Abstract
BackgroundIndividuals with typical circadian rhythm sleep-wake disorders (CRSWDs) have a habitual sleep timing that is desynchronized from social time schedules. However, it is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems. This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Conventional diagnostic methods for typical CRSWDs are insufficient for detecting LCRSWD because sufferers have an apparently normal habitual sleep timing.MethodsWe first evaluated the reliability of circadian phase estimation based on clock gene expression using hair follicles collected at three time points without sleep interruption. Next, to identify detection criteria for LCRSWD, we compared circadian and sleep parameters according to estimated circadian phases, at the group and individual level, between subjects with low and high Pittsburgh Sleep Quality Index (PSQI) scores. To validate the reliability of identified detection criteria, we investigated whether the same subjects could be reproducibly identified at a later date and whether circadian amelioration resulted in sleep improvement.FindingsWe successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness. In particular, a criterion based on the interval between the times of the estimated circadian phase of clock gene expression and getting out of bed on work or school days was promising. We also successfully confirmed the reproducibility of candidate screening and sleep improvement by circadian amelioration, supporting the reliability of the detection criteria.InterpretationAlthough several limitations remain, our present study demonstrates a promising prototype of a detection method for LCRSWD attributed to delayed circadian-driven sleepiness. More extensive trials are needed to further validate this method.FundingThis study was supported mainly by JSPS, Japan.
Highlights
Sleep disorders are caused by a wide range of internal and external factors [1À5], indicating the need for reliable identification of specific causes in a personalized manner for proper medical treatment
We validated the reliability of circadian phase estimation based on expression data from two clock genes (Per3 and Nr1d2) at three time points using sample data sets obtained from healthy subjects (Fig. 2a)
Because the phase interval between Period 3 (Per3) and Nr1d2 circadian expression is mostly constant among individuals [31], cosine fitting was conducted under the condition that the Per3 and Nr1d2 phase interval was within a range of 2 § 0.5 h
Summary
Sleep disorders are caused by a wide range of internal and external factors [1À5], indicating the need for reliable identification of specific causes in a personalized manner for proper medical treatment. Sleep disorders attributed to circadian dysfunction are called circadian rhythm sleep-wake disorders (CRSWDs), which are subdivided into several disorders: advanced sleep-wake phase disorder, delayed sleep-wake phase disorder, non-24 h sleep-wake rhythm disorder and irregular sleep-wake rhythm disorder [6À10]. These typical CRSWDs have been reported to affect approximately 1% to 3% of the population [11À14]. It is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Findings: We successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness.
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