Towards a Real-Time Estimate of Circadian Phase During Spaceflight

The 24-hour circadian clock, located in the hypothalamus of the brain, controls the timing and pattern of sleep, alertness, performance, and mood, disruption of which has a major impact on safety. The circadian clock also controls many other aspects of human physiology, perturbation of which will affect longer-term health and well-being. It is imperative that the timing of the circadian clock is measured routinely, as a standard measure of health and behavior, during long-duration space missions to ensure that these multiple brain and body systems are not disrupted and misaligned from either each other (internal desynchronization) or with the work schedule (external desynchronization). Once measured, and if out of phase, circadian rhythms can be resynchronized to the desired time using a number of countermeasures, including bright light, melatonin, and potentially exercise and meal timing. The effectiveness of these countermeasures depends critically, however, on the circadian phase at which they are administered; mistimed countermeasures can exacerbate circadian disruption, leading to worsening of health and performance outcomes rather than improvement. Circadian phase is highly individualized, however, varying by up to 5 hours in healthy individuals under stable conditions, and is even more variable in space. To date, no feasible method exists to measure circadian phase accurately and reliably in real-time during spaceflight. Existing methods currently being used in-flight require collection of serial urine samples for up to 48 hours, from which the concentration of the urinary metabolite 6-sulphatoxymelatonin is measured to determine the timing of the circadian rhythm. Importantly, however, no technology exists to measure concentrations of urinary 6-sulphatoxymelatonin directly in-flight; therefore, knowledge about in-flight circadian disruption can be determined only during post-hoc analyses once the samples have been returned to Earth, which limits the ability to treat circadian disruption in real time. This proposal addresses this critical gap by (1) validating the use of commercially available meters to derive circadian phase in real-time from other biomarkers that exhibit robust circadian rhythms; and (2) developing a metric that estimates circadian phase from only two samples, thereby minimizing the need for serial data collection. The successful validation of this approach will enable circadian phase to be measured in real-time during spaceflight with minimal burden to the crew such that countermeasures to mitigate the effects of circadian misalignment can be tailored to individual crewmembers needs, thereby enhancing the safety, performance, and well-being of all crewmembers during spaceflight.

NASA has invested significant research into the design of countermeasures to mitigate the effects of circadian misalignment. These countermeasures will be ineffective if not timed appropriately relative to circadian phase. Our real-time circadian phase estimate is expected to significantly improve the impact of such countermeasures. In addition, treatments for a wide range of conditions, including circadian rhythm sleep disorders, hypertension, and cancer, are maximally effective when timed relative to circadian phase, yet circadian phase remains absent from standard clinical assessments due to significant time and cost constraints in obtaining an accurate measure. The ability to estimate circadian phase non-invasively in real-time over a short collection window is therefore expected to enable ‘circadian medicine’ within standard clinical practice.

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