NASA astronauts and ground crew must meet high-level cognitive and physical demands around-the-clock. These tasks place extreme stress on human physiology, which evolved under conditions of 24-h days with ample rest. The effects of sleep loss, circadian misalignment, and extended schedules on performance and subjective alertness pose serious risks to mission success. It is therefore crucial that countermeasures are developed for optimizing schedules and guiding pharmaceutical use.

Mathematical modeling provides a means of predicting performance and alertness under many different conditions, including untested conditions. Improved knowledge of sleep physiology has enabled development of more sophisticated models of sleep and wake. A physiologically based model of the sleep-wake switch has been developed and applied to sleep deprivation, shift work, pharmacologic stimuli, and fatigue. Meanwhile, a circadian model developed at the Brigham and Women's Hospital (BWH), has been applied to predicting performance and alertness, designing pre-mission countermeasures, and optimizing mission scheduling.

Our original aims were to combine the sleep-wake switch and circadian models, and incorporate pharmaceutical effects. We have successfully combined the sleep-wake switch and circadian models, including physiological interactions between these systems, thereby developing the most comprehensive model of human sleep/wake dynamics to date. This model has since been used to understand the physiological mechanisms underlying (1) interindividual differences in chronotype (i.e., morningness/eveningness preference) and (2) spontaneous desynchrony of the endogenous circadian rhythm from sleep/wake patterns during self-selected schedules. It has also been tested against data collected at the BWH research facilities during forced desynchrony experiments in which sleep/wake schedules are desynchronized from endogenous circadian rhythms using a non-24 h sleep/wake cycle. Results show that the model is capable of predicting the sleep/wake patterns observed during this imposed schedule, including difficulty initiating and maintaining sleep when scheduled at inappropriate circadian phases. The model has now been extended to include pharmaceutical effects, including both caffeine and melatonin. Recently, we showed that the model can be used to predict the effects of exogenous doses of melatonin on melatonin concentration in the blood and phase shifts of the circadian pacemaker. We are currently also testing the model against data for caffeine from experiments conducted at BWH. Development of our model has resulted in improved estimates of performance measures, and new diagnostics for assessing schedule suitability on an individual basis, including chronotype.

With much of the basic science completed, we have been developing a predictive software tool for optimizing the timing and use of pharmaceutical countermeasures for extended wake durations and circadian misalignment conditions. This tool will be usable by a non-specialist, and will allow the user to compare the efficacy of a user-inputted alternative countermeasure timing to the optimized solution so as to be flexible to the realities of schedule design. This tool will allow our findings to be deployed to the operational environment.

This research program will not only significantly reduce risks on future NASA missions, but also has broad applications to optimizing shift work and other work schedules on Earth. The tool we develop will be easily generalizable to managing extended wake and circadian misalignment conditions in industries such as defense, healthcare, transport, and shift workers. Furthermore, we anticipate that our research will lead to better understanding and regulation of pharmaceuticals for use in treating sleep disorders.

Providing a framework for better understanding and predicting the effects of pharmaceuticals that interact with the circadian and sleep/wake systems is also of wide importance. With the explosion in use of over-the-counter products such as caffeine and melatonin, it is important to develop models that can aid in understanding the physiological and performance impacts of self-medication. Furthermore, since our model is physiologically based, it could be used to help identify target pathways for future pharmaceuticals, and to better understand drugs of known efficacy but unknown mode of action (e.g., modafinil).

Developing mathematical models of sleep/wake and circadian rhythms is also a problem of basic scientific value. Such models serve multiple roles, including: (1) Improving our understanding of how the underlying physiology gives rise to the observed dynamics; (2) Making predictions about how the system will respond under untested conditions; and (3) Aiding the design of experimental protocols by predicting which conditions will provide the most informative results, thus making better use of available resources. The two-way dialogue between experimentalists and theorists is proving to be highly valuable to the sleep/wake and circadian scientific communities. New experimental findings inform the design and refinement of mathematical models, while models provide insight into the observed phenomena. In our case, the unexpected finding that our model can reproduce the sleep of other species is an excellent example of how modeling provides us with the tools to expand our scientific horizons.

Specific Aim 2 (incorporating the effects of pharmaceuticals): We have successfully included the effects of melatonin on the circadian pacemaker and the effects of caffeine on the sleep homeostat. We are now investigating interactions between the circadian pacemaker and the sleep homeostat, as well as the effects of caffeine under forced desynchrony.

Specific Aim 3 (developing user-friendly software): Over the past 12 months, we have continued to improve the modular structure and functions of our MATLAB implementation of the model. These changes have made the model easier to implement in different settings. We have also successfully implemented software that can be used to simulate the effects of sleep, light, and pharmaceutical countermeasures on a single schedule. We are currently still working toward completing our implementation of a GUI (graphical user interface) system.

NASA astronauts and ground crew must meet high-level cognitive and physical demands around-the-clock. These tasks place extreme stress on human physiology, which evolved under conditions of 24-h days with ample rest. The effects of sleep loss, circadian misalignment, and extended schedules on performance and subjective alertness pose serious risks to mission success. It is therefore crucial that countermeasures are developed for optimizing schedules and guiding pharmaceutical use.

Mathematical modeling provides a means of predicting performance and alertness under many different conditions, including untested conditions. Improved knowledge of sleep physiology has enabled development of more sophisticated models of sleep and wake. A physiologically-based model of the sleep-wake switch has been developed and applied to sleep deprivation, shift work, pharmacologic stimuli, and fatigue. Meanwhile, a circadian model developed at the Brigham and Women's Hospital (BWH), has been applied to predicting performance and alertness, designing pre-mission countermeasures and optimizing mission scheduling.

Our original aims were to combine the sleep-wake switch and circadian models, and incorporate pharmaceutical effects. We have successfully combined the sleep-wake switch and circadian models, including physiological interactions between these systems, thereby developing the most comprehensive model of human sleep/wake dynamics to date. This model has since been used to understand the physiological mechanisms underlying (1) interindividual differences in chronotype (i.e., morningness/eveningness preference) and (2) spontaneous desynchrony of the endogenous circadian rhythm from sleep/wake patterns during self-selected schedules. It has also been tested against data collected at the BWH research facilities during forced desynchrony experiments in which sleep/wake schedules are desynchronized from endogenous circadian rhythms using a non-24 h sleep/wake cycle. Results show that the model is capable of predicting the sleep/wake patterns observed during this imposed schedule, including difficulty initiating and maintaining sleep when scheduled at inappropriate circadian phases. Currently, the model is also being extended to include pharmaceutical effects, and we have already set the groundwork for incorporating the effects of caffeine, melatonin, and modafinil. Recently, we showed that the model can be used to predict the effects of exogenous doses of melatonin on melatonin concentration in the blood and phase shifts of the circadian pacemaker. We are now also incorporating data for caffeine from experiments conducted at BWH. Further development of our model will result in improved estimates of performance measures, and new diagnostics for assessing schedule suitability on an individual basis, including chronotype.

With much of the basic science now complete, we aim to develop a predictive software tool for optimizing the timing and use of pharmaceutical countermeasures for extended wake durations and circadian misalignment conditions. This tool will be usable by a non-specialist, and will allow the user to compare the efficacy of a user-inputted alternative countermeasure timing to the optimized solution so as to be flexible to the realities of schedule design. This tool will allow our findings to be deployed to the operational environment.

This research program will not only significantly reduce risks on future NASA missions, but also has broad applications to optimizing shift work and other work schedules on Earth. The tool we develop will be easily generalizable to managing extended wake and circadian misalignment conditions in industries such as defense, healthcare, transport, and shift workers. Furthermore, we anticipate that our research will lead to better understanding and regulation of pharmaceuticals for use in treating sleep disorders.

Our NSBRI research project addresses the issue of fatigue through the development of a mathematical model of human sleep and circadian rhythms that is also able to incorporate pharmaceutical effects. This approach provides three separate means of managing and reducing risks associated with fatigue: (1) The model can be used to guide the development of safe schedules; (2) The model can be used to predict times when fatigue-related risks will be greatest; (3) The model can be used to optimize the use and timing of fatigue countermeasures, including light, naps and pharmaceuticals.

Shift work and circadian disruption have been identified as significant risk factors for cancer, cardiovascular disease, diabetes, and suppressed immune function. The need for mathematical tools to circumvent - or at least minimize - occupational risks is thus a growing requirement, given the large proportion of the US population involved in shift work. Providing a framework for better understanding and predicting the effects of pharmaceuticals that interact with the circadian and sleep/wake systems is also of wide importance. With the explosion in use of over-the-counter products such as caffeine and melatonin, it is important to develop models that can aid in understanding the physiological and performance impacts of self-medication. Furthermore, since our model is physiologically based, it could be used to help identify target pathways for future pharmaceuticals, and to better understand drugs of known efficacy but unknown mode of action (e.g., modafinil).

Developing mathematical models of sleep/wake and circadian rhythms is also a problem of basic scientific value. Such models serve multiple roles, including: (1) Improving our understanding of how the underlying physiology gives rise to the observed dynamics; (2) Making predictions about how the system will respond under untested conditions; and (3) Aiding the design of experimental protocols by predicting which conditions will provide the most informative results, thus making better use of available resources. The two-way dialogue between experimentalists and theorists is proving to be highly valuable to the sleep/wake and circadian scientific communities. New experimental findings inform the design and refinement of mathematical models, while models provide insight into the observed phenomena. In our case, the unexpected finding that our model can reproduce the sleep of other species is an excellent example of how modeling provides us with the tools to expand our scientific horizons.

Specific Aim 1 (developing a combined model of sleep/wake and circadian rhythms): Our combined model of sleep/wake regulation and circadian rhythms is now fully implemented in MatLab. This model is based on physiology, and includes bidirectional interactions between the sleep and circadian systems. Our code has been developed in a modular structure, allowing it to be easily modified or extended for new applications, including the software tool we propose to develop in our third year. The model has now been validated against data from both human spontaneous and forced desynchrony experiments. This process has identified potential physiological mechanisms underlying spontaneous desynchrony (a phenomenon which remains poorly understood), and this work has been accepted for publication in the Journal of Biological Rhythms. The model has also been shown to reproduce inter-species and inter-individual differences in sleep/wake timing, and has provided new insights into the mechanisms that determine these timings, including the direct alerting effects of light (a new addition to the model). These findings demonstrate the translational value of this new mathematical model, and are critical to achieving effective countermeasures for fatigue due to circadian misalignment and/or extended wake on an individual basis.

Specific Aim 2 (incorporating the effects of pharmaceuticals): Because our model is physiologically based, the effects of pharmaceuticals on the sleep/wake and circadian systems can be readily incorporated. In the past year, we have incorporated the effects of exogenous doses of melatonin. The model has been shown to reproduce experimental data for both blood melatonin concentration and circadian phase shifts. The groundwork has also been laid for including other sleep-promoting or wake-promoting pharmaceuticals, including caffeine and modafinil. We are currently using data from a forced desynchrony experiment where subjects were given caffeine to validate the model's predictions of the effects of caffeine on alertness at different times of day.

NASA astronauts and ground crew must meet high-level cognitive and physical demands around-the-clock. These tasks place extreme stress on human physiology, which evolved under conditions of 24 h days with ample rest. The effects of sleep loss, circadian misalignment, and extended schedules on performance and subjective alertness pose serious risks to mission success. It is therefore crucial that countermeasures are developed for optimizing schedules and guiding pharmaceutical use.

Mathematical modeling provides a means of predicting performance and alertness under many different, including untested, conditions. Improved knowledge of sleep physiology has enabled development of more sophisticated models of sleep and wake. A physiologically-based model of the sleep-wake switch has been developed and applied to sleep deprivation, shift work, pharmacologic stimuli, and fatigue. Meanwhile, a circadian model developed at the Brigham and Women's Hospital (BWH), has been applied to predicting performance and alertness, designing pre-mission countermeasures and optimizing mission scheduling.

By combining the sleep-wake switch and circadian models, including physiological interactions between these systems, we have developed the most comprehensive model of human sleep/wake dynamics to date. This model has since been used to understand the physiological mechanisms underlying (1) interindividual differences in chronotype (i.e. morningness/eveningness preference) and (2) spontaneous desynchrony of the endogenous circadian rhythm from sleep/wake patterns during self-selected schedules. Currently, the model is being tested against data collected at the BWH research facilities during forced desynchrony experiments in which the sleep/wake schedule is desynchronized from endogenous circadian rhythms using a non-24 h sleep/wake cycle outside the range of entrainment. Preliminary results show that the model is capable of predicting the sleep/wake patterns observed during this imposed schedule, including difficulty initiating and maintaining sleep when scheduled at inappropriate circadian phases. Once this validation procedure is complete, the model will be ready to predict sleep/wake patterns and incidence of insomnia during imposed schedules in both space and Earth environments. Further development of this model will result in improved estimates of performance measures, and new diagnostics for assessing schedule suitability on an individual basis, including chronotype. Alloying our complementary expertise in sleep-wake switch and circadian modeling will thus provide a significant step forward in assessment and design of mission schedules.

Since the model is physiological it is also readily extended to include pharmaceuticals that target sleep/wake physiology. We have set the groundwork for incorporating the effects of caffeine, melatonin, and modafinil on the sleep/wake and circadian systems; data for this work are available from studies already conducted at the BWH research facilities. Preliminary results indicate that the model captures the key effects of these drugs, and future work will allow us to calibrate the model to other experimental data obtained at the BWH. Our goal is to thus incorporate into our models predictions of the efficacy of pharmaceuticals as countermeasures for reducing fatigue and combating insomnia. These models will facilitate recommendations for administration of pharmaceuticals before, during and after missions.

This research program will not only significantly reduce risks on future NASA missions, but also has broad applications to optimizing shift work and other work schedules on Earth. Furthermore, we anticipate it will lead to better understanding and regulation of pharmaceuticals for use in treating sleep disorders.

Providing a framework for better understanding and predicting the effects of pharmaceuticals that interact with the circadian and sleep/wake systems is also of wide importance. With the explosion in use of over-the-counter products such as caffeine and melatonin, it is important to develop models that can aid in understanding the physiological and performance impacts of self-medication. Furthermore, since our model is physiologically based, it could be used to help identify target pathways for future pharmaceuticals, and to better understand drugs of known efficacy but unknown mode of action (e.g., modafinil).

Developing mathematical models of sleep/wake and circadian rhythms is also a problem of basic scientific value. Such models serve multiple roles, including: (1) Improving our understanding of how the underlying physiology gives rise to the observed dynamics; (2) Making predictions about how the system will respond under untested conditions; and (3) Aiding the design of experimental protocols by predicting which conditions will provide the most informative results, thus making better use of available resources. The two-way dialogue between experimentalists and theorists is proving to be highly valuable to the sleep/wake and circadian scientific communities. New experimental findings inform the design and refinement of mathematical models, while models provide insight into the observed phenomena. In our case, the unexpected finding that our model can reproduce the sleep of other species is an excellent example of how modeling provides us with the tools to expand our scientific horizons.

We have also shown that the combined model is able to identify the physiological sources of interindividual and interspecies differences in sleep/wake timings. These findings are of significant translational value in terms of designing individualized countermeasures, and in using animal experiments to gain additional information about the underlying sleep/wake physiology.

Specific Aim 2 (incorporating the effects of pharmaceuticals): With model validation now nearing completion, we are well poised to incorporate pharmaceuticals into the model. We are presently incorporating the effects of melatonin by extending a previous model of endogenous melatonin output to include the effects of exogenous doses. To date, we have achieved a working model of the phase-shifting effects of melatonin, and intend to next include the hypnotic effects of melatonin. Once this is complete, the model will be validated against forced desynchrony data in which subjects were administered melatonin or placebo. Similar methodologies can then be used to model the effects of other drugs, including caffeine and modafinil (since BWH also has forced desynchrony data for both of these).

NASA astronauts and ground crew must meet high-level cognitive and physical demands around-the-clock. These tasks place extreme stress on human physiology, which evolved under conditions of 24-hour days with ample rest. The effects of sleep loss, circadian misalignment and extended schedules on performance and alertness pose serious risks to mission success. It is therefore crucial that countermeasures are developed for optimizing schedules and guiding pharmaceutical use.

Mathematical modeling provides a means of predicting performance and alertness under many different, including untested, conditions. Improved knowledge of sleep physiology has enabled development of more sophisticated models. A physiologically-based model of the sleep-wake switch has been developed and applied to sleep deprivation, shift work, pharmacologic stimuli and fatigue. Meanwhile, a circadian model developed at the Brigham and Women's Hospital has been applied to predicting neurobehavioral performance and alertness, designing pre-mission countermeasures and optimizing mission scheduling.

This project will combine the sleep-wake switch and circadian models, including physiological interactions between these systems, yielding the most comprehensive model to date. This will result in improved estimates of performance measures and new diagnostics for assessing schedule suitability on an individual basis, including chronotype (morning/evening preference). Alloying our complementary expertise in sleep-wake switch and circadian modeling will thus provide a significant step forward in assessment and design of mission schedules.

Since the model is physiological, it is readily extended to include pharmaceuticals. We will thus also predict the efficacy of drugs such as caffeine, modafinil and melatonin as countermeasures for reducing fatigue and combating insomnia. This will facilitate recommendations for administration before, during and after missions.