Circadian acclimatization of performance, sleep, and 6-sulfatoxymelatonin using multiple phase shifting stimuli

Abstract

Misalignment between the environment and one's circadian system is a common phenomenon (e.g., jet lag) which can have myriad negative effects on physical and mental health, mental and physiological performance, and sleep. Absent any intervention, the circadian system adjusts only 0.5-1.0 h per day to a shifted light-dark and sleep-wake schedule. Bright light facilitates circadian adjustment, but in field studies, bright light is only modestly better than no stimulus. Evidence indicates that exercise and melatonin can be combined with bright light to elicit larger shifts but no study has combined all of these stimuli or administered them at the times that are known to elicit the largest effects on the circadian system. The aims of this study are to compare the effects of different treatments on circadian adjustment to simulated jet lag in a laboratory. Following 2 weeks of home recording, 36 adults will spend 6.5 consecutive days in the laboratory. Following an 8 h period of baseline sleep recording on the participant's usual sleep schedule on Night 1 (e.g., 0000-0800 h), participants will undergo a 26 h circadian assessment protocol involving 2 h wake intervals in dim light and 1 h of sleep in darkness, repeated throughout the 26 h. During this protocol, all urine voidings will be collected; mood, sleepiness, psychomotor vigilance, and pain sensitivity will be assessed every 3 h, forehead temperature will be assessed every 90 min, and anaerobic performance (Wingate test) will be tested every 6 h. Following, the circadian assessment protocol, the participant's sleep-wake and light dark schedule will be delayed by 8 h compared with baseline (e.g., 0800-1400 h), analogous to travelling 8 times zones westward. This shifted schedule will be maintained for 3 days. During the 3 days on the delayed schedule, participants will be randomized to one of 3 treatments: (1) Dim Red Light + Placebo Capsules, (2) Bright Light Alone, (3) Bright Light + Exercise + Melatonin. During the final 26 h, all conditions and measures of the baseline circadian protocol will be repeated. Acclimatization will be defined by shifts in circadian rhythms of aMT6s, psychomotor vigilance, Wingate Anaerobic performance, mood, and sleepiness, and less impairments in these measures during the shifted schedule compared with baseline. We posit that Bright Light Alone and Bright Light + Exercise + Melatonin will elicit greater shifts in circadian rhythms and less impairments in sleep, mood, performance, and sleepiness compared with Dim Red Light + Placebo Capsules. We also posit that Bright Light + Exercise + Melatonin will elicit greater shifts and less impairments than Bright Light Alone.

Keywords: bright light; circadian misalignment; exercise; jet lag disorder; melatonin.

Figure 1

Circadian rhythms of urinary 6-sulfatoxymelatonin excretion (aMT6s, ng/h) in laboratory 2 h wake: 1 h sleep schedules repeated for > 24 h. (A) Schematic figure illustrating an individual baseline rhythm showing times of aMT6s onset (evening rise) and offset (morning decline), each measured, respectively, from upward and downward crossings of the cosine mesor (threshold). Also indicated are the cosine acrophase (time of mean vector of the cosine fit) and the time of the nighttime peak (the single highest ng/h value in the 24 h profile). (B) Robust aMT6s rhythm observed in young subjects studied in a 2 h wake: 1 h sleep schedule for 72 h. Under these conditions, in the absence of 24 h cycles in key environmental time cues, successive times of aMT6s onset and acrophase delayed on average 0.5 h per day from nights 1 to 3 (plotted points represent means ± 95% CI, n=17), demonstrating regulation by an internal endogenous circadian clock demonstrating regulation by an internal endogenous circadian clock. Normally, aMT6s and other circadian rhythms are synchronized to a period of 24 h by the 24 h cycles of our environment.

Figure 2

Example circadian rhythms. Data are from a study by Kline et al. N = 25 young adults followed an ultrashort sleep wake cycle (2 h wake: 1 h sleep) for 55 hours. Six 200 meter swim trials were performed at the indicated lab clock times throughout the day and night portions of the subject’s internal circadian rhythms (8 times/24 h). Similarly, the PVT (median reaction time RT), Profile of Mood States (Total Mood Disturbance: TMD) and Stanford Sleepiness Scale were measured every wake period and the data were z-transformed (normalized). The swim performance and reaction time data are “double-plotted” after averaging over the 2 days to better show circadian patterns. Strong circadian rhythms were found in each of these variables with similar patterns observed on Day 1 and Day 2 (right two panels).

Figure 3

Phase-response curves to bright light (n = 105, top) and exercise (n = 101, bottom). By convention, phase advances and phase delays are denoted by positive and negative values on the ordinate, respectively. Participants followed the ultrashort sleep-wake schedule for 5.5 days, receiving light (3 h, 5,000 lux) or exercise (1 h, moderate) on 3 consecutive days. Shifts in aMT6 onset from baseline to end-of-study (y axes) depended on timing of the stimuli. Note: maximal phase delays for light and exercise occurred at 0100 h and 2200 h circadian body clock time, respectively.

Figure 4

Schematic of laboratory light:dark cycles and timing of scheduled melatonin (M), exercise (E), and bright Light (L) treatments specified in the text and Table 1 . The figure depicts specifics only for the Melatonin + Exercise + Bright-Light treatment For consistency, all times in Table 1 are real world Arizona Standard Time, even after the 8 h delay of Laboratory Clock Time (bottom x-axis).

Figure 5

Expected delays in aMT6s phase markers after 3 days of treatment. Compared to corresponding baseline phase we expect delays of 2.5 h the control group, 4.5 h with bright light alone and 7.5 h in the light + exercise + melatonin treatments. Shifts in the our two aMT6s phase markers, onset and acrophase, are expected to be equivalent and significantly correlated.