An end-to-end framework for real-time automatic sleep stage classification.

Sleep staging is a fundamental but time consuming process in any sleep laboratory. To greatly speed up sleep staging without compromising accuracy, we developed a novel framework for performing real-time automatic sleep stage classification. The client-server architecture adopted here provides an end-to-end solution for anonymizing and efficiently transporting polysomnography data from the client to the server and for receiving sleep stages in an interoperable fashion. The framework intelligently partitions the sleep staging task between the client and server in a way that multiple low-end clients can work with one server, and can be deployed both locally as well as over the cloud. The framework was tested on four datasets comprising ≈1700 polysomnography records (≈12000 hr of recordings) collected from adolescents, young, and old adults, involving healthy persons as well as those with medical conditions. We used two independent validation datasets: one comprising patients from a sleep disorders clinic and the other incorporating patients with Parkinson's disease. Using this system, an entire night's sleep was staged with an accuracy on par with expert human scorers but much faster (≈5 s compared with 30-60 min). To illustrate the utility of such real-time sleep staging, we used it to facilitate the automatic delivery of acoustic stimuli at targeted phase of slow-sleep oscillations to enhance slow-wave sleep

Chromatic Pupillometry Methods for Assessing Photoreceptor Health in Retinal and Optic Nerve Diseases

The pupillary light reflex is mediated by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs), which also receive input from rods and cones. Melanopsin-dependent pupillary light responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower to activate and de-activate compared with rod/cone-mediated responses. Given that rod/cone photoreceptors and melanopsin differ in their response properties, light stimuli can be designed to stimulate preferentially each of the different photoreceptor types, providing a read-out of their function. This has given rise to chromatic pupillometry methods that aim to assess the health of outer retinal photoreceptors and ipRGCs by measuring pupillary responses to blue or red light stimuli. Here, we review different types of chromatic pupillometry protocols that have been tested in patients with retinal or optic nerve disease, including approaches that use short-duration light exposures or continuous exposure to light. Across different protocols, patients with outer retinal disease (e.g., retinitis pigmentosa or Leber congenital amaurosis) show reduced or absent pupillary responses to dim blue-light stimuli used to assess rod function, and reduced responses to moderately-bright red-light stimuli used to assess cone function. By comparison, patients with optic nerve disease (e.g., glaucoma or ischemic optic neuropathy, but not mitochondrial disease) show impaired pupillary responses during continuous exposure to bright blue-light stimuli, and a reduced post-illumination pupillary response after light offset, used to assess melanopsin function. These proof-of-concept studies demonstrate that chromatic pupillometry methods can be used to assess damage to rod/cone photoreceptors and ipRGCs. In future studies, it will be important to determine whether chromatic pupillometry methods can be used for screening and early detection of retinal and optic nerve diseases. Such methods may also prove useful for objectively evaluating the degree of recovery to ipRGC function in blind patients who undergo gene therapy or other treatments to restore vision

Effects of Exposure to Intermittent versus Continuous Red Light on Human Circadian Rhythms, Melatonin Suppression, and Pupillary Constriction

Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21–28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm−2 s−1), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light

Analysis Method and Experimental Conditions Affect Computed Circadian Phase from Melatonin Data

Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used

The Spectral Sensitivity of Human Circadian Phase Resetting and Melatonin Suppression to Light Changes Dynamically with Light Duration

Human circadian, neuroendocrine, and neurobehavioral responses to light are mediated primarily by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs) but they also receive input from visual photoreceptors. Relative photoreceptor contributions are irradiance- and duration-dependent but results for long-duration light exposures are limited. We constructed irradiance-response curves and action spectra for melatonin suppression and circadian resetting responses in participants exposed to 6.5-h monochromatic 420, 460, 480, 507, 555, or 620 nm light exposures initiated near the onset of nocturnal melatonin secretion. Melatonin suppression and phase resetting action spectra were best fit by a single-opsin template with lambdamax at 481 and 483 nm, respectively. Linear combinations of melanopsin (ipRGC), short-wavelength (S) cone, and combined long- and medium-wavelength (L+M) cone functions were also fit and compared. For melatonin suppression, lambdamax was 441 nm in the first quarter of the 6.5-h exposure with a second peak at 550 nm, suggesting strong initial S and L+M cone contribution. This contribution decayed over time; lambdamax was 485 nm in the final quarter of light exposure, consistent with a predominant melanopsin contribution. Similarly, for circadian resetting, lambdamax ranged from 445 nm (all three functions) to 487 nm (L+M-cone and melanopsin functions only), suggesting significant S-cone contribution, consistent with recent model findings that the first few minutes of a light exposure drive the majority of the phase resetting response. These findings suggest a possible initial strong cone contribution in driving melatonin suppression and phase resetting, followed by a dominant melanopsin contribution over longer duration light exposures

Diurnal Regulation of Lipid Metabolism and Applications of Circadian Lipidomics

AbstractThe circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles (e.g., in shift work) results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health

Association of maternal Vitamin D status with glucose tolerance and caesarean section in a multi-ethnic Asian cohort: the growing up in Singapore towards healthy outcomes study

10.1371/journal.pone.0142239PLoS ONE10111-16GUSTO (Growing up towards Healthy Outcomes

Impact of Common Diabetes Risk Variant in MTNR1B

The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58–96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307–10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele

Chromatic Pupillometry Methods for Assessing Photoreceptor Health in Retinal and Optic Nerve Diseases

10.3389/fneur.2019.00076FRONTIERS IN NEUROLOGY10FE