Circadian phase delay using the newly developed re-timer portable light device

Transcription

1 DOI /s ORIGINAL ARTICLE Circadian phase delay using the newly developed re-timer portable light device Nicole Lovato 1 Leon Lack 2 Received: 24 July 2015 / Accepted: 4 October 2015 Japanese Society of Sleep Research 2015 Abstract Appropriately timed exposure to bright light has been shown to phase shift the circadian rhythm and alleviate associated sleeping difficulties. This study evaluated the effectiveness of a newly developed re-timer portable light device for phase delaying the circadian rhythm. Participants included 12 healthy, good sleepers (M = 32.3 years, SD = 12.5, male = 5). A repeated measures counterbalanced design was used to assess circadian phase delay following the use of either the re-timer or no device on two consecutive evenings. Outcome measures included dim light melatonin onset (DLMO), subjective sleepiness, and adverse effects of the re-timer. Analyses revealed a significant phase delay of DLMO following use of the re-timer (M = 46 min, SD = 76 min) on two consecutive evenings when compared to no light control (M = 3 min, SD = 81 min; p =.016). There was a trend for evening subjective sleepiness to decrease after using the re-timer compared to no light control, however this trend was not statistically significant. Adverse effects of the re-timer were headache, eye irritation, and light bothersome to eyes, however these were not severe and treatment was not requested or required. The re-timer device is an effective method of delaying the circadian rhythm in good sleepers. & Nicole Lovato nicole.lovato@flinders.edu.au 1 2 Adelaide Institute for Sleep Health, Repatriation General Hospital, Flinders University Centre for Research Excellence, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia School of Psychology, Flinders University of South Australia, Bedford Park, Adelaide, SA 5001, Australia Keywords Bright light Circadian rhythms Endogenous melatonin Sleep Portable light device Re-timer Introduction Circadian rhythms are fundamental in determining the timing of sleep and wakefulness across the 24-h day. Circadian rhythms play an important role in regulating our daily hormonal and behavioural rhythms of melatonin secretion, sleepiness, alertness, and performance. An individual with a normally timed circadian rhythm will typically fall asleep at approximately 11 pm and wake around 7 am. However, chronic sleep difficulties can occur when the timing of the circadian rhythm is mis-timed leading to a sleep-wake rhythm that does not coincide with an individual s preferred sleep-wake schedule. A late timed circadian rhythm can lead to difficulty falling asleep, while an early timed rhythm is associated with the difficulty of early morning awakenings [1]. Circadian mis-timing is also common in night shift workers and in individuals after flying across time zones (jet-lag). Mis-timing of the circadian rhythm not only impairs night-time sleep but also daytime functioning, resulting in serious health and safety consequences. Appropriately timed exposure to bright light has been shown to re-time (or phase shift) the circadian rhythm and consequently alleviate the associated sleep and daytime sequelae. Exposure to bright light has been demonstrated to suppress melatonin and phase shift melatonin and core body temperature rhythms [2 4]. The direction and magnitude of the circadian phase shift is greatly influenced by the timing of exposure to light and the wavelength (or colour) of the light. Exposure to bright light in the late subjective evening will delay the circadian rhythm, while

2 exposure in the morning will advance the circadian rhythm to an earlier time [4]. Short wavelength (blue/green) light between 435 and 540 nm has consistently been demonstrated to successfully phase shift the circadian rhythm [5 10]. Longer wavelengths ([560 nm) are ineffective in phase advancing or delaying the circadian rhythm [5 10]. Bright light has traditionally been administered using a light box emitting broad-spectrum white light. A light box typically consists of an incandescent or fluorescent light source mounted behind a translucent screen, and connected to a fixed mains power source. Light boxes require individuals to maintain a fixed position in front of the box, which can be impractical and may impact significantly on treatment compliance. Additionally, the efficacy of light boxes is moderated by the distance of the light source from the eyes and alteration in direction of gaze [11, 12]. A selfcontained portable light device that administers light directly into the visual field regardless of head position or direction of gaze is likely to provide a solution to these problems. A newly available wearable light device, retimer, has been developed with these aims in mind. The retimer device administers light directly into the visual field at a fixed distance from the retina regardless of the head position and direction of gaze. It is completely portable and battery operated. The aim of the current study was to evaluate the effectiveness of a newly developed re-timer portable light device comprising blue/green light emitting diodes (LEDs) for phase delaying the circadian rhythm of 12 good sleepers. The timing of the circadian rhythm was assessed using salivary dim light melatonin onset, which is a reliable marker of the timing of the circadian rhythm [13]. Following exposure to bright light on two consecutive evenings, it was expected the timing of the dim light melatonin onset would delay (or occur at later time) relative to a control condition following the same procedure but without evening bright light exposure. Materials and methods Participants Participants included 12 healthy, good sleepers (male = 5) with a mean age of 32.3 years (SD = 12.48). Participants were included in this study if their typical sleep occurred between 11 pm and 8 am, and were neither morning nor evening types (based on the Morningness Eveningness Questionnaire [14]). Individuals were excluded from participation if they met any of the following criteria, (a) taking medications known to affect sleep and/or decrease melatonin release (i.e., betablockers), (b) indicated presence of sleep disorders, (c) had recent eye surgery or chronic eye conditions, (d) suffered clinically diagnosed depression, (e) smoked ([1 cigarette/day), (f) habitually consumed caffeine ([250 mg/day) or alcohol ([14 standard drinks/week), (g) indicated a history of substance abuse in the last 12 months, (h) worked a night shift in the last 2 months (night shift defined as a work schedule that includes at least 6 h of work between 10 pm and 8 am), (i) undertook transmeridian travel (C2 time zones) in the last 2 months. This study was conducted between August 2013 January 2014 and not during the 2 weeks either immediately before or after changes in daylight savings time. The Southern Adelaide Clinical Human Research Ethics committee approved this study. All participants provided written informed consent and were reimbursed (AU$320) for their time. Design A repeated measures counterbalanced design was used to assess the circadian phase delay of good sleepers in two different conditions: following use of the re-timer portable light device and following the same protocol but with no device. Participants wore the re-timer device for 1 h on two consecutive evenings. Outcome measures included dim light melatonin onset (DLMO), subjective sleepiness, and side effects of re-timer device. The order in which participants completed the light and no light control conditions was counterbalanced and randomly determined. Participants had an equal probability of assignment to the two conditions for the first occasion. A random allocation list was developed using block randomization and a computer-generated random number sequence. Light device Re-timer, is a portable light device intended to deliver light therapy for re-timing (or phase shifting) the human circadian rhythm. Re-timer is wearable and administers light directly into the visual field via light emitting diodes mounted on the lower frame ( Retimer emits blue-green 500 nm light at an intensity of 506 Lux lm/m 2 and 230 lw/cm 2 (high setting), when measured at the surface of the eye (20 mm from the light source). The device and further specifications are shown in Fig. 1 below. Measures Sleep diaries A sleep/wake diary was used to screen participants for inclusion into the study, and to ensure participants adhered

3 Subjective sleepiness Subjective sleepiness scores were obtained each evening using the Stanford Sleepiness Scale [16] at 22:00 h. The Stanford Sleepiness Scale is a 7-item scale with items ranging from 1 = Feeling active and vital, alert, wide awake to 7 = Almost in reverie, sleep onset soon, lost struggle to remain awake. Higher scores indicate greater sleepiness. The Stanford Sleepiness Scale has been demonstrated as a valid and reliable indicator of subjective sleepiness [17] and a valid measure of objective sleepiness in the evening [18]. Side effects The side effects of the re-timer device were assessed using the Light Effect Questionnaire (developed by the Authors, see Fig. 2). This questionnaire was administered following 1 h of light exposure. Procedure Fig. 1 Specifications of the re-timer portable light device to bedtime and out-of-bed time instructions during the study. Participants were asked to record their bedtime, lights out time and out-of-bed time on a daily basis. Participants were also required to provide subjective estimates of their sleep onset latency (elapsed time from lights out to sleep onset), number and duration of awakenings, final wake up time, total sleep time across the night, and the amount of time they spent in bed. Circadian rhythm timing assessment Dim light melatonin onset was used to assess the timing (or phase) of each participant s circadian rhythm prior to and following the light and no light conditions. DLMO was calculated from saliva samples, which participants collected half-hourly using standard procedures [13]. Samples were collected prior to and following the light exposure protocol (see protocol below). Melatonin was analysed using a sensitive (4.3 pm) direct radioimmunoassay (RIA) with reagents from Buhlmann Laboratories AG, Allschwill, Switzerland [13]. DLMO was defined as the time at which melatonin concentration reached a threshold of 10 pm and continued to remain elevated for a minimum of 2 samples (or 1-h) following this time [13]. Research has demonstrated moderate to strong correlations between salivary and serum melatonin concentrations in young healthy adults [15]. A summary of the experimental protocol is shown in Fig. 3 below. Participants collected saliva samples half-hourly from 19:00 h until 01:00 h while remaining seated in a dimly lit room (lux\10), watching television. At 22:00 h, participants were required to complete the Stanford Sleepiness Scale. In the light condition, participants wore the re-timer device for 1-h from midnight to 01:00 h. Participants were required to use the high setting (506 lux lm/m 2 and 230 lw/cm 2 ). At 01:00 h, participants turned off the re-timer device and completed the Light side effects questionnaire before going to bed. In the no light condition, participants followed the same protocol but from midnight to 01:00 h sat quietly for the hour watching television. Participants were instructed to ensure they got out of bed by 09:00 h. On the second evening, participants followed the same protocol as the first evening but without saliva collections and completed the Stanford Sleepiness Scale at 22:00 h. In the light condition, participants wore the re-timer device from 01:00 to 02:00 h. At 02:00 h participants turned off the re-timer device and completed the light side effect questionnaire before going to bed. In the no light condition, participants followed the same protocol but without the retimer device. Participants were instructed to ensure they got out of bed by 10:00 h. On the third evening, participants were required to collect saliva samples from 19:00 to 01:00 h and complete the Stanford Sleepiness scale at 22:00 h. It should be noted that the effect of the protocol on bedtimes and wake up times was a delay from their typical bedtime (M = 22:23, SD = 34.8 min) of about 2 h on night 1, 3 h on night 2, and 2 h on night 3 as shown in Fig. 3. Because of the possible delaying effects of both the

4 Fig. 2 Light Effect Questionnaire Light Effect Questionnaire After wearing Retime for the hour, did you experience any of the following? Tick any symptom that you experienced and please give a short description. Symptom Comment Headache Dizziness Nausea Eye irritation Eye redness Blurred vision Light bothersome to eyes Restlessness Excessive energy Irritability Other Fig. 3 Experimental protocol ½ hrly saliva samples L Sleep L Sleep ½ hrly saliva samples evening light condition and delay of sleep timing, participants were instructed to revert to their typical sleep times between conditions and a wash-out period of at least 1 week was given between conditions. Overview of statistical analyses Repeated measures analysis of variance (ANOVA) was used to evaluate the differences in dim light melatonin onset (DLMO) and subjective sleepiness with use of the retimer device compared to the no light control condition. It was expected that DLMO will delay and subjective sleepiness will decrease (at the fixed clock time of 22:00 h) significantly in the re-timer condition relative to the no light condition. Results Phase delay following use of re-timer portable light device The mean half-hourly melatonin concentration profiles for night 1 (indicated by the solid line) and night 3 (indicated by the dashed line) are shown for the re-timer and no light control conditions in Fig. 4 below, with each participants profile illustrated individually in Fig. 5. On night 3 following use of the re-timer device, the melatonin profile is clearly delayed (or timed later) when compared to the melatonin profile prior to use of the device on night 1. A lack of phase change is demonstrated by the melatonin profiles for the no light condition, with little difference in timing on night 1 and night 3. The increasingly late melatonin profile after using the re-timer device indicates a greater and more robust delay relative to no light control condition. Two-way repeated measures analysis of variance (ANOVA) were used to evaluate the differences in DLMO and subjective sleepiness with use of the re-timer device compared to a no light control condition. Mean (and standard deviation) DLMO and subjective sleepiness is shown for retimer and no light conditions in Table 1 below. Following use of the re-timer device on two consecutive evenings, the DLMO of participants delayed an average of 46 min relative to a delay of only 3 min in the no light condition. The two-way repeated measures ANOVA revealed a significant interaction term indicating DLMO delayed significantly more in the re-timer condition when

5 Summary of adverse events A summary of adverse device effects reported by participants is shown in Table 2 below. The most commonly reported adverse device effects were headache, eye irritation, and light bothersome to eyes. These adverse device effects were not severe or prolonged and treatment was not requested or required on any occasion. The incidence of adverse device effects was low on night 1 (M = 1.42, SD = 1.08) and night 2 (M = 1.33, SD = 1.07) of use. A paired samples t test revealed the incidence of adverse device effects was similar on both nights t(11) =.432, p =.67. There were no other adverse events reported by participants. Discussion Fig. 4 Mean salivary melatonin concentrations on night 1 (solid line) and night 3 (dashed line) for the re-timer and no light conditions compared to no delay in the no light control condition, F(1,11) = 8.04, p =.016. Although there was a trend for subjective sleepiness to decrease more (at the fixed clock time of 22:00 h) in the retimer condition when compared to the no light condition, this trend was not statistically significant F(1,11) = 1.00, p =.339. The current study evaluated the effectiveness of the newly developed re-timer portable light device in phase delaying the circadian rhythm. The delay was assessed using DLMO. Two consecutive evenings each of 1 h exposure to light using the re-timer portable device produced a significant delay in DLMO of 46 min when compared to the no light control condition delay of only 3 min. The phase delay following the use of the re-timer device is comparable to those of other studies that have administered light using portable devices. Wright, Lack and Partridge assessed the efficacy of a portable light source comprising either blue/green LEDs (similar to the re-timer device) or white LEDs in phase delaying DLMO [8]. These portable devices were compared to a light box and a no light control condition. Light was administered on one occasion for 2-h from midnight to 02:00 h. DLMO was assessed using half-hourly saliva samples collected from 19:00 to 02:00 h. A delay in DLMO of 42 min was observed following use of the blue/green LED device. The smaller delays of DLMO following the use of the white LED device (22 min) and the light box (23 min) did not reach statistical significance. Similar to the earlier study no significant delay in DLMO was reported in the present study for the no light control condition. In a similar study, Wright and Lack used portable devices to administer light of differing wavelengths in their investigation on the effect of wavelength (colour) to phase delay DLMO [8]. These were experimental antecedents of the re-timer devices and emitted similar intensity light to participants. The portable light device comprised blue (470 nm), blue/green (497 nm), green (525 nm), amber (595 nm), or red (660 nm) LEDs. Fifteen good sleepers participated in all five-wavelength conditions and a no light control condition. Light was administered on a single occasion for 2-h from midnight to 02:00 h for each

6 Fig. 5 Melatonin concentrations on night 1 and 3 for the re-timer and no light conditions shown for each participant condition. Light devices comprising medium-to-short wavelengths showed the greatest phase delay, while longer wavelengths resulted in minimal and non-significant phase delays when compared to the no light control condition. The greatest delay in DLMO, of 36 min was reported following use of the blue/green LED device. The phase delays of DLMO following the use of the re-timer are not only comparable to those reported following the use of other portable devices comprising blue/green LEDs, but also fixed white light sources of much greater light intensity and duration [17, 18]. It is important to note, the re-timer device produced a comparable phase delay of DLMO relative to earlier studies with only half the time commitment on any one evening but the same total duration of 2 h over two nights. Therefore, it seems that the total duration of light exposure at the appropriate time in the evening is the critical ingredient for phase change regardless of whether it is

7 Table 1 Mean (and standard deviation) for dim light melatonin onset (DLMO) and subjective sleepiness for the re-timer and no light control condition across time (evening 1, evening 3) Re-timer No light Evening 1 Evening 3 Evening 1 Evening 3 DLMO a 20:38 (72) 21:24 (80) 20:44 (85) 20:47 (76) Sleepiness 4.42 (1.08) 3.67 (1.30) 4.33 (1.28) 4.00 (.89) a DLMO is shown in clock time and standard deviation in minutes Table 2 Summary of adverse effects reported by participants on the Light-Side Effect Questionnaire Adverse event Number of participants reporting side effects Night 1 Night 2 Headache 4 3 Eye irritation 3 3 Light bothersome to eyes 3 4 Blurred vision 3 1 Eye redness 1 1 Dizziness 2 2 Restlessness 1 0 distributed in one longer exposure or two exposures of half the duration. This spaced type of treatment schedule is anticipated to increase treatment compliance by reducing the daily time commitment required by patients. There was a trend for subjective sleepiness to decrease more following use of the re-timer device (at the fixed clock time of 22:00 h) compared to the no light control, however, this greater decline was not statistically significant. It was expected that because sleepiness is increasing rapidly around the clock time of 22:00 h due mainly to circadian rhythm declines of core body temperature and metabolic rate [19] that a delay of circadian rhythm would result in a decrease of sleepiness at the fixed clock time. Given subjective measures inherently attract greater variance than objective assessments; the lack of a statistically significant decline in subjective sleepiness in the current small sample is not surprising. Had the sample size been larger, it is expected this moderate effect size trend (g 2 =.422) would reach statistical significance. The current study has demonstrated the re-timer portable device is safe for the administration of light therapy. Participants reported minor adverse effects when using the re-timer device, including headache, eye irritation, and light bothersome to eyes. These effects required no treatment or intervention. However, it remains unclear if the minor incidence of adverse effects reported while using the re-timer device is due to the device itself or the experimental protocol (i.e., staying awake later than normal). Future research should also collect data on adverse events in the no light control condition. The safety of the re-timer device over prolonged periods of use (i.e., 1 2 weeks) is yet to be confirmed. The newly developed re-timer portable light device is an effective method of delaying the circadian rhythm, as measured using DLMO, in good sleepers. A substantial delay of 46 min was observed following 1-h uses on two consecutive evenings. Research was required to establish the efficacy of the re-timer device for phase delaying the circadian rhythm in good sleepers before extending clinical trials to populations suffering sleep disorders with circadian components such as advanced sleep phase disorder (ASPD) or early morning awakening insomnia. With circadian rhythms timed too early evening bright light therapy, with the ability to phase delay circadian rhythms, has been shown to be an effective treatment for ASPD [20, 21]. Therefore, the retimer light therapy device should provide an effective treatment for ASPD or early morning awakening insomnia as well as other problems requiring a circadian phase delay such as night shift work disorder, and jet-lag difficulties following Westward trans-meridian travel. Compliance with ethical standards Conflict of interest LL is a stock shareholder in the company RE- Time, PTY. LTD and was involved in the development of the re-timer device. NL has no conflict of interest to disclose. RE-Time, PTY. LTD provided the re-timer devices used in this study. References 1. Lack LC, Wright HR. Treating chronobiological components of chronic insomnia. Sleep Med. 2007;8(6): Czeisler CA, Allan JS, Strogatz SH, Ronda JM, Sanchez R, Rios CD, Freitag WO, Richardson GS, Kronauer RE. Bright light resets the human circadian pacemaker independent of the timing of the sleep wake cycle. Science. 1986;223: Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in humans. Science. 1980;210: Lewy AJ, Sack RL, Miller LS, Hoban TM. Antidepressant and circadian phase-shifting effects of light. Science. 1987;235: Minors SD, Waterhouse JM, Wirz-Justice A. A human phase response curve to light. Neurosci Lett. 1991;133: Brainard G, Lewy A, Menaker M, Fredrickson R, Miller L, Weleber R, Cassone V, Hudson D. Effect of light wavelength on the suppression of nocturnal plasma melatonin in normal volunteers. Ann N Y Acad Sci. 1985;453: Smith MR, Revell VL, Eastman CI. Phase advancing the human circadian clock with blue-enriched polychromatic light. Sleep Med. 2009;10: Wright HR, Lack L. Effect of light wavelength on suppression and phase delay of the melatonin rhythm. Chronobiol Int. 2001;18(5):801 8.

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