How light intensity and colour impact nonvisual functions in humans:Effects of light on entrainment, sleep and pupil constriction

Besides visual perception, light has many more functions such as pupil constriction, synchronisation of our biological clocks with the day-night cycle and our sleep-wake cycle. One biological clock is not the same as the other, and in this thesis, a method is presented to characterise fundamental biological clock-properties on the level of the individual, with the use of ambulatory light reception measurements. The cells in our eyes that send information to our biological clocks, are the same cells that mediate pupil constriction. By studying how our pupil responds to changes in colour, it may be possible to directly conclude on how our biological clocks would respond to such changes. Our results suggest that red and cyan light have opposite effects on the pupil than blue and green light, which may thus also be true for our biological clocks. This provides an opportunity for the treatment of jet lag, or the minimisation of unhealthy effects of evening light. Although it is known that the biological clocks of mice are colour sensitive, this is not known for humans. In this thesis, I show that also for humans an integration of colour and intensity information may be evolutionary beneficial.: these two factors together provide a more accurate indication of time of day than both factors separately. Finally, I show with ambulatory light and EEG-measurements that humans who expose themselves to more light during the day have deeper and better sleep

Machine learning estimation of human body time using metabolomic profiling

This work was supported in part by the Netherlands Forensic Institute, Netherlands Genomics Initiative/Netherlands Organization for Scientific Research within the framework of the Forensic Genomics Consortium Netherlands, the 6th Framework project EUCLOCK (018741), and UK Biotechnology and Biological Sciences Research Council Grant BB/I019405/1. Additional funding was received from the Cancer Research UK Cancer Therapeutics Unit award (Ref: C2739/A22897) and a Cancer Therapeutics Centre award (Ref: C309/A25144 to FR), the NWO-STW Perspective Program grant ‘OnTime’ (project 12185 to TW and RAH).Circadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.Publisher PDFPeer reviewe

Linking light exposure and subsequent sleep:A field polysomnography study in humans

Study objectives: To determine the effect of light exposure on subsequent sleep characteristics under ambulatory field conditions. Methods: Twenty healthy participants were fitted with ambulatory PSG and wrist-actigraphs to assess light exposure, rest-activity, sleep quality, timing and architecture. Laboratory salivary dim-light melatonin onset (DLMO) was analyzed to determine endogenous circadian phase. Results: Later circadian clock phase was associated with lower intensity (R2=0.34, χ2(1)=7.19, p <0.01), later light exposure (quadratic, controlling for daylength, R2=0.47, χ2(3)=32.38, p <0.0001), and to later sleep timing (R2=0.71, χ2(1)=20.39, p<0.0001). Those with later first exposure to more than 10 lux of light had more awakenings during subsequent sleep (controlled for daylength, R2=0.36, χ2(2)=8.66, p<0.05). Those with later light exposure subsequently had a shorter latency to first REM sleep episode (R2=0.21, χ2(1)=5.77, p<0.05). Those with less light exposure subsequently had a higher percentage of REM sleep (R2=0.43, χ2(2)=13.90, p<0.001) in a clock phase modulated manner. Slow wave sleep accumulation was observed to be larger after preceding exposure to high maximal intensity and early first light exposure (p<0.05). Conclusions: The quality and architecture of sleep is associated with preceding light exposure. We propose that light exposure timing and intensity does not only modulate circadian-driven aspects of sleep but also homeostatic sleep pressure. These novel ambulatory PSG findings are the first to highlight the direct relationship between light and subsequent sleep, combining knowledge of homeostatic and circadian regulation of sleep by light. Upon confirmation by interventional studies, this hypothesis could change current understanding of sleep regulation and its relationship to prior light exposure

Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats

Funding Information: This research was funded by the Dobberke foundation, grant number UPS/BP/4151 2016-27.Peer reviewedPublisher PD

Daily light exposure patterns reveal phase and period of the human circadian clock

Light is the most potent time cue that synchronizes (entrains) the circadian pacemaker to the 24-h solar cycle. This entrainment process is an interplay between an individual's daily light perception and intrinsic pacemaker period under free-running conditions. Establishing individual estimates of circadian phase and period can be time-consuming. We show that circadian phase can be accurately predicted (SD = 1.1 h for dim light melatonin onset, DLMO) using 9 days of ambulatory light and activity data as an input to Kronauer's limit-cycle model for the human circadian system. This approach also yields an estimated circadian period of 24.2 h (SD = 0.2 h), with longer periods resulting in later DLMOs. A larger amount of daylight exposure resulted in an earlier DLMO. Individuals with a long circadian period also showed shorter intervals between DLMO and sleep timing. When a field-based estimation of tau can be validated under laboratory studies in a wide variety of individuals, the proposed methods may prove to be essential tools for individualized chronotherapy and light treatment for shift work and jetlag applications. These methods may improve our understanding of fundamental properties of human circadian rhythms under daily living conditions

The method of silent substitution for examining melanopsin contributions to pupil control

The human pupillary light response is driven by all classes of photoreceptors in the human eye-the three classes of cones, the rods, and the intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. These photoreceptor classes have distinct but overlapping spectral tuning, and even a monochromatic light with a wavelength matched to the peak spectral sensitivity of a given photoreceptor will stimulate all photoreceptors. The method of silent substitution uses pairs of lights ("metamers") to selectively stimulate a given class of photoreceptors while keeping the activation of all others constant. In this primer, we describe the method of silent substitution and provide an overview of studies that have used it to examine inputs to the human pupillary light response