Limits...
Taking the lag out of jet lag through model-based schedule design.

Dean DA, Forger DB, Klerman EB - PLoS Comput. Biol. (2009)

Bottom Line: One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule.With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule.The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention.

View Article: PubMed Central - PubMed

Affiliation: Division of Sleep Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. ddean@rics.bwh.harvard.edu

ABSTRACT
Travel across multiple time zones results in desynchronization of environmental time cues and the sleep-wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep-wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep-wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions.

Show MeSH

Related in: MedlinePlus

Phase response contours from simulations of phase response protocols.The horizontal axis represents the timing of the countermeasure center (in hours), relative to the time of the predicted core body temperature minimum (Circadian Phase = 0). The vertical axis represents the specific parameter being studied: duration (Panel A), intensity (Panel B), endogenous circadian period (Panel C). The magnitude of the phase shift (in hours) is color coded according to the legend. The maximum delay and advance regions are colored dark blue and dark red, respectively. Panel A. Duration (1 to 12 hr) response contours for light pulses with different intensities (1,000–10,000 lux). Simulations were run with an endogenous period of 24.2 hr. Panel B. Intensity (1000–10,000 lux) response contours for different light pulse durations (1–12 hr). Simulations were run with an endogenous period of 24.2 hr. Panel C. Endogenous period (23.8–24.6 hr) response contours for different intensities (1,000–10,000 lux). Simulations were run with 3-hr light pulse durations.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2691990&req=5

pcbi-1000418-g003: Phase response contours from simulations of phase response protocols.The horizontal axis represents the timing of the countermeasure center (in hours), relative to the time of the predicted core body temperature minimum (Circadian Phase = 0). The vertical axis represents the specific parameter being studied: duration (Panel A), intensity (Panel B), endogenous circadian period (Panel C). The magnitude of the phase shift (in hours) is color coded according to the legend. The maximum delay and advance regions are colored dark blue and dark red, respectively. Panel A. Duration (1 to 12 hr) response contours for light pulses with different intensities (1,000–10,000 lux). Simulations were run with an endogenous period of 24.2 hr. Panel B. Intensity (1000–10,000 lux) response contours for different light pulse durations (1–12 hr). Simulations were run with an endogenous period of 24.2 hr. Panel C. Endogenous period (23.8–24.6 hr) response contours for different intensities (1,000–10,000 lux). Simulations were run with 3-hr light pulse durations.

Mentions: The Circadian Adjustment Method (CAM) requires stable phase advance and delay regions. This condition was verified with phase response contour maps that were created from 3240 simulations using the mathematical model of the effects of light on the human circadian pacemaker (see Methods) of phase response protocols with two-way combinations of varying CM duration (1–12 hr), CM intensity (1,000–10,000 lux), and endogenous circadian period (23.8–24.6 hr) (Figure 3). The phase response protocol is a standard chronobiology technique for assessing the response of the circadian system to a scheduled light stimulus [41]. The phase response protocol contains three sections: 1) The pre-stimulus section contains an 8-hour sleep episode followed by a wake episode. The length of the wake episode ranges from 28 hours to 52 hours so that the scheduled CM (see section 2) can be placed at any phase of the circadian system. 2) The stimulus section contains an 8-hour sleep episode followed by a 16-hour wake episode. 3) The post-stimulus section contains an 8-hour sleep episode followed by a variable length wake episode. The length of the post-stimulus wake episode is selected to insure that the duration of the entire phase response protocol is constant. The shift in circadian phase (reported in Figure 3) is calculated as the difference in predicted circadian phase in the post- and pre-stimulus sections. As shown in Figure 3, the phase regions of maximum delay and advance are relatively constant. The relative stability of the phase delay region supports the use of a constant offset (parameter C in Equation 9; See Methods). The plots also demonstrate that the circadian system has a larger amplitude for phase delay responses than for phase advance responses to light stimuli of different durations and intensities.


Taking the lag out of jet lag through model-based schedule design.

Dean DA, Forger DB, Klerman EB - PLoS Comput. Biol. (2009)

Phase response contours from simulations of phase response protocols.The horizontal axis represents the timing of the countermeasure center (in hours), relative to the time of the predicted core body temperature minimum (Circadian Phase = 0). The vertical axis represents the specific parameter being studied: duration (Panel A), intensity (Panel B), endogenous circadian period (Panel C). The magnitude of the phase shift (in hours) is color coded according to the legend. The maximum delay and advance regions are colored dark blue and dark red, respectively. Panel A. Duration (1 to 12 hr) response contours for light pulses with different intensities (1,000–10,000 lux). Simulations were run with an endogenous period of 24.2 hr. Panel B. Intensity (1000–10,000 lux) response contours for different light pulse durations (1–12 hr). Simulations were run with an endogenous period of 24.2 hr. Panel C. Endogenous period (23.8–24.6 hr) response contours for different intensities (1,000–10,000 lux). Simulations were run with 3-hr light pulse durations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691990&req=5

pcbi-1000418-g003: Phase response contours from simulations of phase response protocols.The horizontal axis represents the timing of the countermeasure center (in hours), relative to the time of the predicted core body temperature minimum (Circadian Phase = 0). The vertical axis represents the specific parameter being studied: duration (Panel A), intensity (Panel B), endogenous circadian period (Panel C). The magnitude of the phase shift (in hours) is color coded according to the legend. The maximum delay and advance regions are colored dark blue and dark red, respectively. Panel A. Duration (1 to 12 hr) response contours for light pulses with different intensities (1,000–10,000 lux). Simulations were run with an endogenous period of 24.2 hr. Panel B. Intensity (1000–10,000 lux) response contours for different light pulse durations (1–12 hr). Simulations were run with an endogenous period of 24.2 hr. Panel C. Endogenous period (23.8–24.6 hr) response contours for different intensities (1,000–10,000 lux). Simulations were run with 3-hr light pulse durations.
Mentions: The Circadian Adjustment Method (CAM) requires stable phase advance and delay regions. This condition was verified with phase response contour maps that were created from 3240 simulations using the mathematical model of the effects of light on the human circadian pacemaker (see Methods) of phase response protocols with two-way combinations of varying CM duration (1–12 hr), CM intensity (1,000–10,000 lux), and endogenous circadian period (23.8–24.6 hr) (Figure 3). The phase response protocol is a standard chronobiology technique for assessing the response of the circadian system to a scheduled light stimulus [41]. The phase response protocol contains three sections: 1) The pre-stimulus section contains an 8-hour sleep episode followed by a wake episode. The length of the wake episode ranges from 28 hours to 52 hours so that the scheduled CM (see section 2) can be placed at any phase of the circadian system. 2) The stimulus section contains an 8-hour sleep episode followed by a 16-hour wake episode. 3) The post-stimulus section contains an 8-hour sleep episode followed by a variable length wake episode. The length of the post-stimulus wake episode is selected to insure that the duration of the entire phase response protocol is constant. The shift in circadian phase (reported in Figure 3) is calculated as the difference in predicted circadian phase in the post- and pre-stimulus sections. As shown in Figure 3, the phase regions of maximum delay and advance are relatively constant. The relative stability of the phase delay region supports the use of a constant offset (parameter C in Equation 9; See Methods). The plots also demonstrate that the circadian system has a larger amplitude for phase delay responses than for phase advance responses to light stimuli of different durations and intensities.

Bottom Line: One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule.With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule.The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention.

View Article: PubMed Central - PubMed

Affiliation: Division of Sleep Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. ddean@rics.bwh.harvard.edu

ABSTRACT
Travel across multiple time zones results in desynchronization of environmental time cues and the sleep-wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep-wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep-wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions.

Show MeSH
Related in: MedlinePlus