Effective human performance is dependent on the bodys synchronization of its circadian rhythm with environmental cues such as the light-dark cycle, sleep-wake patterns or work schedules. In space, astronauts are often exposed to patterns and schedules that are different from those encountered on Earth, resulting in disruption of the normal synchronization of environmental cues to the circadian clock and its outputs. To allay this problem, countermeasures are being designed to ensure optimal neurobehavioral performance, subjective alertness and quality sleep. Dr. Elizabeth B. Klerman and her colleagues will extend the current mathematical model developed by Dr. Megan E. Jewett and Dr. Richard E. Kronauer by incorporating new inputs including melatonin phase and different wavelengths of light information. In addition, Klerman is developing countermeasure design strategies involving mathematical models, which are powerful tools for the design of countermeasures because a large number of possibilities can be efficiently assessed. Klerman’s mathematical model is currently available in a user-friendly software program on the internet.
Overview
Mathematical Modeling of Circadian/Performance Countermeasures
Principal Investigator:
Elizabeth B. Klerman, M.D., Ph.D.
Organization:
Harvard - Brigham and Women's Hospital
Technical Summary
Specific Aims
- 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.
- Refine and validate the current model by using data from chronic sleep restriction protocols.
- Refine the current model to incorporate wavelength of light information.
- Develop Schedule Assessment and Countermeasure Design Software using the amended CNPA model from Specific Aims 1, 2 and 3 to evaluate schedules and design and test appropriate countermeasures.
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 photo pigment 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, building blocks as a flexible software technology that can be used to design any schedule and 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 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 a 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 bed-rest 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.
Earth Applications
- Of mathematical models of circadian rhythms, sleep, alertness and performance, and
- 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-hour schedules or extended-duty schedules (pilots, train and truck drivers, shift workers, healthcare workers, public safety officers, etc.).
The software also 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-hour 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.