BackgroundPeople with epilepsy often experience daytime vigilance problems and fatigue. This may be related to disturbed sleep due to nocturnal seizures.AimTo compare subjective and objective... Show moreBackgroundPeople with epilepsy often experience daytime vigilance problems and fatigue. This may be related to disturbed sleep due to nocturnal seizures.AimTo compare subjective and objective markers of vigilance and circadian function in adults with epilepsy with nocturnal seizures to those with daytime seizures and healthy controls and to identify determinants of impaired daytime vigilance in epilepsy in an explorative study.MethodsWe included 30 adults with epilepsy (15 with daytime seizures and 15 with nocturnal seizures), and 15 healthy controls. All participants filled out the Epworth sleepiness scale (ESS), fatigue severity scale (FSS), Pittsburgh sleep quality index (PSQI) and the Munich chronotype questionnaire (MCTQ). Each participant performed two trials of the sustained attention to response task (SART) as a measure of vigilance, and had a post-illumination pupil response (PIPR) assessment as a marker for the circadian function.ResultsBoth epilepsy groups reported more fatigue on the FSS than healthy controls (p < .001) and had higher SART error scores (p = .026). The poorer FSS and SART scores were most prominent among those with nocturnal seizures. The ESS, PSQI, MCTQ and the primary PIPR outcome did not differ between groups. Having nocturnal seizures (p = .010) and using more antiseizure medications (p = .004) were related to increased SART error scores.ConclusionsNocturnal epilepsy is associated with poorer vigilance, indicating lower quality of wake time. We could not relate this to circadian dysfunction. Further studies should focus on vigilance problems in people with nocturnal epilepsy and explore interventions to improve the quality of wake time. Show less
Leeuw, M. de; Verhoeve, S.I.; Wee, N.J.A. van der; Hemert, A.M. van; Vreugdenhil, E.; Coomans, C.P. 2023
Circadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily... Show moreCircadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily functions including appetite, sleep, activity and cortisol levels. The circadian clock synchronizes itself to the external world mainly by environmental light cues and can be disturbed by a variety of factors, including shift-work, jet-lag, stress, ageing and artificial light at night.Interestingly, mood has also been shown to follow a diurnal rhythm. Moreover, circadian disruption has been associated with various mood disorders and patients suffering from depression have irregular biological rhythms in sleep, appetite, activity and cortisol levels suggesting that circadian rhythmicity is crucially involved in the etiology and pathophysiology of depression.The aim of the present review is to give an overview and discuss recent findings in both humans and rodents linking a disturbed circadian rhythm to depression. Understanding the relation between a disturbed circadian rhythm and the etiology of depression may lead to novel therapeutic and preventative strategies. Show less
Exposed to the natural light-dark cycle, living beings show robust 24 h rhythms in physiology and behavior. Interestingly, even in the absence of a light-dark cycle, for example in constant... Show moreExposed to the natural light-dark cycle, living beings show robust 24 h rhythms in physiology and behavior. Interestingly, even in the absence of a light-dark cycle, for example in constant conditions, such as under the constant darkness or the constant light, living beings maintain a robust rhythm of which the endogenous period (named free running period, FRP) is close to 24 h. The endogenous rhythms are regulated by a master clock located in the suprachiasmatic nucleus (SCN) of mammals, where the SCN neurons show heterogeneity in the sensitivity to the light. In this article, we examined how this heterogeneity influences the FRP under constant light. Using a Poincare model for the SCN network it is shown that the FRP increases with the increase of the degree of heterogeneity in the sensitivity of neuronal subpopulations to light. Moreover, the presence of a critical value where the periods of the subpopulation diverge, presents a mechanism dictating how some animals remain rhythmic under constant light conditions, while others lose their rhythms completely. Our findings help to understand how the neuronal heterogeneity to light sensitivity in the SCN influences the circadian behavior of the animal. (C) 2022 Elsevier B.V. All rights reserved. Show less
Disruption of circadian (similar to 24 h) rhythms is associated with an increased risk of cardiometabolic diseases. Therefore, unravelling how circadian rhythms are regulated in different metabolic... Show moreDisruption of circadian (similar to 24 h) rhythms is associated with an increased risk of cardiometabolic diseases. Therefore, unravelling how circadian rhythms are regulated in different metabolic tissues has become a prominent research focus. Of particular interest is brown adipose tissue (BAT), which combusts triglyceride-derived fatty acids and glucose into heat and displays a circannual and diurnal rhythm in its thermogenic activity. In this review, the genetic, neuronal and endocrine generation of these rhythms in BAT is discussed. In addition, the potential risks of disruption or attenuation of these rhythms in BAT, and possible factors influencing these rhythms, are addressed. Show less
The main clock in mammals, located in the suprachiasmatic nucleus (SCN) of hypothalamus, not only regulates the daily rhythms in physiological and behavioral activities, but also plays a key role... Show moreThe main clock in mammals, located in the suprachiasmatic nucleus (SCN) of hypothalamus, not only regulates the daily rhythms in physiological and behavioral activities, but also plays a key role as one of the control nodes in the brain regulating behavioral activity. As such, it induces scale-invariance in the temporal patterns of behavioral activity and of multi-unit neural activity of the SCN network. In particular, the scale-invariant patterns maintain across multiple time scales from 3 minutes to 10 hours, characterized by a scaling exponent around 1. Thus far, no study found the origin of the scale-invariance of the SCN network. Using the method of correlation-dependent balance estimation of diffusion entropy (cBEDE), we found that scale-invariance also exists in the individual neurons of the SCN, and the scale invariance properties are significantly increased when the neurons are coupled in a network of neurons. Improved scale invariance in the single neurons is, therefore, imposed by the emergent network properties of the SCN network. Our findings show that the scale-invariance of the SCN can already be found at the level of the individual neurons and that the application of a scale invariance measure, such as cBEDE, can help in determining the network status of the SCN. Show less
Maintenance and repair is of key importance for the proper functioning of cells, tissues, and integrated physiology. We hypothesize that the balance between investments in growth, development, and... Show moreMaintenance and repair is of key importance for the proper functioning of cells, tissues, and integrated physiology. We hypothesize that the balance between investments in growth, development, and reproduction versus maintenance and repair is regulated by the brain. Specifically (the interplay of) hormones of the different hypothalamic-pituitary-target gland axes seem to be key regulators in constantly adjusting this balance to its optimal state. This thesis describes the associations between familial longevity and hormones of different hypothalamic-pituitary-target gland axes. In Chapter 2, the question is addressed whether circulating insulin-like growth factor 1 (IGF‐1) axis parameters associate with old age survival and functional status in nonagenarians from the LLS. In Chapter 3, we use growth hormone (GH) concentrations measured every 10 min over 24 h to derive and compare GH secretion parameters between offspring of long-lived families and their partners. In Chapter 4, we investigate the association between hypothalamic-pituitary-gonadal axis parameters and familial longevity. In Chapter 5, we use 24-h time series data of pituitary hormones to investigate how changes in the different hormonal axes are correlated with each other over time. In Chapter 6, we determine the circadian rhythm of bone turnover markers in healthy older subjects. Show less
Spoel, E. van der; Oei, N.; Cachucho, R.; Roelfsema, F.; Berbee, J.F.P.; Blauw, G.J.; ... ; Heemst, D. van 2019
Background: The role of chronotype, the individual timing of sleep/activity, has been studied in relation todepressive and anxiety disorders. A cross-sectional association between a depressive... Show moreBackground: The role of chronotype, the individual timing of sleep/activity, has been studied in relation todepressive and anxiety disorders. A cross-sectional association between a depressive episode and evening-typehas been identified. However, until now the predicting capacity of chronotype concerning persistence of psy-chiatric disorders remains unclear. Our aim is to examine whether a later chronotype in patients with a de-pressive and/or anxiety disorder can serve as a predictor of a persistent course.Methods: A subsample of patients with a depressive and/or anxiety disorder diagnosis and chronotype data ofthe longitudinal Netherlands Study of Depression and Anxiety (NESDA) was used. Diagnosis of depressive andanxiety disorders (1-month DSM-IV based diagnosis) were determined at baseline (n = 505). From this grouppersistence was determined at 2-year (FU2) (persistent course: n = 248, non-persistent course: n = 208) and 4-year follow-up (FU4) (persistent course: n = 151, non-persistent course: n = 264). Chronotype was assessed atbaseline with the Munich Chronotype Questionnaire.Results: A later chronotype did not predict a persistent course of depressive and/or anxiety disorder at FU2 (OR(95% CI) = 0.99 (0.83–1.19), P = 0.92) or at FU4 (OR (95% CI) = 0.94 (0.77–1.15), P = 0.57).Limitations: Persistence was defined as having a diagnosis of depressive and/or anxiety disorder at the two-yearand four-year follow-up, patients may have remitted and relapsed between assessments.Conclusion: Chronotype, measured as actual sleep timing, of patients with a depressive or anxiety disorder didnot predict a persistent course which suggests it might be unsuitable as predictive tool in clinical settings. Show less
Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show... Show moreMany favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity. Show less
Vogel, S.W.N.; Bijlenga, D.; Tanke, M.; Bron, T.I.; Heijden, K.B. van der; Swaab, H.; ... ; Kooij, J.J.S. 2015
Conclusions that may be drawn from the data in this thesis: 1. The ideal drug for antagonism of respiratory depression has not yet been found. At present naloxone seems the most appropriate drug... Show moreConclusions that may be drawn from the data in this thesis: 1. The ideal drug for antagonism of respiratory depression has not yet been found. At present naloxone seems the most appropriate drug although reversal of respiratory depression coincides with loss of analgesia. New reversal agents acting via non-opioidergic pathways are under investigation and are aimed at reversal of opioid-induced respiratory depression without compromising analgesia. 2. Mathematical modelling of the non-steady state effects of respiratory depression by opioids yields comprehensible results. Still, despite adequate prediction of a drug's respiratory behaviour on a population level, the model does not allow individual prediction. 3. Utility functions may serve as a composite function to describe the effect-side effect profile of a drug. The utility function of fentanyl is predominantly negative except at low dose, indicating that for the dose tested the probability of respiratory depressions exceeds the probability for analgesia. 4. MR30365/07, an opioid acting at all three classical opioid receptors, produces in contrast to fentanyl ceiling in respiratory depression but not analgesia over the dose range tested. This effect remains to be validated in further studies. Show less
The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN... Show moreThe studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM. Show less
Romeijn, N.; Raymann, R.J.E.M.; Most, E.; Lindert, B.T.; Meijden, W.P. van der; Fronczek, R.; ... ; Someren, E.J.W. van 2012
The nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include... Show moreThe nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include unintended weight loss, sleep and circadian rhythm disturbances, as well as autonomic nervous system dysfunction. However, the pathogenesis of these less well-known features of HD is poorly understood and currently no effective treatment options are available. It is thus of paramount importance to elucidate the pathological basis of these symptoms and signs in order to design and apply more effective therapeutic interventions. Recently, substantial dysfunction of the hypothalamus was reported in both human studies and various knock-in and transgenic animal models of HD. The hypothalamus consists of groups of interconnected neuronal nuclei located at the base of the brain that regulate a broad array of physiologic, homeostatic and behavioural activities. Therefore, in this thesis we attempt to substantiate the premise that hypothalamic dysfunction per se, as well as secondary (neuro)endocrine and metabolic alterations could contribute to the pathogenesis of several non-motor symptoms and signs of HD. Show less
