Papers by Sebastian C Holst
Neuropsychopharmacology, 2018
Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of... more Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shaped relationship, independently of neurophysiological markers of elevated sleep need.
eLife Science, 2017
Increased sleep time and intensity quantified as low-frequency brain electrical activity after sl... more Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knockout mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.
Nature Scientific Reports, 2017
Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulne... more Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D 2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans. Sleep deprivation enhances sleepiness, impairs performance and alters electrical brain activity in a highly predictable fashion 1–4. Modern lifestyle means that these sleep-loss related cognitive deficits have developed to a public health concern. In the laboratory, neurobehavioral deficits of sleep deprivation are accurately indexed by lapses of attention on the psychomotor vigilance task (PVT), which is considered a gold-standard measurement of sustained vigilant attention 3,5. Neurophysiological consequences of sleep loss on the other hand, are reflected by distinct oscillations in the waking electroencephalogram (EEG) 6,7. Importantly, these neurobehavioral and neuro-physiological consequences vary widely among individuals. Ample evidence now demonstrates that genetic influences strongly modulate waking EEG oscillations and alters PVT lapses across prolonged waking, even within consecutive test sessions 8–12. Consistent with a genetic contribution, the impact of sleep loss on distinct subjective, PVT, and neurophysiological markers of alertness, is trait-like and highly robust within individuals. Intriguingly, however, these variables don't typically show a clear association with each other, but rather develop seemingly independently 13,14. Here, we hypothesized that functional variation in genes impacting local dopaminergic neu-rotransmission affects sleep loss-induced changes in PVT lapses and the waking EEG along a similar trajectory.
Science, 2016
Brain electrical activity differs markedly between wakefulness and sleep. Concomitant shifts in t... more Brain electrical activity differs markedly between wakefulness and sleep. Concomitant shifts in the ion composition of brain extracellular fluids were thought to be a consequence rather than a cause of the sleep-wake–dependent changes in neuronal activity. On page 550 of this issue, Ding et al. (1) report the surprising observation that ionic changes in the extracellular fluid are a potent control of sleep-wake–dependent neuronal activity.
Annual Review of Pharmacology and Toxicology, 2016
Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordere... more Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, γ-amino-butyric acid, and adenosine as important players in the regulation and maintenance of sleep-wake-dependent changes in neuronal activity and the sleep-wake continuum. Dysregulation of these neurochemical systems leads to sleep-wake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. To evaluate opportunities for evidence-based personalized medicine with present and future sleep-wake therapeutics, we review here the impact of known genetic variants affecting exposure of and sensitivity to drugs targeting the neurochemistry of sleep-wake regulation and the pathophysiology of sleep-wake disturbances. Many functional polymorphisms modify drug response phenotypes relevant for sleep. To corroborate the importance of these and newly identified variants for personalized sleep-wake therapy, human sleep pharmacogenetics should be complemented with pharmacogenomic investigations, research about sleep-wake-dependent pharmacological actions, and studies in mice lacking specific genes. These strategies, together with future knowledge about epigenetic mechanisms affecting sleep-wake physiology and treatment outcomes, may lead to potent and safe novel therapies for the increasing number of sleep-disordered patients (e.g., in aged populations).
Current Sleep Medicine Reports, 2015
Sleep is an integral and constitutive part of life, invariably observed in animals with even a si... more Sleep is an integral and constitutive part of life, invariably observed in animals with even a simple nervous system. Importantly, sleep is an active and highly regulated state. Sleep propensity or sleep need and its best established biological marker, electroencephalographic (EEG) slow-wave (or delta) activity, is tightly associated to prior wakefulness and sleep and is homeostatically regulated. Sleep need may be considered an essential aspect of life, just like feeding, drinking, and procreation. Sleep, therefore, likely developed in a primordial state of evolution and should either aid or, at least, not interfere with other essential biological aspects of life such as metabolisms and reproduction. Consistent with this view, brain circuitries regulating sleep need, metabolism, and reward appear to involve the basal ganglia and are tightly linked. They may sense changes in the organism’s major cellular energy store, adenosine-tri-phosphate (ATP), and its derivative adenosine, and act in concert with other important neuromodulatory systems including dopamine, glutamate, and hypocretin.
Background: Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with... more Background: Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain.
Journal of Neuroscience, 2014
While dopamine affects fundamental brain processes such as movement control, emotional responses,... more While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3'-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10-repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype-dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slow-wave activity (0.5-4.5 Hz), and number of low-frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.
Journal of Psychopharmacology, 2016
Objectives:
The purpose of this study was to examine the possible links between type 2 diabetes, ... more Objectives:
The purpose of this study was to examine the possible links between type 2 diabetes, daytime sleepiness, sleep quality and caffeine consumption.
Methods:
In this case-control field study, comparing type 2 diabetic (n=134) and non-type 2 diabetic (n=230) participants, subjects completed detailed and validated questionnaires to assess demographic status, health, daytime sleepiness, sleep quality and timing, diurnal preference, mistimed circadian rhythms and habitual caffeine intake. All participants gave saliva under standardised conditions for CYP1A2 genotyping and quantification of caffeine concentration. Hierarchical linear regression analyses examined whether type 2 diabetes status was associated with caffeine consumption.
Results:
Type 2 diabetic participants reported greater daytime sleepiness (p=0.001), a higher prevalence of sleep apnoea (p=0.005) and napping (p=0.008), and greater habitual caffeine intake (p<0.001), derived from the consumption of an extra cup of coffee each day. This finding was confirmed by higher saliva caffeine concentration at bedtime (p=0.01). Multiple regression analyses revealed that type 2 diabetes status was associated with higher self-reported caffeine consumption (p<0.02) and higher salivary caffeine (p<0.02). Next to male sex, type 2 diabetes status was the strongest predictor of caffeine intake. Subjective sleep and circadian estimates were similar between case and control groups.
Conclusions:
Type 2 diabetic patients may self-medicate with caffeine to alleviate daytime sleepiness. High caffeine intake reflects a lifestyle factor that may be considered when promoting type 2 diabetes management.
ESRS European Sleep Medicine Textbook, 2014
Chronic sleep restriction and acute total sleep loss are highly prevalent in the modern ‘24/7 soc... more Chronic sleep restriction and acute total sleep loss are highly prevalent in the modern ‘24/7 society’ and pose significant risks for quality of life, mental wellbeing, cognitive performance and physical health. The consequences of acute and chronic sleep deprivation have become a public health concern. Based on the catalogue of knowledge and skills for sleep medicine, this chapter focuses on the effects of sleep deprivation on emotional state, mood, cognition, physical health and immune functions. We review the effect sizes of these different consequences of lack of sleep and provide insights into possible neuroanatomical and (neuro) physiological underpinnings of how insufficient sleep could impact upon these health outcomes. A better understanding of these relationships is important, because the avoidance of short and inadequate sleep may be amenable to modification and help to save increasingly high social, financial and health-related costs for the affected individuals and for ...
Chronobiology International, 2014
Accumulating evidence suggests that dopamine plays a key role in sleep-wake regulation. Cerebral ... more Accumulating evidence suggests that dopamine plays a key role in sleep-wake regulation. Cerebral dopamine levels are regulated primarily by the dopamine transporter (DAT) in the striatum and by catechol-O-methyl-transferase (COMT) in the prefrontal cortex. We hypothesized that the variable-number-tandem-repeat (VNTR) polymorphism in the 3'-untranslated region of the gene encoding DAT (DAT1, SLC6A3; rs28363170) and the Val158Met polymorphism of COMT (rs4680) differently affect actigraphy-derived rest-activity cycles and sleep estimates in healthy adults (65 men; 45 women; age range: 19-35 years). Daytime sleepiness, continuous rest-actigraphy and sleep diary data during roughly 4-weeks were analyzed. Nine-repeat (9R) allele carriers of DAT1 (n = 48) more often reported elevated sleepiness (Epworth sleepiness score ≥10) than 10-repeat (10R) allele homozygotes (n = 62, p < 0.02). Moreover, male 9R allele carriers showed higher wrist activity, whereas this difference was not present in women ("DAT1 genotype" × "gender" interaction: p < 0.005). Rest-activity patterns did not differ among COMT genotypes. Nevertheless, a significant "COMT genotype" × "type of day" (workdays vs. rest days) interaction for sleep duration was observed (p = 0.04). The Val/Val (n = 36) and Met/Met (n = 24) homozygotes habitually prolonged sleep on rest days compared to workdays by more than 30 min, while Val/Met heterozygotes (n = 50) did not significantly extend their sleep (mean difference: 7 min). Moreover, whereas the proportion of women among the genotype groups did not differ, COMT genotype affected body-mass-index (BMI), such that Val/Met individuals had lower BMI than the homozygous genotypes (p < 0.04). While awaiting independent replication and confirmation, our data support an association of genetically-determined differences in cerebral dopaminergic neurotransmission with daytime sleepiness and individual rest-activity profiles, as well as other sleep-associated health characteristics such as the regulation of BMI. The differential associations of DAT1 and COMT polymorphisms may reflect the distinct local expression of the encoded proteins in the brain.
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Papers by Sebastian C Holst
The purpose of this study was to examine the possible links between type 2 diabetes, daytime sleepiness, sleep quality and caffeine consumption.
Methods:
In this case-control field study, comparing type 2 diabetic (n=134) and non-type 2 diabetic (n=230) participants, subjects completed detailed and validated questionnaires to assess demographic status, health, daytime sleepiness, sleep quality and timing, diurnal preference, mistimed circadian rhythms and habitual caffeine intake. All participants gave saliva under standardised conditions for CYP1A2 genotyping and quantification of caffeine concentration. Hierarchical linear regression analyses examined whether type 2 diabetes status was associated with caffeine consumption.
Results:
Type 2 diabetic participants reported greater daytime sleepiness (p=0.001), a higher prevalence of sleep apnoea (p=0.005) and napping (p=0.008), and greater habitual caffeine intake (p<0.001), derived from the consumption of an extra cup of coffee each day. This finding was confirmed by higher saliva caffeine concentration at bedtime (p=0.01). Multiple regression analyses revealed that type 2 diabetes status was associated with higher self-reported caffeine consumption (p<0.02) and higher salivary caffeine (p<0.02). Next to male sex, type 2 diabetes status was the strongest predictor of caffeine intake. Subjective sleep and circadian estimates were similar between case and control groups.
Conclusions:
Type 2 diabetic patients may self-medicate with caffeine to alleviate daytime sleepiness. High caffeine intake reflects a lifestyle factor that may be considered when promoting type 2 diabetes management.
The purpose of this study was to examine the possible links between type 2 diabetes, daytime sleepiness, sleep quality and caffeine consumption.
Methods:
In this case-control field study, comparing type 2 diabetic (n=134) and non-type 2 diabetic (n=230) participants, subjects completed detailed and validated questionnaires to assess demographic status, health, daytime sleepiness, sleep quality and timing, diurnal preference, mistimed circadian rhythms and habitual caffeine intake. All participants gave saliva under standardised conditions for CYP1A2 genotyping and quantification of caffeine concentration. Hierarchical linear regression analyses examined whether type 2 diabetes status was associated with caffeine consumption.
Results:
Type 2 diabetic participants reported greater daytime sleepiness (p=0.001), a higher prevalence of sleep apnoea (p=0.005) and napping (p=0.008), and greater habitual caffeine intake (p<0.001), derived from the consumption of an extra cup of coffee each day. This finding was confirmed by higher saliva caffeine concentration at bedtime (p=0.01). Multiple regression analyses revealed that type 2 diabetes status was associated with higher self-reported caffeine consumption (p<0.02) and higher salivary caffeine (p<0.02). Next to male sex, type 2 diabetes status was the strongest predictor of caffeine intake. Subjective sleep and circadian estimates were similar between case and control groups.
Conclusions:
Type 2 diabetic patients may self-medicate with caffeine to alleviate daytime sleepiness. High caffeine intake reflects a lifestyle factor that may be considered when promoting type 2 diabetes management.