This thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain... Show moreThis thesis aimed to investigate the neurobiological mechanisms of adolescent onset depression and anxiety disorders. A longitudinal fMRI study design was used that included both task related brain activation and resting state functional connectivity. All participants were scanned three times in a six-month period. In between scan sessions the adolescents from the clinical group received treatment as usual. Adolescents from the control group were scanned within the same time interval but did not receive treatment. During a scan session several MRI parameters were collected including task based fMRI (emotional face processing task) and resting state fMRI. We also administered several questionnaires about derpession and anxiety symptomatology. It was demonstrated that adolescents with depressive and anxiety disorders show differentiating patterns of amygdala reactivity and connectivity compared to a healthy control group. Furthermore, using a dimensional approach and taking individual differences in self-reported depression and anxiety symptoms into account highlighted the role of self-reported anxiety symptoms in amygdala reactivity during emotional faces processing. These findings indicate that the amygdala indeed is an important region involved in emotional face processing and that focusing on this region can provide further insights in the development and persistence of depressive and anxiety disorders in adolescents. Show less
It is well known that military deployment can lead to mental health problems in veterans, but the long-term impact is still unclear. This thesis discusses the results of the PRISMO-study, a large... Show moreIt is well known that military deployment can lead to mental health problems in veterans, but the long-term impact is still unclear. This thesis discusses the results of the PRISMO-study, a large cohort study in a group of Dutch Afghanistan veterans with a follow-up period of ten years. It shows that at ten years post-deployment, 8% of the cohort reported severe symptoms of posttraumatic stress disorder (PTSD). Agoraphobia, anxiety, depression, and hostility symptoms are also reported more frequently at ten years post-deployment compared to pre-deployment. Furthermore, this thesis demonstrates the large heterogeneity in PTSD symptom development among veterans. Of note is the delayed onset group that experienced increasing symptom levels between five and ten years post-deployment and did not show significant symptom reduction. The results from this thesis also show that various psychological factors, such as social support, and biological factors, such as DNA methylation, are associated with the development of PTSD or other mental health symptoms after deployment. Combining these factors in a prediction model for PTSD symptoms has not led to a useful screening instrument. It does, however, offer important leads for the identification of risk factors for PTSD and the development of intervention programs. Show less
This thesis focuses on patients with Binge Eating Disorder. The thesis consists of three parts. In the first part the validity of the diagnosis of BED will be discussed. The results of two... Show moreThis thesis focuses on patients with Binge Eating Disorder. The thesis consists of three parts. In the first part the validity of the diagnosis of BED will be discussed. The results of two literature reviews and an empirical cross-sectional study suggested that BED is a distinct eating disorder and should be added to a next version of the DSM. In the second part results of a randomized controlled trial were described. The effectiveness of cognitive behavioural therapy was compared to a waiting list control group. As expected, objective binge eating frequency, eating disordered psychopathology, and comorbid psychopathology decreased significantly in the CBT group whereas no reduction was found in the control (WLC) group. Mediator analyses indicated that abstinence from binge eating at post treatment was fully mediated by changes in weight concerns and marginally by changes in concerns about shape and eating, depressive symptoms, and more general psychopathological symptoms. In the third and last part the results of two experimental studies were presented. The purpose of the studies was to investigate the causal relationship between negative mood and binge eating. Both experimental studies found evidence for the fact that in individuals with BED depressive symptoms and caloric intake are positively related. Show less
The overriding aim of my thesis was to study the relationship between blood pressure (BP) and cognitive and psychological functioning in older persons. Observational studies indicate that lower BP... Show moreThe overriding aim of my thesis was to study the relationship between blood pressure (BP) and cognitive and psychological functioning in older persons. Observational studies indicate that lower BP increases risk for cognitive decline in older persons. Older persons are at risk for impaired cerebral autoregulation, and lowering their BP may compromise cerebral blood flow and cognitive function. Contradictory to our hypothesis, the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study Leiden, a community-based randomized clinical trial in older persons (aged ≥75 years) with mild cognitive deficits, did not show that discontinuation of antihypertensive treatment improves cognitive functioning. The lack of the effect of this trial may be due to the unintentional inclusion of persons with a relatively intact cerebral autoregulation. Furthermore, we demonstrated that older persons with mild cognitive deficits and with orthostatic hypotension, who discontinued all their antihypertensive medication had an increased probability of being free from orthostatic hypotension 4 months later, compared to persons who continued their medication. Finally, in the DANTE MRI sub study, the relationship between BP and both conventional features of small vessel disease (SVD) and microstructural damage was explored, as well as the relation between microstructural damage and cognitive and psychological dysfunction. Show less
The overarching goal of this dissertation was to investigate parenting processes in relation to affective well-being in families in the daily flow of life from different perspectives (i.e.,... Show moreThe overarching goal of this dissertation was to investigate parenting processes in relation to affective well-being in families in the daily flow of life from different perspectives (i.e., adolescent, mother, father), on different levels (i.e., objective, momentary, and daily), and in a clinical sample (families with an adolescent with a depression) in addition to community samples. Our findings underline the importance of daily parental warmth and criticism of mothers and fathers for adolescents’ well-being. In addition, we showed that adolescents, parents, and their perceptions of parenting influence each other and that becoming more attuned to each other’s intention and needs is essential. Importantly, we consistently demonstrated that not only the extent and direction of the dynamic processes between parenting and affect in daily life differs between, but also within persons and families. This stresses the need for research focusing on individual processes and combining quantitative with qualitative measures. The use of more idiographic approaches would not only enable gaining more insight into these differences between individuals, but also contribute to identifying parenting practices that work for almost all adolescents. This would facilitate the development of interventions combining universal parenting principles with suggestions for tailoring it to individual- or family-specific situations. 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
In this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was... Show moreIn this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was to determine which predictors and associated factors contributed to the development of certain non-motor symptoms in Parkinson’s disease (PD). Strengths of our cohort study include the length of the follow-up period, broad clinical characterization, limited loss-to-follow-up and the large cohort size. The following non-motor symptoms have been addressed in this thesis: psychosis (hallucinations), dementia, excessive daytime sleepiness (EDS), insomnia, depression and anxiety. We found that while certain non-motor symptoms are inherent components of PD that increase in severity as the disease progresses, others symptoms such as excessive daytime sleepiness are inarguably caused by antiparkinsonian medication. For the future, we hope to see more longitudinal data on the disease progression in PD from large cohorts. Knowledge from longitudinal studies does not only contribute to more insight in the underlying pathobiology of PD, but it could also help the caregiver to monitor patients with particular risk factors more closely and adjust treatment if necessary. Show less
This thesis explores cognitive vulnerability to depression and the interplay between genetic and environmental influences. Cognitive vulnerability to depression is characterized by negative... Show moreThis thesis explores cognitive vulnerability to depression and the interplay between genetic and environmental influences. Cognitive vulnerability to depression is characterized by negative patterns of information processing. One aspect is cognitive reactivity - the tendency to respond with maladaptive thoughts when mood is challenged. Vulnerable individuals also show negative cognitive biases in emotion perception and attention, and impaired decision-making. How one processes personal and socially relevant information plays an important role in the development and maintenance of depression. The first part of the thesis reports how the interplay between genes and environment affects cognitive reactivity and emotional information processing. We observed that genes and environmental stressors interact to determine a person’s vulnerability to depression or resilience. Cognitive reactivity was also found to be a residual vulnerability factor in individuals with history of suicidal tendencies. The second part of the thesis is comprised of two experimental manipulations on emotional cognition. Effects of omega-3 fatty acid supplementation were examined on mood and cognition of healthy participants and recovered depressed individuals. Omega-3 fatty acids can have selective effects on mood and cognition of individuals, but the pathways through which this happens remain to be investigated. Show less
This thesis aimed to lay the foundation for a new set of Dutch mental health instruments to measure depression and anxiety in an efficient, reliable, valid, and responsive manner. More specifically... Show moreThis thesis aimed to lay the foundation for a new set of Dutch mental health instruments to measure depression and anxiety in an efficient, reliable, valid, and responsive manner. More specifically, the Dutch-Flemish PROMIS adult v1.0 item banks for Depression and Anxiety were psychometrically evaluated for computerized adaptive test (CAT) administration in the Dutch clinical and general population. CAT is a modern methodology that can be used to develop instruments that measure both efficiently and reliably as only the most appropriate questions are administered, and assessment terminates as soon as sufficient reliability is achieved. For the PROMIS CAT instruments, this was demonstrated in the thesis: measuring depression and anxiety in Dutch persons was highly efficient and reliable. Moreover, the CAT instruments were shown to measure depression and anxiety sufficiently responsive and valid as well. This even includes longitudinal validity, which has barely been studied for other Dutch mental health instruments. Overall, it was concluded that the new instruments are an improvement over available instruments. Therefore, using the PROMIS CAT instruments in clinical practice may lead to more efficient and reliable measurement that supports professionals and patients in evaluating patients' treatment. Show less
This thesis leads to empirical insights in the relationship between anger and aggression, on the one hand, and psychopathology, on the other hand, using robust study designs and a broad spectrum of... Show moreThis thesis leads to empirical insights in the relationship between anger and aggression, on the one hand, and psychopathology, on the other hand, using robust study designs and a broad spectrum of anger manifestations. It became clear that the occurrence of anger and aggression are common among both psychiatric outpatients, including individuals with depressive-, anxiety-, and bipolar disorders, and psychiatric inpatients, including individuals with psychotic- and personality disorders. Aggressive behaviour regularly leads to a referral to long-stay inpatient care. As supported by this thesis, the costs of aggression within long-stay wards are high. However, despite the increased awareness and efforts to reduce violence in clinical care among healthcare workers and policymakers, aggression incidents remain highly prevalent in psychiatric inpatient facilities. Research suggests diet to be a modifiable factor affecting mood and behaviour. Yet, the promising effects of nutritional supplementation on aggressive incidents found in previous studies were not replicated in psychiatric inpatients. These results strengthen the need for study of additional preventative and treatment options. Furthermore, our results underline the importance of including vulnerable populations, who are often underrepresented in RCTs, to provide evidence-based care for these groups. Show less
Depression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the... Show moreDepression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the sum score on psychometric scales as a total indicator for depression severity. The present dissertation aimed to expand our knowledge of depression by researching its symptom-specific longitudinal characteristics, its predictive factors, and methods for predicting depression and anxiety while taking individual symptoms into account. We demonstrated that individual depressive symptoms are not synchronized over time within patients and in groups of patients. We found that individual symptoms of depression are associated to different risk factors, as preceding chronicity, neuroticism, and inflammation were related to individual symptoms with vastly different magnitudes. Taken these findings together we have demonstrated that depressive disorder can not be characterized as an unified syndrome. Addressing depression at the syndrome level may obscure insights into both patient and symptom-specific characteristics. Our findings strengthen the idea that employing a symptom-focused approach in both clinical care and research is of value. With this dissertation, we hope to have contributed to the development of alternative ways to define and study depression and its symptoms. Show less
In this thesis four studies assessing putative pathways implicated in cognitive models of depression are presented and discussed. In two initial studies the possibility to manipulate attention... Show moreIn this thesis four studies assessing putative pathways implicated in cognitive models of depression are presented and discussed. In two initial studies the possibility to manipulate attention allocation bias using two types of attention bias modification (ABM) procedures was explored. Neither method successfully or consistently modified attention allocation bias in dysphoric individuals. Putative interactions between 5-HTTLPR genotype and life stress were studied in the third study. Adopting an endophenotype approach, effects on measures of biased information processing were assessed. S-allele carriers showed increased recognition of negative mood state as a function of recent negative life events. Hypothesized interactions with childhood emotional abuse or affection attention allocation bias were found non-significant. A main effect of 5-HTTLPR was observed such that s- allele carriers selectively oriented attention towards negative information. In the fourth study the predictive value of cognitive reactivity to sad mood (measured with the LEIDS-r questionnaire) for the first onset of depression was assessed. Among 834 never previously depressed participants, cognitive reactivity predicted first onset of depression over the subsequent two years, even when various other factors, including baseline symptoms and negative life events, were statistically controlled for. Finally, these findings are discussed and related to the existing literature Show less
The main objective of this thesis is to describe the epidemiology of long term BZD use as well as its long term consequences. This thesis is structured into three sections: In section one, the... Show moreThe main objective of this thesis is to describe the epidemiology of long term BZD use as well as its long term consequences. This thesis is structured into three sections: In section one, the correlates of BZD use, new use, chronic use, inappropriate use, and BZD dependence severity are investigated. The possible influence of the prescribing physicians on patient BZD use is also considered. In section two, the focus is on the physiological consequences of long-term BZDs use on the HPA axis and the ANS. In section three, cognitive effects of BZDs in long-term users are addressed Show less
De uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische... Show moreDe uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische onderbouwing, overwogen dient te worden. Inmiddels wordt adipositas in de dagelijkse praktijk op meer dan alleen het BMI beoordeeld, namelijk ook de tailleomtrek en het lipidenprofiel. Echter, dergelijke aandacht bestaat nog niet voor de heterogeniteit van depressie. Een grotere bewustwording van de verschillende manifestaties van depressie-symptomatologie, die het gevolg kunnen zijn van uiteenlopende pathofysiologische mechanismen, is van essentieel belang. Wanneer een patiënt met depressie een atypisch energie-gerelateerd symptoomprofiel heeft, kan het nuttig zijn om diens metabole biomarkers te controleren om mogelijke ontwikkeling van cardiometabole ziekten te voorkomen. In de klinische praktijk moeten wij ons bij de behandeling van patiënten met depressie ook meer bewust worden van de correlatie tussen symptoomprofielen van depressie en afzonderlijke biologische en klinische manifestaties. Het is cruciaal om goed te kijken naar de symptomen die bij elke patiënt tot uiting komen. De resultaten van dit proefschrift tonen aan dat patiënten met een depressie die atypische energie-gerelateerde depressieve symptomen vertonen, genetisch en klinisch kwetsbaar zijn voor aan insulineresistentie gerelateerde ziekten (namelijk adipositas, metabole ontregelingen en diabetes mellitus type 2). Een gepersonaliseerde aanpak kan behulpzaam zijn in preventie van deze chronische en complexe ziekten. Hierbij dient er rekening gehouden worden met de heterogeniteit van depressie en de associatie tussen atypische energie-gerelateerde symptomen van depressie en deze ziekten. Show less
This dissertation focuses on identifying neural mechanisms underlying social evaluations and self-views from a parent-adolescent perspective among adolescents with and without depression, and their... Show moreThis dissertation focuses on identifying neural mechanisms underlying social evaluations and self-views from a parent-adolescent perspective among adolescents with and without depression, and their parents. As part of RE-PAIR, affective and neural responses to praise and criticism about the adolescent child, and neural responses to reliving positive autobiographical memories were assessed, using ecologically valid fMRI-tasks. Particularly criticism seems to be highly salient to parents and adolescents, activating the salience network and decreasing mood. Both praise and reliving positive autobiographical memories activate areas important for self-referential processing in adolescents, which might reflect the ‘positive self’. Aberrant self-related processing when reliving autobiographical memories and increased sensitivity to parental criticism might be key underlying neural mechanisms in adolescent depression. By feeling more negatively, having more negative self-views, interpreting the environment as more negatively, memorizing past experiences in a more negative way, and focusing on negative events more often, adolescents with depression seem to have multiple negativity biases. These negativity biases are likely to negatively impact social relationships, potentially further reinforcing negative feelings and a negative self. Interventions exploring and strengthening the positive self, in particular the positive self aligning with the current self, might be useful for treating, or even preventing adolescent depression. Show less
This dissertation describes the findings of six studies on mental health problems in the family context, specifically focusing on the associations with the parent-child relationship, parenting... Show moreThis dissertation describes the findings of six studies on mental health problems in the family context, specifically focusing on the associations with the parent-child relationship, parenting behaviors and experiences of childhood maltreatment. The aim is to better understand the risk factors, development and transmission of common psychological problems in order to contribute to prevention and treatment strategies for common psychological problems such as anxiety and depression.Overall, the findings underline the importance of the family context in the development and levels of mental health problems. In addition to the impact of one's own negative parenting experiences, including lack of warmth and experiences of emotional or physical abuse, negative parenting experiences of one's siblings are also associated with elevated anxiety and depressive symptom levels.We also found that externalizing problems of fathers and children have a negative impact on the parent-child interactions. In addition, we found that children with behavioral problems during early adolescence experience harsher parental discipline, even three years later.In the current treatment guidelines for common mental disorders, most therapies focus on the individual. An (additional) systemic approach and considering past and present family relationships in therapy, can be of additional value. For example, supporting families with interventions to improve the parent-child relationship can be helpful in the short and long term. Moreover, (early) treatment of psychological and behavioral problems of the parent or child might be beneficial for all family members. Show less
In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
In this thesis Marcelo Gerona and Silvana Sosa undertake an analysis of the Great Depression (1928-1934) in a sample of three highly interconnected South American countries: Argentina, Brazil and... Show moreIn this thesis Marcelo Gerona and Silvana Sosa undertake an analysis of the Great Depression (1928-1934) in a sample of three highly interconnected South American countries: Argentina, Brazil and Uruguay (ABU). The problem tackled in this work is the relative vulnerabilities of ABU, which contributed to the strong impact of the Great Depression, as well as the nature of the policy responses to the economic emergency. In this context, the hypothesis is that ABU were highly vulnerable to the Great Depression, and among them the smallest country, Uruguay, was the most vulnerable of all. This research is original not only for having assessed jointly these three scarcely analysed countries from a historical-comparative perspective during this uneasy period of time, but also because of the introduction of a new eclectic conception of ‘complex vulnerability’ that involves many paradigms and points of view. Furthermore, the historic research along with a comparative reference to the Financial Crisis of 2008 helps the reader to understand the role of the semi-periphery, in an effort that is appealing for both historians and policymakers worldwide. Show less
Many common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to... Show moreMany common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to unraveling the genetic architecture of these polygenetic disorders, a large amount of ‘missing heritability’ remains. A possible explanation is that GWAS, aside single-nucleotide polymorphisms cannot assess the contribution of other important genetic polymorphisms, especially tandem repeats. Tandem repeats constitute 3% of the human genome. Nine hereditary neurodegenerative diseases, known as polyglutamine diseases, including Huntington disease (HD), are the most prevalent disorders associated with tandem repeat variations. These diseases are caused by an elongated cytosine-adenine-guanine (CAG) repeat sequence in the respective polyglutamine disease-associated gene (PDAG). In this dissertation, we provide ample evidence that CAG repeat variations within the ‘normal’ range in PDAGs can affect various aspects of disease, including the age of onset in HD, cognitive function, depression and body mass index. Finally, we found a relatively large prevalence of intermediate and pathological PDAG alleles in the general population. Therefore, we provided support for the role of repetitive DNA polymorphisms in elucidating the ‘missing heritability’ of polygenetic disorders and emphasized the necessity to include these variations in future genetic research. Show less
Het boek is een biografie van Karl Abraham (1877-1925), de eerste psychoanalyticus van Duitsland, waar hij de psychoanalyse tot grote bloei heeft gebracht. Zijn klinisch-theoretische bijdragen... Show moreHet boek is een biografie van Karl Abraham (1877-1925), de eerste psychoanalyticus van Duitsland, waar hij de psychoanalyse tot grote bloei heeft gebracht. Zijn klinisch-theoretische bijdragen werden al snel klassiekers die veel invloed hebben gehad op de psychoanalytische theorievorming. Hij was de eerste die een psychoanalytische theorie over depressie ontwierp, enkele jaren voor Freuds 'Trauer und Melancholie' zou verschijnen. Abraham was de laatste jaren van zijn leven na Freud de belangrijkste analyticus van de psychoanalytische beweging, voorzitter van de IPA - International Psychoanalytic Association, voorzitter van de Berlijnse psychoanalytische vereniging en lid van het geheime comit_. Hij is betrokken geweest bij een aantal grote conflicten die zich in de beginjaren van de psychoanalyse hebben afgespeeld, waarbij postuum de schuld nogal eens naar hem is geschoven. Zo kon het gebeuren dat Abraham, tijdens zijn leven zo gewaardeerd, na zijn dood regelmatig werd verguisd. Show less
