Exploration of Circadian Rhythms in Patients with Bilateral Vestibular Loss

Abstract

Background: New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants.

Methodology and principal findings: Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day.

Conclusion: We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.

Fig 1. Salivary cortisol levels.

Salivary cortisol profiles are shown for Patients (black) and Controls (grey). * indicates a significant effect of time of day. § indicates a significant difference between groups.

Fig 2. Body Temperature curves.

Temperature COSINOR curves (blue) and smoothed curves by local polynomial regression (function “LOESS” in red) for Patients (upper pattern) and Control group (lower pattern). The solid blue lines corresponds to results from the estimated cosinor function The dashed lines around the solid line correspond to a confidence band of level $100\times \sqrt{0.95}\mathrm{\%}$ for the estimated cosinor curve. Solid red lines result from local polynomial regression (with span parameter α = 0.25). As before, dashed red lines correspond to the borders of the confidence band of level $100\times \sqrt{0.95}\mathrm{\%}$. Thus, areas in which the two confidence bands do not overlap indicate a difference between the two functions with confidence level 95%. The highest and lowest values estimated by the LOESS method are respectively observed at 4:29 PM and 7:40 AM (although a nearly equally low minimum is already attained much earlier in the morning). The deviations were marginal since the local smoother mostly overlaps the COSINOR modeling only around 5:00 AM and 8:00 AM and around 4:00 PM and 7:00 PM. More precisely, the local smoother indicates that the temperature remains at a lower level than the COSINOR in the morning, with the largest difference attained at about 6:30 AM. In the following hours, the temperature rises faster than the COSINOR captures, and attains its steady state about 12:40 PM. In the following hours, the temperature remains relatively stable at a high level, roughly between 37.25 and 37.35°C. Then, in the evening at about 9:10 PM, the temperature drops, and the decline is stronger than the COSINOR is able to capture.

Fig 3. Body temperature rhythms and phase.

(A) Circadian rhythm of gastrointestinal temperature: Mean values (-) and SD (grey line) recorded every 60 s is shown for Patients (upper panel) and Controls (lower panel). The dashed blue lines represent modeling using the COSINOR method. Dark frame represents the sleeping period in the laboratory. (B) Individual acrophases of temperature in Controls (◇) and Patients (●). The 6^th control participant was removed from the analyses. The F-test revealed a larger variability (p<0.05) in the time of acrophase in Patients compared to Controls.

Fig 4. Timing between circadian rhythms and sleep.

Association between the timing of acrophase of temperature (h) and sleep onset (h) recorded during the 15-day actigraphy in Patients (upper panel) and in Controls (lower panel) groups.