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Project Title:  Mathematical Modeling of Circadian/Performance Countermeasures Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 06/01/2004  
End Date: 08/31/2008  
Task Last Updated: 12/16/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Klerman, Elizabeth B. M.D., Ph.D. / Brigham and Women's Hospital/Harvard Medical Center 
Address:  Department of Medicine 
Division of Sleep Medicine 
Boston , MA 02115-5804 
Email: ebklerman@hms.harvard.edu 
Phone: 617-732-8145  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical Center 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-HPF00405 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-HPF00405 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
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 04:We need to identify indicators of individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption, to aid with individualized countermeasure regimens, for autonomous, long duration and/or distance exploration missions (IRP Rev E)
(2) 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: Manned space flight requires crewmembers and ground-based staff to function at a high level of performance, often for long durations of time and without adequate opportunity for sleep, while operating sophisticated instruments. In space, sleep and circadian rhythms are disrupted. We have developed a mathematical model of the effects of light on the human circadian pacemaker that has been used successfully to design a pre-flight light exposure regimen as a countermeasure to the circadian misalignment associated with early morning launch times and slam-shifting of schedules present during missions. This mathematical model of light and the circadian system has been incorporated into our mathematical Circadian, Neurobehavioral Performance and Alertness (CPNA) Model so that we can now predict the effects of unusual light/dark and sleep/wake patterns on human performance and alertness at under any schedule on the ground or in space. This model is available in a user-friendly Circadian Performance Simulation Software (CPSS) package for use by NASA personnel, scientists, engineers, teachers, and others.

Our Specific Aims are:

Specific Aim 1: Develop and refine the current circadian, neurobehavioral performance and subjective alertness (CNPA) model with melatonin as a marker rhythm to accurately predict phase and amplitude of the circadian pacemaker.

Specific Aim 2: Refine and validate the current model by using data from chronic sleep restriction protocols.

Specific Aim 3: Refine the current model to incorporate wavelength of light information.

Specific Aim 4: Develop Schedule Assessment and Countermeasure Design Software using the amended CPNA model from Specific Aims 1, 2, and 3 to evaluate schedules and design and test appropriate countermeasures.

Our progress includes:

Specific Aim 1: We revised an existing mathematical model of the diurnal variations of plasma melatonin levels to include an effect of light suppression and a new compartment to model salivary melatonin levels. This revised model of melatonin has been incorporated into our CNPA model. CNPA can now provide an estimate of two melatonin phase markers, melatonin synthesis onset (Synon) and offset (Synoff), as well as melatonin amplitude and melatonin suppression by light. This revised model has been validated on several independent datasets to test predictions of circadian entrainment and phase-shift response. A manuscript of this work has been published.

Specific Aim 3: We have revised the circadian model to include effects of different wavelengths of light. The revised model assumes circadian photoreception acts via two processes: a synaptic process via the rods and cones of the visual system and a second process via the photopigment melanopsin, which is found in intrinsically photosensitive retinal ganglion cells. This revised model can predict the circadian phase-shifting responses to monochromatic light exposures at wavelengths of 460nm and 555nm, based on fluence-response data collected under another NSBRI project (Brainard, P.I.). and the response under polychromatic light exposure. A manuscript of this work is in preparation. The revised equations can easily be incorporated into CNPA model.

Specific Aim 4: We have developed a schedule/countermeasure program that allows a user to automatically design a mathematically optimal countermeasure schedule after a shift in sleep/wake schedule or during non-24-hour days. Our schedule building block technology is composed of two components: (1) building blocks as a flexible software technology that can be used to design any schedule, and (2) the Circadian Iterative Adjustment method that we developed to determine optimal countermeasure intensity and placement within a schedule. The work can be easily expanded to include other countermeasures, including pharmacologic agents. The software including this work has been demonstrated and taught to NASA and National Space Biomedical Research Institute (NSBRI) personnel so that they can use it to evaluate and design schedule alternatives for missions.

Other work: We began work on quantifying inter-individual differences in response to circadian phase-shifting stimuli and extended wake durations. One approach of quantifying inter-individual differences not currently addressed in the circadian literature is to evaluate inter-individual differences using the appropriate model structure for analyzing circadian data. To explore this line of research, we used a Bayesian network framework. Within this framework, a model is defined as a graph where arrows designate an association and the strength of the association is defined by a corresponding probability distribution. The benefit of the framework is that models are easily understandable by non-mathematician and that the probability distributions can be approximated by existing data. Using this method, we have shown that optimal model structure can vary by individual and that simple adjustment of parameters may not suffice to accurately predict inter-individual differences in performance after circadian phase shifts or during extended wake durations. This work has been presented at scientific meetings and a manuscript of this work is in progress.

We have also explored inter-individual differences in model parameters for extended wake durations without circadian disruption. We found a best-fit model to individual performance and alertness data using the CNPA model. We investigated inter-individual differences in parameter values of these best-fit models and the relationship of these values to individual subject characteristics, including age, gender, morningness-eveningness preference, habitual bedrest duration, and habitual sleep/wake times. Several important correlations between model parameters and subject characteristics have been found. These correlations indicate important trait-like differences in the underlying circadian and homeostatic processes represented by the model equations. This work has been presented at scientific meetings.

Research Impact/Earth Benefits: The development (1) of mathematical models of circadian rhythms, sleep, alertness, and performance and (2) of software based on these models that aid in schedule design can improve performance and alertness and thereby effectiveness and public safety for people who work at night, on rotating schedules, on non-24-hr schedules or extended duty schedules (pilots, train and truck drivers, shift workers, health care workers, public safety officers, etc.). Attempting to sleep at adverse circadian phases is difficult and sleep efficiency is poor. Attempting to work at adverse circadian phases and/or after long durations of time awake results in poor worker performance and productivity, increased accidents, and decreased safety for workers and for others affected by the workers. For example, the accidents at the Chernobyl and Three Mile Island nuclear reactors and the Exxon Valdez grounding all were partially caused by workers working at adverse circadian phases (~ 4 am). The mathematical modeling and the available Circadian Performance Simulation Software (CPSS) can be used to simulate and quantitatively evaluate different scenarios of sleep/wake schedules and light exposure to predict the resulting circadian phase and amplitude, subjective alertness, and performance. CPSS has been requested by members of academia, government, and industry (transportation (especially airline personnel), safety, medical, military). Its use could help produce improved schedules for working for people in space and on Earth.

The software also now includes optimal countermeasure design, so that countermeasures can be planned for times of predicted poor performance and alertness. The schedule/countermeasure design program allows a user to interactively design a schedule and to automatically design a mathematically optimal countermeasure regime (intensity, duration, and placement). This will be valuable to those who schedule people who work at night, on rotating schedules, on non-24-hr schedules, or extended duty schedules. Individuals can design countermeasures for their assigned work schedules so that their sleep and wake rhythms will be adjusted for optimal performance at desired times.

Using these tools, we have completed systematic simulation studies of the effect of circadian shifting on phase re-entrainment and performance recovery. For example, we examined the effect of light levels within cockpits and passenger cabins on circadian phase and performance during trans-meridian travel and polar flight paths for an article that appeared in The Wall Street Journal in 2004.

The mathematical modeling has been used for basic scientific research. Inclusion of mathematical models in the planning process to optimize measures to be studied in experimental protocols enables more efficient use of research resources and directs new research. If the modeling of existing data is unsatisfactory, then the model assumptions need to be revised. This revision may include identification of a new physiological process not previously described. As an example, an additional component (non-linear response to ocular light stimuli) was added to the circadian rhythms component of our mathematical model to describe data collected in our clinical research facilities, even before the anatomic and physiologic basis of this component of the mathematical model was found. Later experiments validated this mathematical finding. The mathematical model had demonstrated that previously unknown additional physiological processes were involved.

The modeling work on the differential effects of different wavelength of light on circadian rhythms and alertness can be used for designing artificial (indoor) lighting systems that can maximize circadian or alerting response.

The mathematical modeling efforts and CPSS have also been used in educational programs and in the popular press to teach students and teachers about circadian rhythms and sleep and their effects on alertness and performance.

Task Progress & Bibliography Information FY2008 
Task Progress: We developed and refined our current mathematical model of circadian rhythms to incorporate melatonin as a marker rhythm. We used an existing physiologically based mathematical model of the diurnal variations in plasma melatonin levels. The revised model can predict melatonin amplitude, markers of melatonin phase (melatonin synthesis onset (Synon) and synthesis offset (Synoff)), melatonin suppression by light, and salivary melatonin concentrations. Our model has been validated on several independent data sets. A manuscript of this work has been published.

We incorporated wavelength sensitivity into our current mathematical model. We have revised the light input to our model from lux to an irradiance measure (microW/cm2) for both polychromatic and monochromatic light exposures. We have developed a two-channel photoreceptor model, in which one channel is driven by rod/cone input and the other channel is driven by a melanopsin input with peak sensitivity in the short wavelength range (~480nm). Our model can predict the response of the circadian pacemaker to 1-pulse light exposures of 460nm and 555nm at different irradiances to generate fluence-response curves of circadian phase-shifts to polychromatic light. This work has been presented at scientific meetings. A manuscript of this work is in preparation.

We developed schedule assessment and countermeasure design software. We have developed a schedule/countermeasure design program that allows a user to interactively design a schedule and to automatically design a mathematically optimal countermeasure regime (intensity, duration, and placement). We have demonstrated this tool to NASA personnel. We have substantially redesigned the user interface for CPSS, the software implementation of our mathematical model, based on feedback from NASA users and operational requirements. We have shown that our methods can be used to design a variety of schedules and countermeasures relevant to NASA operations including shifting sleep wake (slam shifting), sleep deprivation, and non-24 hour schedules. This work has been presented at scientific meetings. A manuscript is in progress.

We have begun to explore inter-individual differences in performance. (1) We have begun developing methodologies for determining how optimal model structure may differ by individual. The benefit of the framework is that models are easily understandable by non-mathematicians and that the probability distributions can be approximated by existing data. (2) We have conducted data analysis to quantify differences in model parameter values and we have correlated these model parameter differences with individual characteristics such as age, gender, morningness-eveningness, habitual bedrest duration, and habitual sleep/wake times. We have demonstrated the trait-like characteristics in the robustness of parameters associated with the homeostatic process under experimental light interventions. This work has been presented at scientific meetings.

Bibliography Type: Description: (Last Updated: 02/16/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Dean DA, Wyatt JK, Dijk D, Czeisler CA, Klerman EB. "Quantifying practice effects within groups and individuals: examples from a month long forced desynchrony protocol." Sleep 2008, Baltimore, MD, June 7-12, 2008.

Sleep. 2008;31 Suppl:A54. , Jun-2008

Abstracts for Journals and Proceedings St. Hilaire MA, Klerman EB. "Robustness of parameters in a circadian and neurobehavioral performance and alertness model suggest trait-like characteristics of the homestatic process." Sleep 2008, Baltimore, MD, June 7-12, 2008.

Sleep. 2008;31 Suppl:A117. , Jun-2008

Abstracts for Journals and Proceedings Dean DA 2nd, Nguyen DP, Schmid CH, Adler GK, Klerman EB, Brown EN. "Computing cortisol secretion times with a biophysical model." 11th Biennial Meeting of the Society for Research in Biological Rhythms, Destin, FL, May 17-21, 2008.

Program and Abstracts, 11th Biennial Meeting of the Society for Research in Biological Rhythms, Destin, FL, May 17-21, 2008. p. 135-136. , May-2008

Articles in Peer-reviewed Journals Dean DA 2nd, Adler GK, Nguyen DP, Klerman EB. "Biological time series analysis using a context free language: applicability to pulsatile hormone data." PLoS One. 2014 Sep 3;9(9):e104087. eCollection 2014. http://dx.doi.org/10.1371/journal.pone.0104087 ; PubMed PMID: 25184442; PubMed Central PMCID: PMC4153563 , Sep-2014
Articles in Peer-reviewed Journals St Hilaire MA, Gronfier C, Zeitzer JM, Klerman EB. "A physiologically based mathematical model of melatonin including ocular light suppression and interactions with the circadian pacemaker." J Pineal Res. 2007 Oct;43(3):294-304. http://dx.doi.org/10.1111/j.1600-079X.2007.00477.x ; PMID: 17803528 , Oct-2007
Articles in Peer-reviewed Journals St Hilaire MA, Klerman EB, Khalsa SB, Wright KP Jr, Czeisler CA, Kronauer RE. "Addition of a non-photic component to a light-based mathematical model of the human circadian pacemaker." J Theor Biol. 2007 Aug 21;247(4):583-99. http://dx.doi.org/10.1016/j.jtbi.2007.04.001 ; PMID: 17531270 , Aug-2007
Project Title:  Mathematical Modeling of Circadian/Performance Countermeasures Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 06/01/2004  
End Date: 05/31/2008  
Task Last Updated: 10/18/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Klerman, Elizabeth B. M.D., Ph.D. / Brigham and Women's Hospital/Harvard Medical Center 
Address:  Department of Medicine 
Division of Sleep Medicine 
Boston , MA 02115-5804 
Email: ebklerman@hms.harvard.edu 
Phone: 617-732-8145  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical Center 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-HPF00405 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-HPF00405 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
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 04:We need to identify indicators of individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption, to aid with individualized countermeasure regimens, for autonomous, long duration and/or distance exploration missions (IRP Rev E)
(2) 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: Manned space flight requires crewmembers and ground-based staff to function at a high level of cognitive performance and vigilance, often for long durations of time and without opportunity for rest or sleep, while operating and monitoring sophisticated instrumentation. Due to the unusual light/dark patterns and sleep/wake schedules to which they are exposed, astronauts may frequently experience circadian misalignment, during which their circadian rhythms are not appropriately synchronized with their work schedules such that both their waketime performance and alertness and their ability to sleep can be severely compromised.

We have developed a mathematical model of the effects of light on the human circadian pacemaker that has been used successfully to design a pre-flight light exposure regimen as a countermeasure to the circadian misalignment associated with early morning launch times often necessary for space shuttle flights. This mathematical model of light and the circadian system has been incorporated into our mathematical Circadian, Neurobehavioral Performance and Subjective Alertness Model so that we can now predict the effects of unusual light/dark and sleep/wake patterns on human performance at the time of launch. This model is available in a user-friendly Circadian Performance Simulation Software package for use by NASA personnel, scientists, engineers, teachers, and others.

Our Specific Aims are:

Specific Aim 1: Develop and refine the current circadian, neurobehavioral performance and subjective alertness model with melatonin as a marker rhythm to accurately predict phase and amplitude of the circadian pacemaker.

Specific Aim 2: Refine and validate the current model by using data from chronic sleep restriction protocols.

Specific Aim 3: Refine the current model to incorporate wavelength of light information.

Specific Aim 4: Develop Schedule Assessment and Countermeasure Design Software using the amended CPNA model from Specific Aims 1, 2 and 3 to evaluate schedules and design and test appropriate countermeasures.

Our progress on these aims includes:

Specific Aim 1: We revised an existing mathematical model of the diurnal variations of plasma melatonin levels to include an effect of light and incorporated this into our model. This model provides an estimate of two melatonin phase markers, melatonin synthesis onset (Synon) and offset (Synoff), as well as melatonin amplitude and melatonin suppression by light. The phase relationships between Synon/Synoff and CBTmin have been determined and incorporated into our mathematical model. The revised model has been tested against experimental melatonin data in which subjects were exposed to 1-pulse of continuous bright light, continuous dim light or a pattern of intermittent bright and dim light. This model will be validated on several independent datasets to test predictions of circadian entrainment and phase-shift response.

Specific Aim 3: We began to revise the light input to our model from lux to an irradiance measure of photons/cm2/sec for both polychromatic and monochromatic light exposures. We explored the physiological basis of a two-channel photoreceptor model, in which one channel is driven by rod/cone input and the other channel is driven by a melanopsin input with peak sensitivity at short wavelengths.~464nm. We also analyzed the effects of pupil diameter on circadian response.

Specific Aim 4: Over the last year we have developed a schedule/countermeasure design prototype program that allows a user to interactively design a schedule and to automatically design a countermeasure regime. Mathematical optimization of schedule design has been added to the program. We have begun transitioning our previously developed schedule building blocks into prototype scheduling applications with the goal of building a tool that will facilitate the use of our models by NASA personnel to evaluate and design mission alternatives. As we reported previously our schedule building block technology is composed of two sections. The building blocks are a flexible software technology that can be used to design any schedule. The second component is the Circadian Iterative Adjustment method that we developed to determine optimal countermeasure placement within a schedule. Used together, we have shown that our methods can be used to design a variety of schedules relevant to NASA operations including shifting sleep-wake (slam shifting) and non-24 hour schedules. We have begun expanding our framework to include methods that determine the minimum amount of light required to maintain entrainment. Future work will involve expanding our prototype to evaluate a wider range of protocols and countermeasures, including pharmacologic agents.

Other work: An aspect of individual difference not currently addressed in the circadian literature is to evaluate differences in the appropriate model structure for analyzing circadian data. Therefore, we have begun developing methodologies for determining how optimal model structure may differ by individual. To explore this line of research we used a Bayesian network framework. Within this framework, a model is defined as a graph where arrows designate an association and the strength of the association is defined by a corresponding probability distribution. The benefit of the framework is that models are easily understandable by non-mathematician and that the probability distributions can be approximated by existing data. Our initial results are promising and have shown that optimal model structure can vary by individual.

Research Impact/Earth Benefits: This research focuses on the further development of mathematical models and software that aid in schedule design to improve performance and thereby public safety for people who work at night, on rotating schedules, on non-24 h schedules or extended duty schedules (pilots, train and truck drivers, shift workers, health care workers, public safety officers). Attempting to work at adverse circadian phases and/or after long durations of time awake causes poor worker performance and productivity, increased accidents and decreased safety for workers and for others affected by the workers. For example, the Chernobyl, Three Mile Island, and the Exxon Valdez disasters were all were partially caused by workers attempting to perform at adverse circadian phases (~ 4 am). The mathematical modeling and the available Circadian Performance Simulation Software (CPSS) can be used to simulate different scenarios of sleep/wake schedules and light exposure to predict the resulting subjective alertness and neurobehavioral performance. CPSS has been used by members of academia, government and industry.

We also examined the effect of light levels within cockpits and passenger cabins on circadian phase and performance during trans-meridian travel and polar flight paths for an article that appeared in The Wall Street Journal.

The mathematical modeling has been used to design new research protocols. Using mathematical models to optimize measures to be studied in the protocol enables more efficient use of research resources. The modeling work can also direct new research in physiology. If the modeling of existing data is unsatisfactory, then the model assumptions need to be revised. This revision may include identification of physiological process not previously described.

The mathematical modeling and CPSS have also been used in educational programs and in the popular press to teach students and teachers about circadian rhythms and sleep and their effects on alertness and performance.

Task Progress & Bibliography Information FY2007 
Task Progress: Specific Aim 1 is to develop and refine our current model to incorporate melatonin as a marker rhythm. We have incorporated an existing physiologically-based mathematical model of the diurnal variations in plasma melatonin levels into our mathematical circadian rhythms model. The revised model can predict melatonin amplitude, markers of melatonin phase (melatonin synthesis onset and synthesis offset), melatonin suppression by light, and salivary melatonin concentrations. Our model has been validated on several independent data sets. This work has been presented at scientific meetings. A manuscript has been submitted for publication and is under review.

Specific Aim 3 is to incorporate wavelength sensitivity into our current model. We have begun to revise the light input to our model from lux to an irradiance measure (photons/cm2/sec) for both polychromatic and monochromatic light exposures. We explored the physiological basis of a two-channel photoreceptor model, in which one channel is driven by rod/cone input and the other channel is driven by a melanopsin input with peak sensitivity in the short wavelength range. We have also analyzed the effects of pupil diameter on circadian response. We started to analyze the effects of the aging of the lens of light transmission and we have begun to incorporate new 460nm and 555nm fluence response data. This work has been presented at a scientific meeting.

Specific Aim 4 is to develop Schedule Assessment and Countermeasure Design Software. Over the last year we have developed a schedule/countermeasure design prototype program that allows a user to interactively design a schedule and to automatically design a countermeasure regime (intensity, duration and placement). We have begun transitioning our previously developed schedule building blocks into prototype scheduling applications to build a tool that will facilitate the use of our models by NASA personnel. Used together we have shown that our methods can be used to design a variety of schedules and countermeasures relevant to NASA operations including shifting sleep wake (slam shifting) and non-24 hour schedules. This work has been presented at scientific meetings. A manuscript is in progress.

By request of the reviewers, we have begun to explore inter-individual differences in performance. (1) We have begun developing methodologies for determining how optimal model structure may differ by individual. The benefit of the framework is that models are easily understandable by non-mathematicians and that the probability distributions can be approximated by existing data. Our initial results have shown that optimal model structure can vary by individual. (2) We have begun data analysis to quantify differences in model parameter values and correlate these with differences between individuals such as age, gender, morningness-eveningness, habitual bedrest duration and habitual sleep/wake times. This work has been presented at a scientific meeting.

Bibliography Type: Description: (Last Updated: 02/16/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings St Hilarie M, Klerman EB. "A tool to analyze melatonin phase and amplitude using a physiologically based model of melatonin." Sleep 2006, 20th Anniversary Meeting of the Association of Professional Sleep Societies, Salt Lake City, UT, June 17-22, 2006.

Sleep. 2006;29(Suppl):A53-4. , Jun-2006

Abstracts for Journals and Proceedings St Hilaire MA, Klerman EB. "Inter-individual variability in the parameters of a mathematical model of neurobehavioral performance and alertness." Sleep 2007, Annual Meeting, Minneapolis, MN, June 9-14, 2007.

Sleep 2007;30(Suppl):A52. , Jun-2007

Articles in Peer-reviewed Journals Dean DA 2nd, Fletcher A, Hursh SR, Klerman EB. "Developing mathematical models of neurobehavioral performance for the “real world“." J Biol Rhythms. 2007 Jun;22(3):246-58. Review. PMID: 17517914 , Jun-2007
Articles in Peer-reviewed Journals Kronauer RE, Gunzelmann G, Van Dongen HP, Doyle FJ 3rd, Klerman EB. "Uncovering physiologic mechanisms of circadian rhythms and sleep/wake regulation through mathematical modeling." J Biol Rhythms. 2007 Jun;22(3):233-45. Review. PMID: 17517913 , Jun-2007
Articles in Peer-reviewed Journals Klerman EB, Hilaire MS. "On mathematical modeling of circadian rhythms, performance, and alertness." J Biol Rhythms. 2007 Apr;22(2):91-102. Review. http://dx.doi.org/10.1177/0748730407299200 ; PMID: 17440211 , Apr-2007
Articles in Peer-reviewed Journals Indic P, Gurdziel K, Kronauer RE, Klerman EB. "Development of a two-dimension manifold to represent high dimension mathematical models of the intracellular Mammalian circadian clock." J Biol Rhythms. 2006 Jun;21(3):222-32. PMID: 16731662 , Jun-2006
Project Title:  Mathematical Modeling of Circadian/Performance Countermeasures Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 06/01/2004  
End Date: 05/31/2008  
Task Last Updated: 01/08/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Klerman, Elizabeth B. M.D., Ph.D. / Brigham and Women's Hospital/Harvard Medical Center 
Address:  Department of Medicine 
Division of Sleep Medicine 
Boston , MA 02115-5804 
Email: ebklerman@hms.harvard.edu 
Phone: 617-732-8145  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical Center 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-HPF00405 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-HPF00405 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
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 04:We need to identify indicators of individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption, to aid with individualized countermeasure regimens, for autonomous, long duration and/or distance exploration missions (IRP Rev E)
(2) 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: Manned space flight requires crewmembers and ground-based staff to function at a high level of cognitive performance and vigilance, often for long durations of time and without opportunity for rest or sleep, while operating and monitoring sophisticated instrumentation. Due to the unusual light/dark patterns and sleep/wake schedules to which they are exposed, astronauts may frequently experience circadian misalignment, during which their circadian rhythms are not appropriately synchronized with their work schedules such that both their waketime performance and alertness and their ability to sleep can be severely compromised.

We have developed a mathematical model of the effects of light on the human circadian pacemaker that has been used successfully to design a pre-flight light exposure regimen as a countermeasure to the circadian misalignment associated with early morning launch times often necessary for space shuttle flights. This mathematical model of light and the circadian system has been incorporated into our mathematical Circadian, Neurobehavioral Performance and Subjective Alertness Model so that we can now predict the effects of unusual light/dark and sleep/wake patterns on human performance at the time of launch. This model is available in a user-friendly Circadian Performance Simulation Software package for use by NASA personnel, scientists, engineers, teachers, and others.

Our Specific Aims are:

Specific Aim 1: Develop and refine the current circadian, neurobehavioral performance and subjective alertness model with melatonin as a marker rhythm to accurately predict phase and amplitude of the circadian pacemaker.

Specific Aim 2: Refine and validate the current model by using data from chronic sleep restriction protocols.

Specific Aim 3: Refine the current model to incorporate wavelength of light information.

Specific Aim 4: Develop Schedule Assessment and Countermeasure Design Software using the amended CPNA model from Specific Aims 1, 2 and 3 to evaluate schedules and design and test appropriate countermeasures.

Our progress on these aims includes:

Specific Aim 1: We revised an existing mathematical model of the diurnal variations of plasma melatonin levels to include an effect of light and incorporated this into our model. This model provides an estimate of two melatonin phase markers, melatonin synthesis onset (Synon) and offset (Synoff), as well as melatonin amplitude and melatonin suppression by light. The phase relationships between Synon/Synoff and CBTmin have been determined and incorporated into our mathematical model. The revised model has been tested against experimental melatonin data in which subjects were exposed to 1-pulse of continuous bright light, continuous dim light or a pattern of intermittent bright and dim light. This model will be validated on several independent datasets to test predictions of circadian entrainment and phase-shift response.

Specific Aim 3: We began to revise the light input to our model from lux to an irradiance measure of photons/cm2/sec for both polychromatic and monochromatic light exposures. We explored the physiological basis of a two-channel photoreceptor model, in which one channel is driven by rod/cone input and the other channel is driven by a melanopsin input with peak sensitivity at short wavelengths.~464nm. We also analyzed the effects of pupil diameter on circadian response.

Specific Aim 4: Over the last year we have developed a schedule/countermeasure design prototype program that allows a user to interactively design a schedule and to automatically design a countermeasure regime. Mathematical optimization of schedule design has been added to the program. We have begun transitioning our previously developed schedule building blocks into prototype scheduling applications with the goal of building a tool that will facilitate the use of our models by NASA personnel to evaluate and design mission alternatives. As we reported previously our schedule building block technology is composed of two sections. The building blocks are a flexible software technology that can be used to design any schedule. The second component is the Circadian Iterative Adjustment method that we developed to determine optimal countermeasure placement within a schedule. Used together, we have shown that our methods can be used to design a variety of schedules relevant to NASA operations including shifting sleep-wake (slam shifting) and non-24 hour schedules. We have begun expanding our framework to include methods that determine the minimum amount of light required to maintain entrainment. Future work will involve expanding our prototype to evaluate a wider range of protocols and countermeasures, including pharmacologic agents.

Other work: An aspect of individual difference not currently addressed in the circadian literature is to evaluate differences in the appropriate model structure for analyzing circadian data. Therefore, we have begun developing methodologies for determining how optimal model structure may differ by individual. To explore this line of research we used a Bayesian network framework. Within this framework, a model is defined as a graph where arrows designate an association and the strength of the association is defined by a corresponding probability distribution. The benefit of the framework is that models are easily understandable by non-mathematician and that the probability distributions can be approximated by existing data. Our initial results are promising and have shown that optimal model structure can vary by individual.

Research Impact/Earth Benefits: This work advances science and applications in other areas besides our specific aims.

This research focuses on further development of mathematical models and software that aid in schedule design to improve performance and thereby public safety for people who work at night, on rotating schedules, on non-24 h schedules or extended duty schedules. (pilots, train and truck drivers, shift workers, health care workers, public safety officers, etc.). The mathematical modeling and the available CPSS software can be used to simulate different scenarios of sleep/wake schedules and light exposure and predict the resulting circadian phase and amplitude, subjective alertness and neurobehavioral performance. Attempting to sleep at adverse circadian phases is difficult and the sleep efficiency is poor. Attempting to work at adverse circadian phases and/or after long durations of time awake causes poor worker performance and productivity, increased accidents and decreased safety for workers and for others affected by the workers. For example, the accidents at Chernobyl and Three Mile Island nuclear reactors and the Exxon Valdez grounding all were partially caused by workers attempting to perform at adverse circadian phases (~ 4 am). CPSS has been requested by members of academia, government and industry. Its use could help produce improved schedules for working. The development of optimal and interactive scheduling tools will also be applicable to earth-based industry and government.

We have completed systematic simulation studies of the effect of circadian shifting on phase re-entrainment and performance recovery. For example, we examined the effect of light levels within cockpits and passenger cabins on circadian phase and performance during trans-meridian travel and polar flight paths for an article that appeared in The Wall Street Journal.

The mathematical modeling can and has been used to design new research protocols. Inclusion of mathematical models in the process to optimize measures to be studied in the protocol enables more efficient use of research resources.

The modeling work can also direct new research.If the modeling of existing data is unsatisfactory, then the model assumptions need to be revised. This revision may include identification of a new physiological process not previously described. As an example, Process L was added to our mathematical model to describe data collected in the BWH laboratory. Only recently has the anatomic and physiologic basis of Process L in our mathematical model been found.

The mathematical modeling efforts and CPSS have been used in educational programs and in the popular press to teach students and teachers about circadian rhythms and sleep and their effects on alertness and performance.

Task Progress & Bibliography Information FY2006 
Task Progress: Specific Aim 1 is to develop and refine our current model to incorporate melatonin as a marker rhythm. We have incorporated an existing physiologically-based mathematical model of the diurnal variations in plasma melatonin levels into our model to predict melatonin synthesis onset (Synon) and synthesis offset (Synoff) as two markers of melatonin phase. The phase relationships between Synon, Synoff and the fit minimum of Core Body Temperature CBTmin, another accepted marker of circadian rhythms, have been determined. The revised model can predict melatonin amplitude, melatonin suppression by light and phase-shifting of melatonin rhythms at bright light levels. Our model has been tested with experimental melatonin data in which subjects were exposed to 1-pulse of continuous bright light, continuous dim light or a pattern of intermittent bright and dim light.

Specific Aim 3 is to incorporate wavelength sensitivity into our current model. We have begun to revise the light input to our model from lux to an irradiance measure (photons/cm2/sec) for both polychromatic and monochromatic light exposures. We explored the physiological basis of a two-channel photoreceptor model, in which one channel is driven by rod/cone input and the other channel is driven by a melanopsin input with peak sensitivity in the short wavelength range. We have also analyzed the effects of pupil diameter on circadian response. This model has been tested with data from a 460nm fluence response curve and will be validated on future datasets.

Specific Aim 4 is to develop Schedule Assessment and Countermeasure Design Software. Over the last year we have developed a schedule/countermeasure design prototype program that allows a user to interactively design a schedule and to automatically design a countermeasure regime. We have begun transitioning our previously developed schedule building blocks into prototype scheduling applications to build a tool that will facilitate the use of our models by NASA personnel. Used together we have shown that our methods can be used to design a variety of schedules relevant to NASA operations including shifting sleep wake (slam shifting) and non-24 hour schedules. We have also begun expanding our framework to include methods that determine the minimum amount of light required to maintain entrainment.

By request of the reviewers, we have began to explore inter-individual differences in performance. An aspect of individual difference not currently addressed in the circadian literature is to evaluate differences in the appropriate model structure. Consequently, we have begun developing methodologies for determining how optimal model structure may differ by individual. The benefit of the framework is that models are easily understandable by non-mathematicians and that the probability distributions can be approximated by existing data. Our initial results are promising and have shown that optimal model structure can vary by individual.

Bibliography Type: Description: (Last Updated: 02/16/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Dean DA 2nd, Klerman EB. "Optimum scheduling of countermeasures." Society for Industrial and Applied Mathematics - Society for Mathematical Biology (SIAM-SMB) Joint Session on the Life Sciences, Raleigh, NC, July 31-August 4, 2006.

Society for Industrial and Applied Mathematics - Society for Mathematical Biology (SIAM-SMB) Joint Session on the Life Sciences, in press June 2006. , Jun-2006

Abstracts for Journals and Proceedings Dean DA 2nd, Forger DB, Klerman EB. "Designing optimal light intervention schedules for experimental and operational settings." Associated Professional Sleep Societies 19th Annual Meeting, Denver, Colorado, June 18-23, 2005.

Sleep. 2005;28A:A69. , Jun-2005

Abstracts for Journals and Proceedings St Hilarie M, Gronfier C, Klerman EB. "Addition of a light effect to a physiologically-based model of melatonin." SLEEP 2006: 20th Anniversary Meeting of the Associated Professional Sleep Societies, Salt Lake City, Utah, June 17 - 22, 2006.

Sleep. In Press, 2006. , Apr-2006

Abstracts for Journals and Proceedings St Hilaire MA, Klerman EB, Lockley SW, Brainard GC, Kronauer RE. "Revision of a mathematical model of circadian photic resetting to incorporate spectral sensitivity." Associated Professional Sleep Societies 19th Annual Meeting, Denver, Colorado, June 18-23, 2005.

Sleep. 2005;28A:A56. , Jun-2005

Abstracts for Journals and Proceedings Dean DA 2nd, Barger LK, Livingston G, Klerman EB. "Understanding Bayesian network sensitivity in classifiers derived from human experimental data." Life Science Society Computational Systems Bioinformatics Conference. Stanford, CA, 2006 August.

Life Science Society Computational Systems Bioinformatics Conference. Submitted for Publication, 2006 August. , Aug-2006

Abstracts for Journals and Proceedings Dean DA 2nd, Barger LK, Livingston G, Klerman EB. "Using Bayesian Networks to understand individual differences that affect the use of actigraphy as a predictor of sleep." SLEEP 2006: 20th Anniversary Meeting of the Associated Professional Sleep Societies, Salt Lake City, Utah, June 17 - 22, 2006.

Sleep. In Press, 2006. , Apr-2006

Abstracts for Journals and Proceedings Dean DA 2nd, Klerman EB. "Using domain specific information to design optimal circadian adjustment schedules." 35th International Congress of Physiological Sciences, March 2005.

35th International Congress of Physiological Sciences, 2005. , Mar-2005

Abstracts for Journals and Proceedings Klerman EB, Dean DA 2nd, Gurdziel K, St Hilaire M, Kronauer RE. "Mathematical modeling of human circadian physiology applications in space and for the general public." 15th International Academy of Astronautics Humans in Space Symposium, Graz, Austria, 2005 May.

15th International Academy of Astronautics Humans in Space Symposium, 2005 May. , May-2005

Abstracts for Journals and Proceedings Klerman EB, Dean DA 2nd, Gurdziel K, St Hilaire M, Kronauer RE. "Mathematical modeling of human circadian physiology." Habitation 2006 Conference, Orlando, FL, 2006 February.

Habitation 2006;10(3-4):197-8. , Feb-2006

Abstracts for Journals and Proceedings St Hilarie M, Klerman EB. "A tool to analyze melatonin phase and amplitude using a physiologically based model of melatonin." SLEEP 2006: 20th Anniversary Meeting of the Associated Professional Sleep Societies, Salt Lake City, Utah, June 17 - 22, 2006.

Sleep. In Press, 2006. , Apr-2006

Abstracts for Journals and Proceedings Thompson P, Klerman EB, Dean DA 2nd. "Identifying two-process performance models using limited data." Society for Industrial and Applied Mathematics - Society for Mathematical Biology (SIAM-SMB) Joint Session on the Life Sciences, Raleigh, NC, July 31-August 4, 2006.

Society for Industrial and Applied Mathematics - Society for Mathematical Biology (SIAM-SMB) Joint Session on the Life Sciences. In Press, June 2006. , Jun-2006

Articles in Peer-reviewed Journals Indic P, Gurdziel K, Kronauer RE, Klerman EB. "Development of a two-dimension manifold to represent high dimension mathematical models of the intracellular Mammalian circadian clock." J Biol Rhythms. 2006 Jun;21(3):222-32. PMID: 16731662 , Jun-2006
Articles in Peer-reviewed Journals Klerman EB. "Clinical aspects of human circadian rhythms." J Biol Rhythms. 2005 Aug;20(4):375-86. Review. PMID: 16077156 , Aug-2005
Awards Dean DA 2nd. "Mr. Dean (graduate student) received Travel Sponsorship to attend Case Studies in Bayesian Statistics 8, a nationally recognized conference that reviews applications of Bayesian statistics, September 2005." Sep-2005
Awards Dean DA 2nd. "Mr. Dean (graduate student) designated a Partners Healthcare scholar and awarded an Association of Multi-cultural Members at Partners Educational Scholarship, 2005." May-2005
Project Title:  Mathematical Modeling of Circadian/Performance Countermeasures Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 06/01/2004  
End Date: 05/31/2008  
Task Last Updated: 01/04/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Klerman, Elizabeth B. M.D., Ph.D. / Brigham and Women's Hospital/Harvard Medical Center 
Address:  Department of Medicine 
Division of Sleep Medicine 
Boston , MA 02115-5804 
Email: ebklerman@hms.harvard.edu 
Phone: 617-732-8145  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical Center 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-HPF00405 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-HPF00405 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
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 04:We need to identify indicators of individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption, to aid with individualized countermeasure regimens, for autonomous, long duration and/or distance exploration missions (IRP Rev E)
(2) 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: Objective neurobehavioral performance, subjective alertness and mood, and sleep are critically important to astronaut health and the success of space missions. Neurobehavioral performance, alertness and mood are affected by circadian rhythms, homeostatic sleep regulation, sleep inertia, and interactions of these processes. Countermeasures to ensure optimal neurobehavioral performance, subjective alertness, and quality sleep therefore are required for space missions, during which circadian rhythms and sleep are disrupted. We have developed and validated a mathematical model of the human circadian pacemaker and neurobehavioral performance and alertness that includes these three key processes. A previous version of this model, with a focus on light-dark scheduling, has been used by NASA to design astronaut pre-launch schedules. We propose to extend this model to be useful in testing emerging countermeasures for neurobehavioral problems due to space missions. Since the potential countermeasures, singly or in combination, are different for each crewmember on each mission, it would be difficult, time consuming and expensive to conduct all the experimental protocols required to mimic all combinations of possible situations and proposed countermeasures received by any given crewmember. A mathematical model, on the other hand, is a powerful tool for the design of countermeasures because there are no limits to the number of patterns of astronaut light exposure or sleep/wake schedules and countermeasures that can be efficiently assessed. Our model is available for use via a user-friendly software program for users to test countermeasures. We propose to extend the current model so that it will include: (1) melatonin markers of circadian amplitude and phase; (2) chronic sleep restriction and its effects on neurobehavioral performance; and (3) the effects of specific wavelengths of light on the circadian pacemaker. Then we will amend our current software to include schedule assessment and countermeasure design components. We will cooperate with other members of the selected NSBRI Human Performance Factors team: simulating their protocols, modeling the data and adjusting and re-validating the model as required. The mathematical modeling of circadian rhythms, sleep, subjective alertness and mood, and neurobehavioral performance is a vital and effective component of design and testing of potential countermeasures for optimal astronaut health and mission success.

Our Specific Aims are: Specific Aim 1: Develop and refine the current circadian, neurobehavioral performance and subjective alertness (CNPA) model with melatonin as a marker rhythm to accurately predict phase and amplitude of the circadian pacemaker (Countermeasure Readiness Level (CRL) 4) Specific Aim 2: Refine and validate the current CNPA model by using data from chronic sleep restriction protocols (CRL 4) Specific Aim 3: Refine the current CNPA model to incorporate wavelength of light information (CRL 3) Specific Aim 4: Develop Schedule Assessment and Countermeasure Design Software using the amended CPNA model from Specific Aims 1, 2 and 3 to evaluate schedules and design and test appropriate countermeasures (CRL 5) .

Research Impact/Earth Benefits: This work advances science and applications in other areas besides our specific aims. This research focuses on the further development of mathematical models and software that aid in schedule design to improve performance and thereby public safety for people who work at night, on rotating schedules, on non-24 h schedules or extended duty schedules. (pilots, train and truck drivers, shift workers, health care workers, public safety officers, etc.). The mathematical modeling and the available CPSS software can be used to simulate different scenarios of sleep/wake schedules and light exposure and predict the resulting circadian phase and amplitude, subjective alertness and neurobehavioral performance. Attempting to sleep at adverse circadian phases is difficult and the sleep efficiency is poor. Attempting to work at adverse circadian phases and/or after long durations of time awake causes poor worker performance and productivity, increased accidents and decreased safety for workers and for others affected by the workers. For example, the accidents at Chernobyl and Three Mile Island nuclear reactors and the Exxon Valdez grounding all were partially caused by workers attempting to perform at adverse circadian phases (~ 4 am). CPSS has been requested by members of academia, government and industry. Its use could help produce improved schedules for working. The development of optimal and interactive scheduling tools will also be applicable to earth-based industry and government.

Task Progress & Bibliography Information FY2005 
Task Progress: Specific Aims 1, 3, 4 plus the requested work on inter-individual differences are currently in progress. For Specific Aim 1, we have begun to test a physiologic-based mathematical model of plasma melatonin levels on existing datasets. For Specific Aim 3, a new component has been added to the current model that incorporates wavelength of light information. This new model is capable of predicting the effect of wavelength on the phase-shifting response of the human circadian pacemaker using wavelength and lux as light inputs. For Specific Aim 4, we have developed a methodology for using mathematical models of the effect of light on the circadian pacemaker to automatically generate optimal circadian adjustment schedules that can be applied to our existing user-friendly Circadian Performance Simulation Software (CPSS). For the inter-individual work, which was not in our original proposal, we have begun work to include inter-individual differences in our model. We have begun to look at different methods to incorporate these differences. We are currently working with Dr. Laura Barger, who has worked on both NSBRI and NASA projects, to develop methods to evaluate actigraphy data collected in space and on the ground. Pre-flight prediction of the circadian load of the sleep-wake shift, as determined by our models, is provided prior to launch. Actigraphy data will provide information about the individual sleep/wake and light exposure of each individual; this information can be used to target the model simulations for each individuals.

Bibliography Type: Description: (Last Updated: 02/16/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Indic P, Forger DB, St Hilaire MA, Dean DA 2nd, Brown EN, Kronauer RE, Klerman EB, Jewett ME. "Comparison of amplitude recovery dynamics of two limit cycle oscillator models of the human circadian pacemaker." Chronobiol Int. 2005;22(4):613-29. PMID: 16147894 , Sep-2005
Project Title:  Mathematical Modeling of Circadian/Performance Countermeasures Reduce
Fiscal Year: FY 2004 
Division: Human Research 
Research Discipline/Element:
HRP BHP:Behavioral Health & Performance (archival in 2017)
Start Date: 06/01/2004  
End Date: 05/31/2008  
Task Last Updated: 12/01/2005 
Download report in PDF pdf
Principal Investigator/Affiliation:   Klerman, Elizabeth B. M.D., Ph.D. / Brigham and Women's Hospital/Harvard Medical Center 
Address:  Department of Medicine 
Division of Sleep Medicine 
Boston , MA 02115-5804 
Email: ebklerman@hms.harvard.edu 
Phone: 617-732-8145  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical Center 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. NCC 9-58-HPF00405 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-HPF00405 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
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 04:We need to identify indicators of individual vulnerabilities and resiliencies to sleep loss and circadian rhythm disruption, to aid with individualized countermeasure regimens, for autonomous, long duration and/or distance exploration missions (IRP Rev E)
(2) 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: Objective neurobehavioral performance, subjective alertness and mood, and sleep are critically important to astronaut health and the success of space missions. Neurobehavioral performance, alertness and mood are affected by circadian rhythms, homeostatic sleep regulation, sleep inertia, and interactions of these processes. Countermeasures to ensure optimal neurobehavioral performance, subjective alertness, and quality sleep therefore are required for space missions, during which circadian rhythms and sleep are disrupted. We have developed and validated a mathematical model of the human circadian pacemaker and neurobehavioral performance and alertness that includes these three key processes. A previous version of this model, with a focus on light-dark scheduling, has been used by NASA to design astronaut pre-launch schedules. We propose to extend this model to be useful in testing emerging countermeasures for neurobehavioral problems due to space missions. Since the potential countermeasures, singly or in combination, are different for each crewmember on each mission, it would be difficult, time consuming and expensive to conduct all the experimental protocols required to mimic all combinations of possible situations and proposed countermeasures received by any given crewmember. A mathematical model, on the other hand, is a powerful tool for the design of countermeasures because there are no limits to the number of patterns of astronaut light exposure or sleep/wake schedules and countermeasures that can be efficiently assessed. Our model is available for use via a user-friendly software program for users to test countermeasures. We propose to extend the current model so that it will include: (1) melatonin markers of circadian amplitude and phase; (2) chronic sleep restriction and its effects on neurobehavioral performance; and (3) the effects of specific wavelengths of light on the circadian pacemaker. Then we will amend our current software to include schedule assessment and countermeasure design components. We will cooperate with other members of the selected NSBRI Human Performance Factors team: simulating their protocols, modeling the data and adjusting and re-validating the model as required. The mathematical modeling of circadian rhythms, sleep, subjective alertness and mood, and neurobehavioral performance is a vital and effective component of design and testing of potential countermeasures for optimal astronaut health and mission success.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2004 
Task Progress: This record represents the first year of this task (FY 2004). The first progress report is due in FY 2005.

Bibliography Type: Description: (Last Updated: 02/16/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2004