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Project Title:  Physiologically-Based Modeling of Sleep-Wake Scheduling and the Effects of Pharmaceuticals (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 10/01/2009  
End Date: 10/01/2012  
Task Last Updated: 01/11/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Phillips, Andrew J Ph.D. / Brigham and Women's Hospital 
Address:  Division of Sleep Medicine 
221 Longwood Ave. Suite 438 
Boston , MA 02115 
Email: ajphillips@partners.org 
Phone: 617-278-0057  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Klerman, Elizabeth  MENTOR/Brigham and Women's Hospital 
Project Information: Grant/Contract No. NCC 9-58-PF02101 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02101 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) BHP:Behavioral Health & Performance (archival in 2017)
Human Research Program Risks: (1) Sleep:Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload (IRP Rev F)
Human Research Program Gaps: (1) Sleep Gap 08:We need to develop individualized scheduling tools that predict the effects of sleep-wake cycles, light and other countermeasures on performance, and can be used to identify optimal (and vulnerable) performance periods during spaceflight (IRP Rev E)
Task Description: POSTDOCTORAL FELLOWSHIP

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.

Research Impact/Earth Benefits: Our project is not only important to the space program, but also has broad applicability on Earth. Mathematical models of sleep/wake and circadian rhythms can be used to optimize performance and improve worker schedules in a wide range of environments. They are thus of potential use to all industries that require humans to operate at a high level at adverse times or after long periods awake. Chiefly, this includes the medical, military, aviation, and ground transportation industries, as well as shift workers. Recently, 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. Ultimately, the development of tools that can be used to improve performance in the workplace would have a large potential impact across many industries.

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.

Task Progress & Bibliography Information FY2013 
Task Progress: Specific Aim 1 (developing a combined model of sleep/wake and circadian rhythms): We have successfully combined our physiologically based models of the systems underlying sleep/wake regulation and circadian rhythms, and developed a flexible software implementation to facilitate the incorporation of future modifications. The new integrated model includes bidirectional interactions between the sleep/wake and circadian systems, and is able to dynamically predict sleep/wake behaviors in response to imposed schedules. This includes insomnia when sleep is scheduled at inappropriate circadian phases, which is known to be a significant risk in the space environment. We have simulated data from spontaneous desynchrony protocols as a first stage of validation, and the model has provided insights into the physiological mechanisms underlying this phenomenon. We have also simulated forced desynchrony protocols and are now extending the model to include the effects of caffeine and/or chronic sleep restriction under these conditions. We have also improved the utility of the model by developing linked models of the ultradian REM/NREM cycle and entrainment of circadian rhythms by food.

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.

Bibliography Type: Description: (Last Updated: 04/08/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Phillips AJK, Breslow ER, Huang JM, St Hilaire MA, Klerman EB. "Adding circadian phase shifting effects of exogenous melatonin to a mathematical model of plasma melatonin." 26th Annual Meeting of the Associated Professional Sleep Societies, Boston, MA, June 9-13, 2012.

Sleep. 2012;35 Suppl:A70. http://www.journalsleep.org/Resources/Documents/2012abstractsupplement.pdf , Jun-2012

Abstracts for Journals and Proceedings Phillips AJK, Breslow ER, Huang JM, St Hilaire MA, Klerman EB. "Developing a framework for optimizing use of pharmaceutical countermeasures for fatigue and circadian misalignment." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Abstracts for Journals and Proceedings Phillips AJK, Greenside PG, Mistlberger RE, Klerman EB. "A two-oscillator model of food anticipatory activity." 13th Biennial Meeting, Society for Research on Biological Rhythms (SRBR), Destin, FL, May 19-23, 2012.

Program and Abstracts. 13th Biennial Meeting, Society for Research on Biological Rhythms (SRBR), Destin, FL, May 19-23, 2012. Abstract P132, p. 185. http://www.conferences.uiuc.edu/SRBR/FINAL%20SRBR%202012%20Program%20and%20Abstracts.pdf , May-2012

Abstracts for Journals and Proceedings Phillips AJK, Klerman EB. "The effects of chronic sleep restriction on sleep and performance in a physiologically based model of sleep." 26th Annual Meeting of the Associated Professional Sleep Societies, Boston, MA, June 9-13, 2012.

Sleep. 2012;35 Suppl:A117-8. http://www.journalsleep.org/Resources/Documents/2012abstractsupplement.pdf , Jun-2012

Articles in Peer-reviewed Journals Phillips AJK, Czeisler CA, Klerman EB. "Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology." J Biol Rhythms. 2011 Oct;26(5):441-53. http://dx.doi.org/10.1177/0748730411414163 ; PubMed PMID: 21921298 , Oct-2011
Articles in Peer-reviewed Journals Fulcher BD, Phillips AJ, Postnova S, Robinson PA. "A physiologically based model of orexinergic stabilization of sleep and wake." PLoS One. 2014 Mar 20;9(3):e91982. eCollection 2014. http://dx.doi.org/10.1371/journal.pone.0091982 ; PubMed PMID: 24651580; PubMed Central PMCID: PMC3961294 , Mar-2014
Articles in Peer-reviewed Journals Phillips AJ, Robinson PA, Klerman EB. "Arousal state feedback as a potential physiological generator of the ultradian REM/NREM sleep cycle." J Theor Biol. 2013 Feb 21;319:75-87. Epub 2012 Dec 5. http://dx.doi.org/10.1016/j.jtbi.2012.11.029 ; PubMed PMID: 23220346; PubMed Central PMCID: PMC3653640 , Feb-2013
Articles in Peer-reviewed Journals Breslow ER, Phillips AJ, Huang JM, St Hilaire MA, Klerman EB. "A mathematical model of the circadian phase-shifting effects of exogenous melatonin." J Biol Rhythms. 2013 Feb;28(1):79-89. http://dx.doi.org/10.1177/0748730412468081 ; PubMed PMID: 23382594; PubMed Central PMCID: PMC3733227 , Feb-2013
Articles in Peer-reviewed Journals Phillips AJ, Fulcher BD, Robinson PA, Klerman EB. "Mammalian rest/activity patterns explained by physiologically based modeling." PLoS Comput Biol. 2013;9(9):e1003213. Epub 2013 Sep 5. http://dx.doi.org/10.1371/journal.pcbi.1003213 ; PubMed PMID: 24039566; PubMed Central PMCID: PMC3764015 , Sep-2013
Articles in Peer-reviewed Journals Phillips AJK, Klerman EB, Butler JP. "Modeling the adenosine system as a modulator of cognitive performance and sleep patterns during sleep restriction and recovery." PLoS Comput Biol. 2017 Oct 26;13(10):e1005759. eCollection 2017 Oct. https://doi.org/10.1371/journal.pcbi.1005759 ; PubMed PMID: 29073206; PubMed Central PMCID: PMC5675465 , Oct-2017
Awards Phillips AJK. "Abstract Honorable Mention Award, Sleep Research Society, June 2012." Jun-2012
Awards Phillips AJK. "Research Merit Award, Society for Research on Biological Rhythms, May 2012." May-2012
Project Title:  Physiologically-Based Modeling of Sleep-Wake Scheduling and the Effects of Pharmaceuticals (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 10/01/2009  
End Date: 09/30/2012  
Task Last Updated: 10/12/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Phillips, Andrew J Ph.D. / Brigham and Women's Hospital 
Address:  Division of Sleep Medicine 
221 Longwood Ave. Suite 438 
Boston , MA 02115 
Email: ajphillips@partners.org 
Phone: 617-278-0057  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Klerman, Elizabeth  MENTOR/Brigham and Women's Hospital 
Project Information: Grant/Contract No. NCC 9-58-PF02101 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02101 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) BHP:Behavioral Health & Performance (archival in 2017)
Human Research Program Risks: (1) Sleep:Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload (IRP Rev F)
Human Research Program Gaps: (1) Sleep Gap 08:We need to develop individualized scheduling tools that predict the effects of sleep-wake cycles, light and other countermeasures on performance, and can be used to identify optimal (and vulnerable) performance periods during spaceflight (IRP Rev E)
Task Description: POSTDOCTORAL FELLOWSHIP

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.

Research Impact/Earth Benefits: Risks associated with fatigue due to circadian misalignment or extended wake are a serious danger in many work environments. Specifically, industries such as transportation, aviation, healthcare and defense often demand long and irregular working hours, with performance failures resulting in potentially fatal consequences. Developing effective countermeasures for fatigue is thus a problem with broad applicability on Earth.

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.

Task Progress & Bibliography Information FY2012 
Task Progress: In the past year, we have made substantial progress on this project's original specific aims.

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.

Bibliography Type: Description: (Last Updated: 04/08/2019) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Gharibshahi S, Phillips AJK, Mietus JE, Thomas RJ. "Sleep fragmentation phenotypes in sleep apnea syndromes." 25th Annual Meeting of the Associated Professional Sleep Societies, LLC 2011, Minneapolis, MN, June 11-15, 2011.

Sleep 2011;34 Suppl:A133. http://www.journalsleep.org/Resources/Documents/2011abstractsupplement.pdf , Jun-2011

Abstracts for Journals and Proceedings Phillips AJK, Breslow E, Huang J, St Hilaire MA, Klerman EB. "Adding Melatonin Countermeasures to a Model of Human Sleep/Wake and Circadian Rhythms." 18th IAA Humans in Space Symposium, Houston, TX, April 11-15, 2011.

18th IAA Humans in Space Symposium, Houston, TX, April 11-15, 2011. , Apr-2011

Abstracts for Journals and Proceedings Phillips AJK, Klerman EB, Bianchi MT. "Noise induced transitions reproduce realistic sleep/wake architecture in a mathematical model of human sleep." 25th Annual Meeting of the Associated Professional Sleep Societies, LLC 2011, Minneapolis, MN, June 11-15, 2011.

Sleep 2011;34 Suppl:A36. http://www.journalsleep.org/Resources/Documents/2011abstractsupplement.pdf , Jun-2011

Articles in Peer-reviewed Journals Duffy JF, Cain SW, Chang AM, Phillips AJ, Münch MY, Gronfier C, Wyatt JK, Dijk DJ, Wright KP Jr, Czeisler CA. "Sex difference in the near-24-hour intrinsic period of the human circadian timing system." Proc Natl Acad Sci U S A. 2011 Sep 13;108 Suppl 3:15602-8. Epub 2011 May 2. http://dx.doi.org/10.1073/pnas.1010666108 ; PubMed PMID: 21536890 , Sep-2011
Articles in Peer-reviewed Journals Phillips AJK, Czeisler CA, Klerman EB. "Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology." J Biol Rhythms. In press, August 2011. , Aug-2011
Books/Book Chapters Robinson PA, Phillips AJK, Fulcher BD, Puckeridge M, Roberts JA, Rennie CJ. "Quantitative modeling of sleep dynamics." in "Sleep and anesthesia: neural correlates in theory and experiment." Ed. A. Hutt. New York : Springer, 2011. p. 21-41., Jul-2011
Project Title:  Physiologically-Based Modeling of Sleep-Wake Scheduling and the Effects of Pharmaceuticals (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 10/01/2009  
End Date: 09/30/2011  
Task Last Updated: 11/09/2010 
Download report in PDF pdf
Principal Investigator/Affiliation:   Phillips, Andrew J Ph.D. / Brigham and Women's Hospital 
Address:  Division of Sleep Medicine 
221 Longwood Ave. Suite 438 
Boston , MA 02115 
Email: ajphillips@partners.org 
Phone: 617-278-0057  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Klerman, Elizabeth  MENTOR/Brigham and Women's Hospital 
Project Information: Grant/Contract No. NCC 9-58-PF02101 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02101 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) BHP:Behavioral Health & Performance (archival in 2017)
Human Research Program Risks: (1) Sleep:Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload (IRP Rev F)
Human Research Program Gaps: (1) Sleep Gap 08:We need to develop individualized scheduling tools that predict the effects of sleep-wake cycles, light and other countermeasures on performance, and can be used to identify optimal (and vulnerable) performance periods during spaceflight (IRP Rev E)
Task Description: POSTDOCTORAL FELLOWSHIP

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.

Research Impact/Earth Benefits: Our current funded project is not only important to the space program, but also has broad applicability on Earth. Mathematical models of sleep/wake and circadian rhythms can be used to optimize performance and improve worker schedules in a wide range of environments. They are thus of potential use to all industries that require humans to operate at a high level at adverse times or after long periods awake. Chiefly, this includes the medical, military, aviation, and ground transportation industries, as well as shift workers. Recently, 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.

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.

Task Progress & Bibliography Information FY2011 
Task Progress: Specific Aim 1 (developing a combined model of sleep/wake and circadian rhythms): We have successfully combined our physiologically-based models of the systems underlying sleep/wake regulation and circadian rhythms, and developed a flexible software implementation to facilitate the incorporation of future modifications. The new integrated model includes bidirectional interactions between the sleep/wake and circadian systems, and is able to dynamically predict sleep/wake behaviors in response to imposed schedules. This includes insomnia when sleep is scheduled at inappropriate circadian phases, which is known to be a significant risk in the space environment. We have simulated data from spontaneous desynchrony protocols as a first stage of validation, and the model has provided insights into the physiological mechanisms underlying this phenomenon. We are currently simulating data from forced desynchrony protocols as a second stage of validation.

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).

Bibliography Type: Description: (Last Updated: 04/08/2019) 

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Abstracts for Journals and Proceedings Phillips AJ, Chen PY, Robinson PA, Czeisler CA, Klerman EB. "Using physiologically-based modeling to determine the mechanisms underlying complex sleep/wake dynamics." SIAM Conference on the Life Sciences, Pittsburgh, PA, July 12-15, 2010.

SIAM Conference on the Life Sciences, Abstract Book, July 2010. p. 176. http://www.siam.org/meetings/ls10/LS10_abstracts.pdf , Jul-2010

Abstracts for Journals and Proceedings Phillips AJ, Czeisler C, Klerman E. "Investigating the causes of spontaneous internal desynchrony using a physiologically based sleep model." The 12th Biennial Meeting of the Society for Research on Biological Rhythms, Destin, FL, May 22-26, 2010.

The 12th Biennial Meeting of the Society for Research on Biological Rhythms, Program and Abstracts, May 2010. Abstract P94, p. 126. , May-2010

Abstracts for Journals and Proceedings Phillips AJ, Czeisler CA, Klerman EB. "Predicting sleep/wake schedule compliance using a physiologically based model of sleep." SLEEP 2010 24th Annual Meeting of the Associated Professional Sleep Societies, San Antonio, Texas, June 5-9, 2010.

Sleep 2010;33 Suppl:A71-2. http://www.journalsleep.org/PDF/AbstractBook2010.pdf , Jun-2010

Abstracts for Journals and Proceedings Phillips AJ, Fulcher BD, Robinson PA, Klerman EB. "Diurnal and nocturnal preference in a physiologically based model of mammalian sleep." The 12th Biennial Meeting of the Society for Research on Biological Rhythms, Destin, Florida, May 22-26, 2010.

The 12th Biennial Meeting of the Society for Research on Biological Rhythms, Program and Abstracts, May 2010. Abstract P59, p. 106. , May-2010

Abstracts for Journals and Proceedings Phillips AJ, Klerman EB. "Understanding internal desynchrony and the physiological effects of self-selected schedules using a quantitative model of sleep physiology." SLEEP 2010 24th Annual Meeting of the Associated Professional Sleep Societies, San Antonio, Texas, June 5-9, 2010.

Sleep 2010;33 Suppl:A60. http://www.journalsleep.org/PDF/AbstractBook2010.pdf , Jun-2010

Articles in Peer-reviewed Journals Phillips AJ, Chen PY, Robinson PA. "Probing the mechanisms of chronotype using quantitative modeling." J Biol Rhythms. 2010 Jun;25(3):217-27. http://dx.doi.org/10.1177/0748730410369208 ; PMID: 20484693 , Jun-2010
Articles in Peer-reviewed Journals Phillips AJ, Robinson PA, Kedziora DJ, Abeysuriya RG. "Mammalian sleep dynamics: how diverse features arise from a common physiological framework." PLoS Comput Biol. 2010 Jun 24;6(6):e1000826. http://dx.doi.org/10.1371/journal.pcbi.1000826 ; PMID: 20585613 , Jun-2010
Awards Phillips AJK. "Richard E. Kronauer Award, July 2010." Jul-2010
Awards Phillips AJK. "School of Physics Postgraduate Alumni Prize, May 2010." May-2010
Awards Phillips AJK. "Sleep Research Society First Time Travel Award, June 2010." Jun-2010
Project Title:  Physiologically-Based Modeling of Sleep-Wake Scheduling and the Effects of Pharmaceuticals (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP :
Start Date: 10/01/2009  
End Date: 09/30/2011  
Task Last Updated: 12/22/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Phillips, Andrew J Ph.D. / Brigham and Women's Hospital 
Address:  Division of Sleep Medicine 
221 Longwood Ave. Suite 438 
Boston , MA 02115 
Email: ajphillips@partners.org 
Phone: 617-278-0057  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Klerman, Elizabeth  MENTOR/Brigham and Women's Hospital 
Project Information: Grant/Contract No. NCC 9-58-PF02101 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02101 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
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No. of Master's Degrees:  
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Human Research Program Elements: None
Human Research Program Risks: (1) Sleep:Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload (IRP Rev F)
Human Research Program Gaps: (1) Sleep Gap 08:We need to develop individualized scheduling tools that predict the effects of sleep-wake cycles, light and other countermeasures on performance, and can be used to identify optimal (and vulnerable) performance periods during spaceflight (IRP Rev E)
Task Description: POSTDOCTORAL FELLOWSHIP

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.

Research Impact/Earth Benefits: This research project will not only significantly reduce risks on future NASA missions but also will have broad applications to optimizing shift work and other work schedules on Earth, and better understanding and regulating pharmaceuticals use in treating sleep disorders

Task Progress & Bibliography Information FY2010 
Task Progress: New project for FY2010.

Bibliography Type: Description: (Last Updated: 04/08/2019) 

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 None in FY 2010