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.

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.

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.

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.

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.

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.

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.

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.

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.

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) .