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
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
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
Beurden, M. van; Brouwer, A.M.; Baardewijk, J.U. van; Binsch, O.; Vermetten, E.; Roijendijk, L. 2020
Feedback of physiological responses have a great potential to support virtual training paradigms aimed to increase cognitive task performance under stressful threatening conditions. In the current... Show moreFeedback of physiological responses have a great potential to support virtual training paradigms aimed to increase cognitive task performance under stressful threatening conditions. In the current study, we examined the sensitivity of a range of physiological indicators derived from electrodermal activity (EDA), blood pressure (BP) and heart rate (HR) to measure stress as induced by the threat of an electric shock (ES). In contrast to previous work that studied physiological stress responses compared to a rest condition, we compared conditions with high cognitive load combined with stress caused by threat of an ES, to conditions with high cognitive load without such stress. Twenty-five participants performed a cognitively demanding task in an experimental setup. At certain 10 s time intervals, indicated by a continuous tone, participants were either asked to do their best and increase cognitive task performance (non-threat condition), or they were told that they could receive an ES during this interval if cognitive task performance was not high enough (threat condition). Physiological measures, task performance and self-reported measures of stress and workload were analysed. Task performance and self-reported measures of stress and workload were roughly the same in both conditions. Especially EDA measures were affected by the threat of an ES. Threat and non-threat conditions could be distinguished with an across-participant classifier using EDA and BP features with an accuracy of 70%. These results suggest that EDA and BP can be used to evaluate stress coping training paradigms or to individually adapt the stress levels in virtual training environments. Show less
Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether... Show moreOur research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 +/- 2.1 and 6.4 +/- 2.8) than patients without complications (4.9 +/- 2.2 and 4.1 +/- 1.9), respectively (P= 0.006 andP= 0.000). Unacceptable pain (numeric rating scale [NRS] >= 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P= 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P= 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale >= 6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09,P= 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. Show less
Kumar, M.; Dijk, E.H.C. van; Raman, R.; Mehta, P.; Boon, C.J.F.; Goud, A.; ... ; Chhablani, J. 2020
Background To compare vision-related quality of life (VRQOL) between acute and chronic Central serous chorioretinopathy (CSC) and correlate this with Cohen's Perceived Stress Scale (PSS)... Show moreBackground To compare vision-related quality of life (VRQOL) between acute and chronic Central serous chorioretinopathy (CSC) and correlate this with Cohen's Perceived Stress Scale (PSS) questionnaire. Methods Patients who were diagnosed with both acute and chronic CSC were recruited in this study. Vision-related quality of life (VRQOL) was assessed with Rasch revised National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ25) and perceived stress with Cohen's PSS questionnaire in 118 subjects with either acute or chronic CSC. The quality of life score was compared between patients with acute and chronic CSC. Correlations between the functional score and visual acuity (VA), stage of CSC, and stress were studied. Results There was no significant difference in VRQOL between Acute and Chronic CSC. In Acute CSC, affected eye VA correlated significantly with near vision question of the visual function subscale. Better eye VA correlated significantly with distance vision, social function, role limitation and dependency of the socioeconomic subscale. In chronic CSC, affected eye VA correlated with social function question of the socioemotional subscale and the better eye VA correlated with driving and distance vision of the visual function subscale. No other significant correlations with VA were noted. No correlations were observed between outcome of Cohen's PSS questionnaire and NEI-VFQ25 scores of acute and chronic CSC. Conclusion The VRQOL is similar between acute and chronic CSC. Perceived stress was not found to influence the VRQOL in CSC. Show less
Direct interaction with students operates as the main source of teachers’ job satisfaction as well as a cause of feelings of distress. Teaching student-teacher appropriate coping strategies might... Show moreDirect interaction with students operates as the main source of teachers’ job satisfaction as well as a cause of feelings of distress. Teaching student-teacher appropriate coping strategies might make direct interaction with students a source of greater job satisfaction. A typology has been developed of student-teachers’ responses to stressful classroom events in secondary education with four types of coping: “Varying”, “Being annoyed”, “Problem-solving” and “Avoiding” varying along two underlying dimensions: avoidance-approach and calmness-agitation. The coping types particularly differed in the way student-teachers approached, tolerated, avoided or ignored the classroom event, how agitated they were and the length of the coping response. Implications for teacher education are discussed to support student-teachers with more approach-coping strategies instead of avoidance-coping strategies. Show less
The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
