Angelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and... Show moreAngelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and functions as a transcriptional coregulator of nuclear hormone receptors, including the glucocorticoid receptor (GR). Previous studies showed anxiety-like behavior and hippocampal-dependent memory disturbances in AS mouse models. Hippocampal GR is an important regulator of the stress response and memory formation, and we therefore investigated whether the absence of UBE3A in AS mice disrupted GR signaling in the hippocampus. We first established a strong cortisol-dependent interaction between the GR ligand binding domain and a UBE3A nuclear receptor box in a high-throughput interaction screen. In vivo, we found that UBE3A-deficient AS mice displayed significantly more variation in circulating corticosterone levels throughout the day compared to wildtypes (WT), with low to undetectable levels of corticosterone at the trough of the circadian cycle. Additionally, we observed an enhanced transcriptomic response in the AS hippocampus following acute corticosterone treatment. Surprisingly, chronic corticosterone treatment showed less contrast between AS and WT mice in the hippocampus and liver transcriptomic responses. This suggests that UBE3A limits the acute stimulation of GR signaling, likely as a member of the GR transcriptional complex. Altogether, these data indicate that AS mice are more sensitive to acute glucocorticoid exposure in the brain compared to WT mice. This suggests that stress responsiveness is altered in AS which could lead to anxiety symptoms. Show less
Meijer, O.C.; Buurstede, J.C.; Viho, E.M.G.; Amaya, J.M.; Koning, A.S.C.A.M.; Meulen, M. van der; ... ; Koorneef, L.L. 2022
Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many... Show moreGlucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large-scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non-neuronal) cell types. Next to the set "trait" of cellular context, the "state" of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single-cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation. Show less
Objectives: Several medical and psychiatric disorders have stage-based treatment decision-making methods. However, international treatment guidelines for posttraumatic stress disorder (PTSD) fail... Show moreObjectives: Several medical and psychiatric disorders have stage-based treatment decision-making methods. However, international treatment guidelines for posttraumatic stress disorder (PTSD) fail to give specific treatment recommendations based on chronicity or stage of the disorder. There is convincing evidence of a finite range of PTSD symptom trajectories, implying that different phenotypes of the disorder can be distinguished, which are highly relevant for a staging typology of PTSD. Methods: State-of-the-art review building on prior work on staging models in other disorders as a mapping tool to identify and synthesize toward PTSD. Results: We propose a four-stage model of PTSD ranging from stage 0: trauma-exposed asymptomatic but at risk to stage 4: severe unremitting illness of increasing chronicity. We favor a symptom description in various chronological characteristics based on neurobiological markers, information processing systems, stress reactivity, and consciousness dimensions. We also advocate for a separate phenomenology of treatment resistance since this can yield treatment recommendations. Conclusion: A staging perspective in the field of PTSD is highly needed. This can facilitate the selection of interventions that are proportionate to patients' current needs and risk of illness progression and can also contribute to an efficient framework to organize biomarker data and guide service delivery. Therefore, we propose that a neurobiologically driven trajectory-based typology of PTSD can help deduct several treatment recommendations leading to a more personalized and refined grid to strategize, plan and evaluate treatment interventions. Show less
Measuring physiological parameters of stress in horses during groundwork, for example when involved in equine-assisted interventions, is important to gain insight into the stress levels of the... Show moreMeasuring physiological parameters of stress in horses during groundwork, for example when involved in equine-assisted interventions, is important to gain insight into the stress levels of the horses. Heart rate and heart rate variability can be used as physiological indicators of stress in horses. Heart rate monitors could be easily incorporated into practice, as they are not expensive and easy to use. However, it is questionable whether heart rate monitors present accurate heart rate variability results in exercising horses, similar to electrocardiograms. The aim of this study was to determine the accuracy of heart rate monitors for the assessment of heart rate variability in horses during groundwork exercise. Simultaneous telemetric electrocardiograms (Televet) and heart rate monitor (Polar H10 transmitter and M430 receiver, Hylofit electrodes) recordings were performed on 28 horses (15 mares and 13 geldings). Results indicate that the heart rate monitor accurately determined heart rate and time-domain heart rate variability parameters when compared to electrocardiograms during both baseline and groundwork conditions. As expected, heart rate significantly increased and the heart rate variability significantly decreased during groundwork compared to baseline conditions. This indicates that the heart rate monitor can be used to accurately determine heart rate variability during groundwork. Show less
Setroikromo, S.N.W.; Werff, S.J.A. van der; Smit, A.S.; Vermetten, E.; Wee, N.J.A. van der 2022
BackgroundInsights into the neurobiological basis of resilience can have important implications for the prevention and treatment of stress-related disorders, especially in populations that are... Show moreBackgroundInsights into the neurobiological basis of resilience can have important implications for the prevention and treatment of stress-related disorders, especially in populations that are subjected to high-stress environments. Evaluating large-scale resting-state networks (RSNs) can provide information regarding resilient specific brain function which may be useful in understanding resilience. This study aimed to explore functional connectivity patterns specific for (high) resilience in Dutch policemen after exposure to multiple work-related traumatic events. We investigated resting-state functional connectivity (RSFC) of the salience network (SN), limbic network, and the default-mode network (DMN). MethodsResting-state functional MRI scans were obtained from trauma-exposed executive personnel of the Dutch police force and non-trauma-exposed recruits from the police academy. Participants were divided into three groups: a resilient group (n = 31; trauma exposure; no psychopathology), a vulnerable group (n = 32; trauma exposure, psychopathology), and a control group (n = 19; no trauma exposure, no psychopathology). RSFC of the three networks of interest was compared between these groups, using an independent component analysis and a dual regression approach. ResultsWe found decreased resilience-specific positive RSFC of the salience network with several prefrontal regions. The DMN and limbic network RFSC did not show resilience-specific patterns. ConclusionThis study shows a differential RSFC specific for resilient police officers. This differential RSFC may be related to a greater capacity for internal-focused thought and interoceptive awareness, allowing more effective higher-order responses to stress in highly resilient individuals. Show less
Brain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, as well as the effects of aldosterone itself in relation to salt homeostasis. Brain stem MRs... Show moreBrain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, as well as the effects of aldosterone itself in relation to salt homeostasis. Brain stem MRs respond to aldosterone, whereas forebrain MRs mediate rapid and delayed glucocorticoid effects in conjunction with the glucocorticoid receptor (GR). MR-mediated effects depend on age, gender, genetic variations, and environmental influences. Disturbed MR activity through chronic stress, certain (endocrine) diseases or during glucocorticoid therapy can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. Considering the important role MR plays in cognition and emotional function in health and disease, MR modulation by pharmacological intervention could relieve stress- and endocrine-related symptoms. Here, we discuss recent pharmacological interventions in the clinic and genetic developments in the molecular underpinnings of MR signalling. Further understanding of MR-dependent pathways may help to improve psychiatric symptoms in a diversity of settings. Show less
Purpose: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC)... Show morePurpose: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC) and healthy control subjects. Methods: Prospective multicenter case series, including 80 CSC patients and 88 healthy control subjects. Central serous chorioretinopathy status was classified as either active or inactive, depending on the presence of subretinal fluid on optical coherence tomography. Salivary samples were collected in the morning from patients and control subjects of the main cohort and at midnight for the additional cohort. Salivary alpha-amylase activity was determined in all patients and control subjects. Results: Morning sAA activity was significantly higher in patients with active CSC compared with inactive CSC (P = 0.049) and to healthy control subjects (P = 0.012). There was no significant difference in sAA activity between patients with inactive CSC and control subjects (P = 1.0). Nocturnal sAA activity did not show any significant difference between patients with active CSC and either inactive CSC or control subjects (P = 0.139). Conclusion: Morning sAA activity is increased in patients with active CSC, although diurnal rhythmicity is preserved. Measurement of sAA is easy to perform and might be an eligible tool to further investigate the relation between stress and CSC. Show less
Koenders, M.; Mesbah, R.; Spijker, A.; Boere, E.; Leeuw, M. de; Hemert, B. van; Giltay, E. 2021
Background The coronavirus disease 2019 (COVID-19) pandemic interfered in the daily lives of people and is assumed to adversely affect mental health. However, the effects on mood (in)stability of... Show moreBackground The coronavirus disease 2019 (COVID-19) pandemic interfered in the daily lives of people and is assumed to adversely affect mental health. However, the effects on mood (in)stability of bipolar disorder (BD) patients and the comparison to pre-COVID-19 symptom severity levels are unknown. Method Between April and September, 2020, symptoms and well-being were assessed in the Bipolar Netherlands Cohort (BINCO) study of recently diagnosed patients with BD I and II. The questionnaire contained questions regarding manic and depressive symptoms (YMRS and ASRM, QIDS), worry (PSWQ), stress (PSS), loneliness, sleep, fear for COVID-19, positive coping, and substance use. As manic, depressive and stress symptoms levels were assessed pre-COVID-19, their trajectories during the lockdown restrictions were estimated using mixed models. Results Of the 70 invited BD patients, 36 (51%) responded at least once (mean age of 36.7 years, 54% female, and 31% BD type 1) to the COVID-19 assessments. There was a significant increase (X-2 = 17.06; p = .004) in (hypo)manic symptoms from baseline during the first COVID-19 wave, with a decrease thereafter. Fear of COVID-19 (X-2 = 18.01; p = .003) and positive coping (X-2 = 12.44; p = .03) were the highest at the start of the pandemic and decreased thereafter. Other scales including depression and stress symptoms did not vary significantly over time. Conclusion We found a meaningful increase in manic symptomatology from pre-COVID-19 into the initial phases of the pandemic in BD patients. These symptoms decreased along with fear of COVID-19 and positive coping during the following months when lockdown measures were eased. Show less
Aims To investigate changes in physical activity (PA) and psychological factors during societal lockdown in people with type 2 diabetes.Methods A cross-sectional study among Dutch adults with type... Show moreAims To investigate changes in physical activity (PA) and psychological factors during societal lockdown in people with type 2 diabetes.Methods A cross-sectional study among Dutch adults with type 2 diabetes. Data were collected using online questionnaires. A multivariate multinomial logistic regression was performed with change in PA during societal lockdown as outcome and perceived change in stress, anxiety, perceived risk for COVID-19 infection, emotional well-being and former PA status as determinants.Results Five hundred and sixty seven respondents filled out the questionnaire, 536 were included in the final analysis: mean age of 65.9 +/- 7.9 years; mean diabetes duration 13.3 +/- 8 years; 54% men; 47% reported no change in PA, 27% became less active and 26% became more active during societal lockdown. Participants who were more likely to become less active were participants who experienced more stress (OR: 2.27; 95% CI 1.25-4.13) or less stress (OR: 2.20; 95% CI 1.03-4.71). Participants who were more likely to become more active were participants who experienced more stress (OR: 2.31; 95% CI 1.25, 4.26). Participants with higher emotional well-being (OR: 0.98; 95% CI 0.97, 0.99) were less likely to become less active than to report no change in PA.Conclusions Changes in PA in people with type 2 diabetes during societal lockdown are associated with changes in psychological factors such as perceived stress and emotional well-being. People with diabetes and their caregivers should be aware of these possible changes. Show less
Blase, K.; Vermetten, E.; Lehrer, P.; Gevirtz, R. 2021
Background: Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of... Show moreBackground: Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of HRVB is promising for a variety of disorders, it has not yet been regularly offered in a mental health treatment setting. Aim: To provide a systematic review about the efficacy of HRV-Biofeedback in treatment of anxiety, depression, and stress related disorders. Method: Systematic review in PubMed and Web of Science in 2020 with terms HRV, biofeedback, Post-Traumatic Stress Disorder (PTSD), depression, panic disorder, and anxiety disorder. Selection, critical appraisal, and description of the Random Controlled Trials (RCT) studies. Combined with recent meta-analyses. Results: The search resulted in a total of 881 studies. After critical appraisal, nine RCTs have been selected as well as two other relevant studies. The RCTs with control groups treatment as usual, muscle relaxation training and a "placebo"-biofeedback instrument revealed significant clinical efficacy and better results compared with control conditions, mostly significant. In the depression studies average reduction at the Beck Depression Inventory (BDI) scale was 64% (HRVB plus Treatment as Usual (TAU) versus 25% (control group with TAU) and 30% reduction (HRVB) at the PSQ scale versus 7% (control group with TAU). In the PTSD studies average reduction at the BDI-scale was 53% (HRV plus TAU) versus 24% (control group with TAU) and 22% (HRVB) versus 10% (TAU) with the PTSD Checklist (PCL). In other systematic reviews significant effects have been shown for HRV-Biofeedback in treatment of asthma, coronary artery disease, sleeping disorders, postpartum depression and stress and anxiety. Conclusion: This systematic review shows significant improvement of the non-invasive HRVB training in stress related disorders like PTSD, depression, and panic disorder, in particular when combined with cognitive behavioral therapy or different TAU. Effects were visible after four weeks of training, but clinical practice in a longer daily self-treatment of eight weeks is more promising. More research to integrate HRVB in treatment of stress related disorders in psychiatry is warranted, as well as research focused on the neurophysiological mechanisms. Show less
The acquired immobility response during the "forced swim test (FST)" is not a rodent model of depression, but the test has some validity in predicting a compound's antidepressant potential.... Show moreThe acquired immobility response during the "forced swim test (FST)" is not a rodent model of depression, but the test has some validity in predicting a compound's antidepressant potential. Nevertheless, 60% of the about 600 papers that were published annually the past 2 years label the rodent's immobility response as depression-like behaviour, but the relative contribution per country is changing. When the Editors-in-Chief of 5 journals publishing most FST papers were asked for their point of view on labelling immobility as depression-like behaviour and despair, they responded that they primarily rely on the reviewers regarding scientific merit of the submission. One Editor informs authors of the recent NIMH notice () which encourages investigators to use animal models "for" addressing neurobiological questions rather than as model "of" specific mental disorders. The neurobiological questions raised by use of the FST fall in two categories. First, research on the role of endocrine and metabolic factors, with roots in the 1980s, and with focus on the bottom-up action of glucocorticoids on circuits processing salient information, executive control and memory consolidation. Second, recent findings using novel technological and computational advances that have allowed great progress in charting top-down control in the switch from active to passive coping with the inescapable stressor executed by neuronal ensembles of the medial prefrontal cortex via the peri-aquaductal grey. It is expected that combining neural top-down and endocrine bottom-up approaches will provide new insights in the role of stress-coping and adaptation in pathogenesis of mental disorders. Show less
Background: Recently, internet-based cognitive behavioral therapy (ICBT) and serious gaming interventions have been suggested to enhance accessibility to interventions and engagement in... Show moreBackground: Recently, internet-based cognitive behavioral therapy (ICBT) and serious gaming interventions have been suggested to enhance accessibility to interventions and engagement in psychological interventions that aim to promote health outcomes. Few studies, however, have investigated their effectiveness in the context of simulated real-life challenges.Objective: We aimed to examine the effectivity of a guided ICBT combined with a serious gaming intervention in improving self-reported psychophysiological and immunological health endpoints in response to psychophysiological and immune-related challenges.Methods: Sixty-nine healthy men were randomly assigned to the intervention condition, receiving ICBT combined with serious gaming for 6 weeks, or the control condition, receiving no intervention. Self-reported vitality was the primary endpoint. Other self-reported psychophysiological and immunological endpoints were assessed following various challenges, including a bacillus Calmette-Guerin vaccination evoking pro-inflammatory responses, 1 and 4 weeks after the intervention period.Results: Although the intervention did not affect vitality-associated parameters, self-reported sleep problems (P=.027) and bodily sensations (P=.042) were lower directly after the intervention compared with controls. Furthermore, wellbeing (P=.024) was higher in the intervention group after the psychophysiological challenges. Although no significant group differences were found for the psychophysiological and immunological endpoints, the data provided preliminary support for increased immunoglobulin antibody responses at the follow-up time points (P<.05). Differential chemokine endpoints between conditions were observed at the end of the test day.Conclusions: The present study provides some support for improving health endpoints with an innovative ICBT intervention. Future research should replicate and further extend the present findings by consistently including challenges and a wide range of immune parameters into the study design. Show less
Worry is an important mediator in the relation between stressors and health. This pilot study examined whether a smartphone-based in time worry-reduction training was feasible and improved... Show moreWorry is an important mediator in the relation between stressors and health. This pilot study examined whether a smartphone-based in time worry-reduction training was feasible and improved physiological health (i.e. increased heart rate variability [HRV]). A total of 26 high-worriers were randomised to an experimental or active-control condition (EC and CC respectively). Participants in both conditions registered emotions 5 times daily for a month. The EC additionally received worry-reduction training with mindfulness exercises. Primary outcomes were feasibility and HRV measured at baseline, after 2 weeks (halfway), and at 4 weeks (post-intervention). Both training conditions were feasible and well received. HRV increased in the EC and CC, but this increase did not differ between conditions. Preliminary findings suggest that both training conditions are feasible and might improve HRV, which is an important predictor of cardiovascular disease. This pilot study only provided preliminary evidence, but it laid the groundwork for future randomised controlled trials that ought to include more participants and a waitlist control group in order to get more definitive evidence of the effectiveness of the intervention. Show less
OBJECTIVES The purpose of this study was to derive a biomechanical stress metric that was based on the multifactorial assessment of coronary plaque morphology, likely related to the propensity of... Show moreOBJECTIVES The purpose of this study was to derive a biomechanical stress metric that was based on the multifactorial assessment of coronary plaque morphology, likely related to the propensity of plaque rupture in patients.BACKGROUND Plaque rupture, the most frequent cause of coronary thrombosis, occurs at locations of elevated tensile stress in necrotic core fibroatheromas (NCFAs). Finite element modeling (FEM), typically used to calculate tensile stress, is computationally intensive and impractical as a clinical tool for locating rupture-prone plaques. This study derived a multifactorial stress equation (MSE) that accurately computes peak stress in NCFAs by combining the influence of several morphological parameters.METHODS Intravascular ultrasound and optical frequency domain imaging were conducted in 30 patients, and plaque morphological parameters were defined in 61 NCFAs. Multivariate regression analysis was applied to derive the MSE and compute a peak stress metric (PSM) that was based on the analysis of plaque morphological parameters. The accuracy of the MSE was determined by comparing PSM with FEM-derived peak stress values. The ability of the PSM in locating plaque rupture sites was tested in 3 additional patients.RESULTS The following parameters were found to be independently associated with peak stress: fibrous cap thickness (p < 0.0001), necrotic core angle (p = 0.024), necrotic core thickness (p < 0.0001), lumen area (p < 0.0001), necrotic core including calcium areas (p = 0.017), and plaque area (p = 0.003). The PSM showed excellent correlation (R = 0.85; p < 0.0001) with FEM-derived peak stress, thus confirming the accuracy of the MSE. In only 56% (n = 34) of plaques, the thinnest fibrous cap thickness was a determining parameter in identifying the cross section with highest PSM. In coronary segments with plaque ruptures, the MSE precisely located the rupture site.CONCLUSIONS The MSE shows potential to calculate the PSM in coronary lesions rapidly. However, further studies are warranted to investigate the use of biomechanical stress profiling for the prognostic evaluation of patients with atherosclerosis. (C) 2020 by the American College of Cardiology Foundation. Show less
Adrenal glucocorticoid hormones are crucial for maintenance of homeostasis and adaptation to stress. They act via the mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs)-members of... Show moreAdrenal glucocorticoid hormones are crucial for maintenance of homeostasis and adaptation to stress. They act via the mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs)-members of the family of nuclear receptors. MRs and GRs can mediate distinct, sometimes opposite, effects of glucocorticoids. Both receptor types can mediate nongenomic steroid effects, but they are best understood as ligand-activated transcription factors. MR and GR protein structure is similar; the receptors can form heterodimers on the DNA at glucocorticoid response elements (GREs), and they share a number of target genes. The transcriptional basis for opposite effects on cellular physiology remains largely unknown, in particular with respect to MR-selective gene transcription. In this review, we discuss proven and potential mechanisms of transcriptional specificity for MRs and GRs. These include unique GR binding to "negative GREs," direct binding to other transcription factors, and binding to specific DNA sequences in conjunction with other transcription factors, as is the case for MRs and NeuroD proteins in the brain. MR- and GR-specific effects may also depend on specific interactions with transcriptional coregulators, downstream mediators of transcriptional receptor activity. Current data suggest that the relative importance of these mechanisms depends on the tissue and physiological context. Insight into these processes may not only allow a better understanding of homeostatic regulation but also the development of drugs that target specific aspects of disease. Copyright (C) 2019 Endocrine Society Show less
The main aim of this thesis is to examine the effectiveness of innovative psychological interventions on health optimization by (1) evaluating the effectiveness of innovative psychological tools, i... Show moreThe main aim of this thesis is to examine the effectiveness of innovative psychological interventions on health optimization by (1) evaluating the effectiveness of innovative psychological tools, i.e., serious gaming, verbal suggestions, and internet-based interventions, to optimize various health behaviors and psychophysiological outcomes; (2) providing a concise overview of the currently existing evidence of psychological interventions in optimizing immune function in response to in vitro or in vivo immunological as well as psychophysiological challenges; and (3) incorporating various self-reporting, behavioral and psychophysiological outcome measures, but also physical and psychophysiological challenges, including psychophysiological, physical and/or cognitive stressors, to evaluate the effectiveness of psychological interventions on health outcomes. Show less
Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified... Show moreMineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding. Show less
