Frederik Bes

Lunar cycle effects on sleep and the file drawer problem

Summary Popular beliefs about the influence of the full moon on humans exist, although no solid evidence has so far confirmed these ideas [1]. Cajochen et al. [2] recently presented fascinating data on lunar cycle effects on human sleep. However, in a re-analysis of sleep electroencephalography (EEG) data in three large samples, we were unable to replicate their findings. In addition, we identified further mostly unpublished null findings, suggesting that the conflicting results might be an example of a publication bias (i.e., the file drawer problem).

Blue-Enriched Morning Light as a Countermeasure to Light at the Wrong Time: Effects on Cognition, Sleepiness, Sleep, and Circadian Phase

Light during the day and darkness at night are crucial factors for proper entrainment of the human circadian system to the solar 24-h day. However, modern life and work styles have led to much more time spent indoors, often with lower daytime and higher evening/nighttime light intensity from electrical lighting than outdoors. Whether this has long-term consequences for human health is being currently investigated. We tested if bright blue-enriched morning light over several days could counteract the detrimental effects of inadequate daytime and evening lighting. In a seminaturalistic, within-between subject study design, 18 young participants were exposed to different lighting conditions on 3 evenings (blue-enriched, bright orange, or dim light), after exposure to 2 lighting conditions (mixed blue-enriched light and control light, for 3 days each) in the mornings. Subjective sleepiness, reaction times, salivary melatonin concentrations, and nighttime sleep were assessed. Exposure to the blue-enriched morning lighting showed acute wake-promoting effects and faster reaction times than with control lighting. Some of these effects persisted until the evening, and performance improved over several days. The magnitude of circadian phase shifts induced by combinations of 3 different evening and 2 morning lighting conditions were significantly smaller with the blue-enriched morning light. During the night, participants had longer total sleep times after orange light exposure than after blue light exposure in the evening. Our results indicate that bright blue-enriched morning light stabilizes circadian phase, and it could be an effective counterstrategy for poor lighting during the day and also light exposure at the wrong time, such as in the late evening.

Melatonin Effects in REM Sleep Behavior Disorder Associated with Obstructive Sleep Apnea Syndrome: A Case Series

OBJECTIVES REM sleep behavior disorder (RBD), with its main clinical symptoms of nightmares with dream-enacting behavior, is considered as a possible precursor of neurodegenerative disease. Obstructive Sleep Apnea Syndrome (OSAS) is known to be capable of provoking RBD-like symptoms by apneic event related arousals. The two sleep related pathologies must coincide in a relevant number of individuals because of overlapping prevalence in similar age groups. Until now RBD symptoms coexisting with OSAS are rarely described in scientific literature and in fact considered as OSAS mimicking RBD. METHODS We report four cases with a severe clinical RBD syndrome which were polysomnographically also diagnosed with concomitant OSAS (AHI range: 10.1 -53.2/h). RESULTS Treatment with 2 mg prolonged release melatonin led to a relevant clinical improvement of RBD symptoms in all patients, so far untreated for the sleep related breathing disorder. Measure of REM sleep without atonia (RSWA) in polysomnography showed values ranging from 5.1 to 20.4% determined with the Montplaisir method. Surprisingly, RSWA values in PSG with melatonin were high, probably because of the still untreated OSAS. CONCLUSION We presume that in patients with RBD and OSAS both pathologies contribute in varying degrees to the emergence of RBD symptoms by a destabilization of REM sleep. We suggest by consequence to consider a therapeutic strategy including the treatment of both disorders for an optimal therapeutic response.

High-accuracy determination of internal circadian time from a single blood sample

BACKGROUND. The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing. METHODS. To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes. RESULTS. We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost. CONCLUSION. The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient’s circadian clock. FUNDING. This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.

Twenty Years After: Another Case Report of Melatonin Effects on REM Sleep Behavior Disorder, Using Serial Dopamine Transporter Imaging

Introduction: REM sleep behavior disorder (RBD) is considered a prodromal phase of α-synucleinopathy like Parkinson disease (PD). PD is characterized by a progressive decline of dopamine (DA) in the striatum. Here we report the surprising increase in DA transporter density over successive years in an RBD patient treated with melatonin. Case Presentation: A then 72-year-old man was clinically suspected to suffer from PD in 2011. DA transporter scintigraphy (DaTSCAN) revealed reduced DA transporter density, and the patient was diagnosed with developing PD. Because of outacting dreams every night (speaking, yelling, kicking, pushing) he was referred to our clinic. Video-assisted polysomnography (PSG) confirmed the diagnosis of RBD in 2012. Management and Outcome: Melatonin treatment (2 mg slow release/day; 30 min prior to habitual bedtime; always at the same clock time) was initiated after PSG and continued. After 6 months of gradual improvement, clinical signs of RBD were absent. Control PSG in 2014 confirmed normalized REM sleep with atonia. Furthermore, no clinical sign of neurodegeneration occurred ever since. Additional DaTSCANs were performed in 2013 and 2015. Whereas the 2011 scan prior to melatonin treatment bore clear signs of PD, the 2013 scan was considered borderline and the 2015 scan without any sign of PD. Discussion: To the best of our knowledge, DA transporter density increase over time has never been reported in a single subject, neither healthy aged individuals nor patients suffering from RBD or PD. We interpret these results as a possible neuroprotective role for melatonin in synucleinopathy.

Melatonin Therapy of RBD

Rapid eye movement sleep behavior disorder (RBD) has two recommended Level B pharmacotherapies, according to the Best Practice Guide published by the American Academy of Sleep Medicine: clonazepam and melatonin. Melatonin, the focus of this chapter, manifests a gradual effect on RBD over weeks and lacks significant side effects. Amelioration of RBD symptoms with melatonin has been shown to outlast the time of treatment for weeks and sometimes months. Thus, melatonin treatment in RBD patients may be more than just a symptomatic aid. We summarize our center’s experience over the last 20 years and other published data on the treatment of RBD patients with melatonin. Compared to clonazepam therapy of RBD, outcome data with melatonin therapy of RBD have been reported in far fewer patients. We cite evidence for our hypothesis that one basic mode of melatonin’s therapeutic action on RBD symptoms involves the strengthening influence via the circadian timing system. Clearly, no circadian abnormality has been proven in RBD patients as yet. However, RBD is being considered as a prodromal of neurodegenerative synucleinopathies like Parkinson’s, which are mostly accompanied by a substantial breakdown of the circadian system. Melatonin is a chronobiotic, and REM sleep is under the strongest circadian influence compared to other sleep stages. We assume that restoration of the circadian timing system integrity by melatonin in the early phase before conversion to a full-blown synucleinopathy will lead, mainly via the MT1 receptor, to an improvement of the timely orchestration and integrity of all processes necessary for a proper functioning of REM sleep, which in turn would alleviate RBD. Confirmation of this hypothesis doubtlessly awaits a substantial amount of future research.

The alerting effect of the wake maintenance zone during 40 hours of sleep deprivation

Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.