 4 years, with a specific focus on infants) and their parents in the context of center-based child care, and to examine whether and how we can support families with the aim of reducing stress. We did this by conducting a meta-analysis, a large-scale correlational study, and a small-scale intervention study combining questionnaires, observations, and physiological measures. Results showed that a significant part of children and parents experienced stress during and beyond the transition to center-based child care, irrespective of the quality of child care, and that several child (age and number of hours at child care) and parental (sensitivity and separation anxiety) factors were correlated. We also identified some clues as to what type of support can be helpful to assist families within this context, with the ultimate goal of promoting well-being in both young children and their parents. Show less
In this thesis, we have studied the potential of the zebrafish larval model in studying the ECS, as a complementary model to the existing rodent models. More specifically, we have looked at the... Show moreIn this thesis, we have studied the potential of the zebrafish larval model in studying the ECS, as a complementary model to the existing rodent models. More specifically, we have looked at the role of the ECS in regulating locomotion and anxiety, and its interaction with the hypothalamic-pituitary-interrenal (HPI) axis, or stress axis. This study has provided us with an interesting animal model which allows for pharmacological screening of Cnr1 agonists, and their involvement in the CNS, as shown by a change in locomotion, anxiety-like behavior and HPI axis activity. The zebrafish larval model can be used as a complementary model to the existing rodent animal models, to study the ECS. The zebrafish larval model brings several interesting features, such as optical transparency and possibilities for high-throughput screening. Furthermore, a complete ECS is present, there is lack of endogenous activity, allowing for exogenous compound screening, and zebrafish data is generally in line with rodent literature. Since the ECS is involved in many diseases, more research of this system may result in the discovery of novel drugs and drug targets. Show less
Hypercortisolism causes numerous and potentially severe complications, which are often underestimated and not well recognized in clinical practice. There are two main causes for... Show moreHypercortisolism causes numerous and potentially severe complications, which are often underestimated and not well recognized in clinical practice. There are two main causes for hypercortisolism. Firstly, exogenous hypercortisolism through corticosteroid use, which is highly prevalent, since around 1% of the general population uses corticosteroids. Secondly, endogenous Cushing’s syndrome, which is rare, but the disease burden is considerable through increased morbidity and mortality risks. In this thesis, potential complications of exogenous hypercortisolism, and treatment and clinical outcomes of Cushing’s syndrome, are discussed. These studies on various aspects of hypercortisolism emphasize the importance of suppressing cortisol secretion to physiological ranges. Both hypercortisolism and adrenal insufficiency have enormous, and sometimes deleterious, impact on physical and psychological functioning. Treatment of hypercortisolism and adrenal insufficiency attempting to restore normal cortisol concentrations does not eliminate risk of adverse outcomes. Finally, increasing knowledge on the effects of endogenous Cushing’s syndrome and exogenous hypercortisolism is likely to improve patient care beyond the endocrinology department, as these conditions serve as a model for long-term exposure to stress, which is a highly prevalent condition. Insight into the potential consequences of long-term stress exposure, can aid all individuals exposed to long-term stress, including patients with chronic disease or long-term hospital admission. 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
Parenting influences many aspects of child development, including socio-emotional, cognitive, and behavioral outcomes. Yet most studies report only modest effect sizes. An increasingly likely... Show moreParenting influences many aspects of child development, including socio-emotional, cognitive, and behavioral outcomes. Yet most studies report only modest effect sizes. An increasingly likely explanation is that not all children are equally affected by environmental factors, including parenting. The differential susceptibility theory proposes that some children might be more susceptible to both positive and negative environmental influences, compared to other children. Such differences in susceptibility are thought to be due to genetic, temperamental, or physiological susceptibility factors. In the current thesis, we tested the theory of differential susceptibility of children to the effects of parenting in a large population-based cohort, the Generation R Study. Doing so, we went beyond common methods. First, we investigated differential susceptibility from a developmental perspective by including multiple measures over time. Second, we went beyond single-gene/polymorphisms in the investigation of gene-environment interplay by aggregating genetic variation in a set of dopamine genes. Third, we extended previous research on mild perinatal adversity as a susceptibility factor by examining its moderating role in the association between harsh parenting and hair cortisol levels, taking into account background factors that we demonstrated to be of influence on hair cortisol levels. Show less
Depression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated... Show moreDepression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated by the metabolic syndrome (MetSyn), a cluster of cardiovascular risk factors (waist circumference, blood sugar, cholesterol, triglycerides, blood pressure) and related parameters (BMI, waist-hip-ratio and LDL-cholesterol). Better insights in this association are important in order to better prevent and treat both conditions. This thesis focuses on the association between depression and metabolic disturbances. The results show that there is a significant and longitudinal and bidirectional association between depression and obesity, which is most pronounced among those with a clinical diagnosis depression. When subjects are approached not based on the presence or absence of the diagnosis, but based on the most prevalent symptoms, results show that only __Somatic Arousal__ symptoms (palpitations, dizziness, tension, shortness of breath) are associated with most MetSyn components. Comparing depressed inpatients to depressed outpatients, inpatients show more adverse metabolic disturbances in the lipid-spectrum, while blood pressure is more favorable. Further, inpatients show higher cortisol levels, which are considered to be a measure of the HPA-axis, an important stress-system in the onset and natural course of depression. Show less
The current thesis focuses on the longitudinal development of early-adopted children in the 1887/29874 Leiden Longitudinal Adoption Study (LLAS). In the LLAS, adopted children were followed from... Show moreThe current thesis focuses on the longitudinal development of early-adopted children in the 1887/29874 Leiden Longitudinal Adoption Study (LLAS). In the LLAS, adopted children were followed from infancy until young adulthood. In Chapter 1 we discuss the role of sensitive parenting and the precursors and developmental outcomes of attachment security. In the empirical study in Chapter 2 we report on the concurrent as well as longitudinal relations between maternal sensitivity, child temperament, and externalizing behavior problems. In the second empirical study in Chapter 3, we follow this line of enquiry and investigate concurrent and longitudinal relations between maternal sensitivity, child temperament and internalizing behavior problems. Chapter 4 reports on the final empirical study of the thesis, and focuses on the associations between maternal sensitivity and attachment in infancy and the diurnal cortisol curve in young adulthood. Our empirical studies show that maternal sensitivity in infancy and middle childhood indirectly predicts fewer internalizing behavior problems in adopted adolescents, and that maternal sensitivity in adolescence predicts less concurrent delinquent behavior. Attachment experiences in early life do not predict the adoptees' diurnal cortisol curve in later life. In Chapter 5 we discuss these results and some methodological issues more thoroughly. Show less
Depression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the... Show moreDepression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the Dutch population, striking women twice as often as men. The disorder often comprises persisting disturbances in the neuroendocrine stress system, the hypothalamic- pituitary-adrenal (HPA) axis, including disregulation of its end-hormone cortisol. Cortisol normally stimulates emotional, cognitive and behavioral processes in order to cope with a stressor and promotes recovery, learning and memory. This thesis describes the identification of a specific genetic variant of the mineralocorticoid receptor (MR), one of the two receptors for cortisol, which protects against depression. MR transcript expression was found to be lower in postmortem limbic brain regions of depressed patients compared to non-depressed subjects. In addition, a specific and common MR gene variant was identified that results in higher MR expression in vitro. This same variant was found to associate with personality characteristics that predict the risk of depression later in life and with a lower risk of depression itself. All associations were found only in women and not in men. To conclude, the MR is an important determinant of resilience; increased MR expression seems to be protective against depression. Show less
Psychological, neurobiological and genetics characteristics of Holocaust child survivors and their daughters were studied in population-wide demographic sample in comparison to matched control... Show morePsychological, neurobiological and genetics characteristics of Holocaust child survivors and their daughters were studied in population-wide demographic sample in comparison to matched control groups. Sixty years following the occurrence of the trauma, survivors still report more dissociative symptoms in everyday life, less satisfaction with their lives, and they also perceive their life events as more stressful compared to control group. Moreover, these survivors show more cognitive impairment than their comparisons. Nonetheless, adult offspring of survivors were not different from their comparisons. Survivors also showed elevated levels of daily cortisol secretion than did their comparisons, whereas cortisol level was the same in adult offspring of survivors and their counterparts. But, offspring of survivors with more dissociative symptoms showed lower levels of cortisol production over the day than did offspring of survivors with less dissociation. When exposed to stress, Holocaust survivors displayed elevated levels of cortisol secretion immediately before the onset of the stress, followed by a strong decline of cortisol levels. Nonetheless, comparison participants without Holocaust background showed the expected increase of cortisol levels in response to induced stress. Adult offspring of Holocaust survivors did not display different cortisol reactivity in response to stress than that of their counterparts. Finally, results showed that Holocaust survivors with the wildtype ADRA2B displayed higher cortisol levels than did their comparisons with the same genotype. No difference was found between these groups among carriers of the deletion variant. In sum, although survivors themselves suffer from post traumatic symptomatology, and their offspring may show neurobiological markers of secondary traumatization if their parents still show more dissociative symptomatology, (adult) children of Holocaust survivors show no psychological issues caused by their parents' trauma. Show less
Dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have... Show moreDysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relation between trauma exposure, stress regulation, and psychopathology. Mentally healthy trauma-exposed subjects were compared with non-trauma-exposed healthy controls. To distinguish between the potential effects of childhood trauma as opposed to adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role. Show less
The present thesis contains five experimental studies into the effects of stress on memory I healthy males. Hydrocortisone (and propranolol) administration or the induction of social stress are... Show moreThe present thesis contains five experimental studies into the effects of stress on memory I healthy males. Hydrocortisone (and propranolol) administration or the induction of social stress are used to heighten cortisol levels, and consequently to study its effects on working memory performance and memory retrieval. In addition, by using neutral and emotional distraction during working memory, effects of cortisol on emotional distraction were investigated, also with use of functional imaging. Overall, it was consistently found that high cortisol levels, by hydrocortisone administration or induced by stress, reduced the distraction by emotional irrelevant stimuli, hence improving working memory. The current findings might be relevant for patients suffering from posttraumatic stress disorder, who typically suffer from trauma-related intrusions. Show less
The project described in this thesis was designed to test if genetic variation in the mineralocorticoid receptor (MR) gene is a risk factor for developing major depression. First the MR-gene was... Show moreThe project described in this thesis was designed to test if genetic variation in the mineralocorticoid receptor (MR) gene is a risk factor for developing major depression. First the MR-gene was screened for genetic variation. Two selected single nucleotide polymorphisms (SNPs) were tested for in vitro functionality at different levels including: protein and mRNA expression, transactivational capacity and ligand binding. Functionality in vitro was confirmed leading us to test their influence on electrolyte regulation, stress responsiveness and personality. First, in three different cohorts one SNP influenced blood pressure and salt regulation, as could be expected for the MR. Second, the SNPs were associated with the cortisol awaking response (CAR) after dexamethasone administration and with the cortisol and autonomic response following psychosocial stress. This indicates an important role for the MR in the regulation of the stress-response. Third in a relatively small cohort (n=150) the SNPs were not associated with mood and/or anxiety disorders but in the patient group there was an association with the personality trait neuroticism. We hypothesize that genetic variants in the MR-gene are determinants of vulnerability for psychiatric disorders. Show less
In this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis... Show moreIn this thesis, we provide evidence in research on endophenotypes of psychopathology that it is fruitful not to take the clinical picture central, but the hypothalamus-pituitary-adrenal (HPA) axis as a core stress system underlying psychopathophysiology in stress-related disorders. Homeostatic systems, including the HPA axis, are by nature nonlinear in their function, with suboptimal states of function at both sides of the curve, e.g. hyper- versus hypofunction. By taken the HPA axis as starting point, we were able redefine the clinical phenotype in relation to both dysfunctional states, i.e., hyper- and hypocortisolism. Furthermore, starting with the stress system enabled us to investigate the effects of HPA axis dysfunction on the metabolic and immune system. Based on the studies presented in this thesis, we hypothesize that the nonlinear aspect of HPA axis function reflects different time points during the stress process, from a hyperactive HPA axis when the stress begins to, eventually, a hypoactive HPA axis when stress holds on. Secondly, we hypothesize that both dysfunctional states of the HPA axis, i.e., hyper- and hypocortisolism, differ in their effects on the metabolic and immune system. Show less
This thesis studies the normal developmental pattern of social evaluative fears from childhood to adolescence. We have investigated age differences in self-reported social fears and physical... Show moreThis thesis studies the normal developmental pattern of social evaluative fears from childhood to adolescence. We have investigated age differences in self-reported social fears and physical responses during a public speaking task. In addition, youth's perceptions of speaking in public were studied through a short interview. Finally, two aspects of adolescent development are highlighted, namely resistance to peer influence and self-restraint, in the two concluding chapters. The main finding of the thesis is that social evaluative fears seem to increase with age. However, future research needs to develop more developmentally sensitive measures and further investigate the underlying processes of this increase. Show less
The main goal of the present thesis was to study the effects of stress and stress hormones on the retrieval of emotional memories in healthy humans. In addition, we were interested in the effects... Show moreThe main goal of the present thesis was to study the effects of stress and stress hormones on the retrieval of emotional memories in healthy humans. In addition, we were interested in the effects of stress hormones on post-retrieval processes like reconsolidation. That is, are there only acute and temporary effects of stress hormones on memory retrieval, or are there also long-term effects? Studying effects of stress hormones can be done in two ways; either by (experimentally) inducing stress in humans, or by exogenously administering doses of stress hormones. In the present thesis both ways were used. Furthermore, when investigating emotional memories, we can make use of memories that are created in a laboratory setting or those that derive from real life experiences, i.e. autobiographical memories. Again, both methods were investigated. We found acute stress and a single cortisol administration to have direct and long-term impairing effects on memory for neutral and emotional information that was learned and reactivated in a controlled laboratory situation. Future studies should shed more light on the generalizability of these findings to real life settings and clinical practice. Show less
The objective of this thesis was to validate serial position effects (SPE__S) scoring in the Rey Auditory Verbal Learning Test (RAVLT). The RAVLT is a much used clinical method for assessing memory... Show moreThe objective of this thesis was to validate serial position effects (SPE__S) scoring in the Rey Auditory Verbal Learning Test (RAVLT). The RAVLT is a much used clinical method for assessing memory performance, but the method of scoring obfuscates that two memory processes underlie free recall. This is suggested by SPE__S of single-trial free recall , although the extent of the effects are not defined. The internal and external validity of SPE__S of the RAVLT is studied. The internal validity of SPE__S is studied by means of confirmatory factor analysis. It is shown that the recency effect comprises two to three items, while the primacy effect and middle (prerecency) comprise the remaining items in a list, implying that they arise from two memory functions. Studies testing their external validity show that they play a variant role in memory impairment of Alzheimer__s disease and Major Depression patients and are found to be differentially related to stress hormone activity in these patients, and in healty human subjects. Scoring of accurately determined SPE__S in the RAVLT is a valid improvement of clinical memory assessment. As serial position effects are further found in the recall of a variety of types of information, and also found in the animal, it is argued that they are general to temporal information processing. Show less
Children born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype... Show moreChildren born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype in survivors of preterm birth. In contrast to children born SGA, preterm infants born appropriate-for-gestational-age who experienced neonatal growth retardation, resulting in a small size at term, are excluded from growth hormone therapy if they fail to catch up in height subsequently. We tested in 19-year-olds born before 32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants cohort the effect of early growth on the growth pattern and adult metabolic health. Childhood growth and adult height were similar in preterm infants born SGA and those with neonatal growth retardation (weight and/or length at 3 months <-2 SD score). Young adults born preterm had a waist circumference and a waist-to-hip ratio much greater than the population reference mean, especially women. In addition, they showed a tendency towards insulin resistance and a high prevalence of hypertension. These findings were not explained by antenatal glucocorticoid treatment. Carriers of the 23K variant of the R23K polymorphism in the glucocorticoid receptor, associated with a mild glucocorticoid resistance, were less insulin-resistant and showed complete catch-up growth early in infancy and attained height was similar to the population reference mean, whereas stature in non-carriers was on average 0.5 SD below this mean Show less
In this thesis the development, stability, and correlates of early childhood aggression were investigated. The normative development was examined in a general population sample using questionnaires... Show moreIn this thesis the development, stability, and correlates of early childhood aggression were investigated. The normative development was examined in a general population sample using questionnaires completed by the parents of 12-, 24-, and 36-month-old children and again one year later. Results showed an early childhood aggression curve, with increasing rates of aggression in the second year of life and decreasing rates in the fourth year. One-year stabilities were moderate for 12-month-olds and high for 24- and 36-month-olds. In a subsample of mother-child dyads child physical aggression and parenting were observed from videotapes recorded when the children were 1-3 years old and again one year later. Results indicated that negative discipline was positively related to child aggression one year later, but only when mothers were low in initial sensitivity. Finally, a meta-analysis of the literature showed that basal cortisol levels are positively related to aggression in preschoolers, but that this relation is reversed in school-aged children. The association is stronger in children with clinical levels of problem behavior. This study sheds light on the normative course of early childhood aggression and its physiological and parental correlates. Show less
