Phase response curves to light and to melatonin - Essay Example

?a. Describe the phase response curves to light and to melatonin. A phase response curve (PRC) describes the effect of a particular treatment on circadian time. In general, the x-axis represents local time or the endogenous circadian time of the subject and the y-axis represents the phase shift in hours. In human light PRC (Figure 1), the y-axis of the PRC shows the direction and relative magnitude of the phase shift in hours induced by light exposure (solid line). Circadian Time Zero (CT0) corresponds to 11:00 am and CT22-CT18 is the duration for day time activity. The black bar, which indicates the time period between 12:00 midnight – 8:00am, along x-axis represents the duration for sleeping. Bright light treatment causes the phase-delay of circadian phase, which is represented by the area from CT10 to CT18. During this period, bright light treatment causes later onset of sleeping/awakening cycle. As time progresses from CT10, stronger effect on phase-delay is observed. At CT18, this phase-delay effect is changed dramatically to phase-advancing effect. The peak phase-advancing effect coincides with sunrise. From CT18 to CT3, bright light treatment induces phase-advancing effect, causing earlier onset of sleeping / awakening cycle. This effect gradually decreases from CT19 to CT3. As noted in the graph, little or no effect is observed when bright light treatment is applied from CT14 to CT20, in which this time period corresponds to 2:00pm to 8:00pm. The intensity of the light used in bright light treatment can have direct effect on the magnitude of the phase advancement or delay. Higher light intensity usually corresponds to stronger phase-shifting effect. Bright light is defined as light intensity larger than 3000lux, dim indoor light corresponds to lesser than 60 lux and dim light is designed as lesser 10 lux (1). Figure 1 A phase response curve for light and melatonin administration (modified from Hatonen, T. (2000) (2)) Melatonin PRC (dotted line) is characterized by its 12-hour out-of phase relationship with light PRC. Melatonin PRC is obtained by administering exogenous melatonin to human subjects. Melatonin has a phase-advancing effect when administered at CT0 to CT12, which is during afternoon. Melatonin achieves its greatest phase advancing effect approximately at CT4 (evening time), which leads to early onset of wake-up time. After this time point, this effect decreases to the lowest point to CT12. It should be noted that during this time period, bright light treatment has no phase-shifting effect on circadian rhythm. From CT18 to CT0, melatonin administration induces a phase-delay effect on circadian rhythm, however, this effect is relatively small when compared with the phase advancing effect induced by bright light treatment. From 2 hours before the onset of sleeping (CT12) onwards until time of sunrise (CT18), administration of melatonin does not exert any effect on circadian rhythm. This time duration coincides with phase delaying effect of bright light treatment. b. Using this knowledge of the phase response curves to light and to melatonin, design a protocol to alleviate the effects of jet lag when travelling from London Singapore (8 time zones eastward) The flights for travelling from London to Singapore are available both in the morning and at night. The local time in Singapore is ahead of London by 8 hours (8 time zones eastward). Assuming there are two flights travelling from London to Singapore, one flight has the depart time at 11:00 am (London local time) and arrive in Singapore at 7:00 am (Singapore local time, one day ahead); the other flight departs at 22:00 pm (London local time) and arrives at 18:00 pm (Singapore local time, one day ahead). The total duration of the flight is approximately 13 hours. The circadian rhythm may be entrained by advance or delay the sleep/awake cycle and both intake of melatonin at about 4 hours before to its natural peak in the circadian cycle or bright light treatment may induce an advance response (3). The following protocol is devised from several protocols (1, 3-6) to enhance entrainment to adapt to the local destination time after transmeridian jet travel. For the passenger aboard on the first flight, the departure time coincides with the starting of his/her circadian rhythm (CT0) (refer to Figure 2). Therefore the flight duration overlaps with his/her waking period (CT0 to CT13). According to his/her circadian rhythm, he/she will start her sleeping period from CT13 onwards. However, in terms of local time of Singapore, part of his flight duration overlaps with the local sleeping hours (12:00 midnight to 7:00am). This results in postponing his/her sleep for 16 hours, i.e. until 12:00 midnight (Singapore local time). In order to delay the onset of sleeping, 4 intervals of bright light treatment (>3000lux), each consists of 30 minutes illumination, will be given to the subject starting at CT15 (9:00 am, Singapore local time). At 5 hours before local Singapore bed time (CT2), 5mg of melatonin was administered and this will induce phase-advancement in circadian rhythm. This combination of bright light treatment and administration of melatonin will result in advancement of 2 hours per day. Therefore, if the passenger undergoes this combination treatment for 3 days, he/she will be entrained to local time. Figure 2 A systemic diagram showing the circadian rhythm relative to the local time of London and Singapore for the morning flight On the other hand, if a passenger takes the second flight which departs at 22:00 pm (London local time) (corresponding to CT10) and lands in Singapore on 6:00 pm local time (CT23). As shown in the Figure 3, his/her intrinsic sleeping period falls within the period of the flight. However, since the entrained time for onset of sleep is just 6 hours after landing, suggesting that the passenger experiences a shorter day time (CT20 to CT3), phase-advancement is needed In order to help this passenger to better adjust to local time. A dose of 5mg melatonin should be taken by the passenger at 7:00pm (London local time) and immediately after landing (CT23), the passenger should receive a bright light treatment of 4 intervals of >3000lux, 30 minutes each in order to induce the earlier onset of sleeping hours. Figure 3 A systemic diagram showing the circadian rhythm relative to the local time of London and Singapore for the late night flight References 1. Burgess HJ, Crowley SJ, Gazda CJ, Fogg LF, & Eastman CI (2003) Preflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright light. (Translated from eng) J Biol Rhythms 18(4):318-328 (in eng). 2. Hatonen T (2000) The Impact of Light on the Secretion of Melatonin in Humans. (University of Helsinki,, Helsinki). 3. Samel A, et al. (1991) Influence of melatonin treatment on human circadian rhythmicity before and after a simulated 9-hr time shift. (Translated from eng) J Biol Rhythms 6(3):235-248 (in eng). 4. Burgess HJ, Revell VL, & Eastman CI (2008) A three pulse phase response curve to three milligrams of melatonin in humans. (Translated from eng) J Physiol 586(2):639-647 (in eng). 5. Revell VL, et al. (2006) Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light. (Translated from eng) J Clin Endocrinol Metab 91(1):54-59 (in eng). 6. Beaumont M, et al. (2004) Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. (Translated from eng) J Appl Physiol 96(1):50-58 (in eng). Read More