Uncovering physiologic mechanisms of circadian rhythms and sleep/wake regulation through mathematical modeling

Mathematical models of neurobehavioral function are useful both for understanding the underlying physiology and for predicting the effects of rest-activity-work schedules and interventions on neurobehavioral function. In a symposium titled "Modeling Human Neurobehavioral Performance I: Uncovering Physiologic Mechanisms" at the 2006 Society for Industrial and Applied Mathematics/Society for Mathematical Biology (SIAM/SMB) Conference on the Life Sciences, different approaches to modeling the physiology of human circadian rhythms, sleep, and neurobehavioral performance and their usefulness in understanding the underlying physiology were examined. The topics included key elements of the physiology that should be included in mathematical models, a computational model developed within a cognitive architecture that has begun to include the effects of extended wake on information-processing mechanisms that influence neurobehavioral function, how to deal with interindividual differences in the prediction of neurobehavioral function, the applications of systems biology and control theory to the study of circadian rhythms, and comparisons of these methods in approaching the overarching questions of the underlying physiology and mathematical models of circadian rhythms and neurobehavioral function. A unifying theme was that it is important to have strong collaborative ties between experimental investigators and mathematical modelers, both for the design and conduct of experiments and for continued development of the models.     

Quantitative performance metrics for robustness in circadian rhythms

MOTIVATION: Sensitivity analysis provides key measures that aid in unraveling the design principles responsible for the robust performance of biological networks. Such metrics allow researchers to investigate comprehensively model performance, to develop more realistic models, and to design informative experiments. However, sensitivity analysis of oscillatory systems focuses on period and amplitude characteristics, while biologically relevant effects on phase are neglected. RESULTS: Here, we introduce a novel set of phase-based sensitivity metrics for performance: period, phase, corrected phase and relative phase. Both state- and phase-based tools are applied to free-running Drosophila melanogaster and Mus musculus circadian models. Each metric produces unique sensitivity values used to rank parameters from least to most sensitive. Similarities among the resulting rank distributions strongly suggest a conservation of sensitivity with respect to parameter function and type. A consistent result, for instance, is that model performance of biological oscillators is more sensitive to global parameters than local (i.e. circadian specific) parameters. Discrepancies among these distributions highlight the individual metrics' definition of performance as specific parametric sensitivity values depend on the defined metric, or output. AVAILABILITY: An implementation of the algorithm in MATLAB (Mathworks, Inc.) is available from the authors. SUPPLEMENTARY INFORMATION: Supplementary Data are available at Bioinformatics online.     

Bright light during nighttime: effects on the circadian regulation of alertness and performance

The present studies evaluated to what extent duration (all-night or 4-hour exposures) and timing of nocturnal bright light (BL) (beginning or end of the night) modulate effects on vigilance. The results showed that all-night BL exposure is able to alleviate the nocturnal decrements in alertness and performance. However, under certain circumstances, this continuous BL exposure may induce adverse effects on mood and finally reveal to be counterproductive. Shorter BL exposure (4 h) during nighttime helps improve mood and performance, although the effects of short BL pulses were less efficacious than all-night BL exposure. The latter part of the night appears the best time for using the alerting effect of BL. The immediate alerting effect of BL seems to be mediated by a global activation of the central nervous system.     

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.     

The influence of subjective alertness and motivation on human performance independent of circadian and homeostatic regulation

Endogenous circadian rhythmicity and sleep-wake homeostasis are robust regulators of human alertness and performance, yet few studies have examined how these regulatory processes affect motivation. Moreover, the influence of alertness and motivation on performance, independent of circadian phase and hours awake, has not been studied. Healthy subjects, 12 males and 3 females, ages 20 to 41, participated in a 2-week 28-h forced desynchrony protocol to address these issues. Subjects performed a battery of tests every 2 hours during scheduled wakefulness. Performance on a mathematical addition test and ratings of alertness and motivation on visual analog scales were analyzed. Performance scores were categorized as being associated with the highest or lowest alertness and motivation ratings for each circadian phase/hours awake bin to determine whether high levels of alertness and motivation resulted in higher performance scores above and beyond the effects of circadian and homeostatic regulation. Motivation varied significantly as a function of circadian phase and hours awake. Motivation and alertness were correlated. When circadian phase and hours awake were accounted for, performance was better when alertness and motivation ratings were highest and worse when those ratings were lowest. The present findings suggest that human performance is influenced by alertness and motivation independent of circadian phase and hours awake. Future studies examining the influence of circadian phase and sleep-wake homeostasis on human performance also should assess alertness and motivation to aid in the interpretation of performance data. Such studies also may aid in the development of countermeasures to improve human performance.     

Habitual moderate alcohol consumption desynchronizes circadian physiologic rhythms and affects reaction-time performance

The authors studied longitudinally four healthy young adults to explore if habitual evening intake of a "moderate" amount of wine alters parameters, including period (τ) of circadian rhythms. Subjects, synchronized by diurnal activity from 07.30?h?±?60?min to 23.00?h?±?90?min and nocturnal rest, were studied during a continuous 22-day span: 11 days without alcohol (control) and 11 days with a glass (200?mL) of wine nightly at supper (alcohol). The amount of alcohol ingested with dinner ranged from 0.28 to 0.42?g/kg/24?h/participant and the estimated evening blood alcohol level ranged from 0.02 to 0.10?g/L/participant. Single reaction time (SRT; yellow light signal), three-choice reaction time (CRT) (red, green, and yellow signals) of both hands, related cumulated errors (c-errors), as well as oral temperature (OT) and grip strength (GS) were measured four to seven times/24?h. Time series were analyzed individually to quantify 24-h means (M), circadian τ (power spectra), and cosinor, and correlation, χ(2), and t tests were performed. The sleep-wake τ (actography) was 24?h in every subject for both conditions. With alcohol, all subjects showed an OT circadian τ shorter than the control one. The SRT circadian M was longer (poorer performance) with wine versus control in three subjects, while CRT was longer with wine versus control in only one subject. Correlation analyses also showed the detrimental effect of alcohol on the same variables. Number of days with <2 c-errors was predominant in control and decreased with alcohol, especially for SRT. The desynchronization of the 10 different documented rhythms was greater with alcohol with reference to control in two of the four studied subjects. This work shows that habitual "moderate" wine drinking at supper reduces the performance of subjects, increases the level of c-errors/24?h, especially for SRT, suggesting a "moderate" amount of alcohol has the potential to increase accident risk, and it can also desynchronize circadian time organization.     

Desynchronization of oral temperature, pulse and performance circadian rhythms in shift working Indian nurses.

Circadian time structure in shift working Indian nurses was studied. In shift workers desynchronization between circadian rhythms in different physiological variables was observed. Circadian amplitudes of oral temperature, pulse and random add speed rhythms decreased significantly in shift workers as compared to control subjects. Circadian mesors of performance rhythms increased significantly in shift workers indicating that the time taken by them was more for performing the tasks. It can be concluded that the subjects studied herein are intolerant to shift work and amplitude decrement may be considered as a chronobiologic index to determine the tolerance of individual workers to shift work.     

A neural theory of circadian rhythms: split rhythms, after-effects and motivational interactions

A neural theory of the circadian pacemaker within the hypothalamic suprachiasmatic nuclei (SCN) is used to explain parametric data about mammalian operant behavior. The intensity, duration, and patterning of ultradian activity-rest cycles and the duration of circadian periods due to parametric (LL) and nonparametric (LD) lighting regimes are simulated. Paradoxical data about split rhythms and after-effects are explained using homeostatic and nonhomeostatic neural mechanisms that modulate pacemaker activity. These modulatory mechanisms enable the pacemaker to adjust to pervasive changes in its lighting regime, as during the passage of seasons, and to ultradian changes in internal metabolic conditions. The model circadian mechanisms are homologous to mechanisms that model hypothalamically mediated appetitive behaviors, such as eating. The theory thus suggests that both circadian and appetitive hypothalamic circuits are constructed from similar neural components. Mechanisms of transmitter habituation, opponent feedback interactions between on-cells and off-cells, homeostatic negative feedback, and conditioning are used in both the circadian and the appetitive circuits. Output from the SCN circadian pacemaker is assumed to modulate the sensitivity of the appetitive circuits to external and internal signals by controlling their level of arousal. Both underarousal and overarousal can cause abnormal behavioral syndromes whose properties have been found in clinical data. A model pacemaker can also be realized as an intracellular system.     

Genetic control of circadian rhythms and aging

The review establishes a link between a group of genes which are conserved in evolution and form a molecular oscillator responsible for generation of circadian rhythms and genetic determinants of aging including associated pathways of intracellular signaling. An analysis of mechanisms of development of agedependent pathologies is conducted from the viewpoint of circadian genetics. Systematic data of circadian gene expression studies in animals demonstrating different rates of aging from accelerated to negligible are presented.     

Relationship between alertness,performance, and body temperature in humans

Body temperature has been reported to influence human performance. Performance is reported to be better when body temperature is high/near its circadian peak and worse when body temperature is low/near its circadian minimum. We assessed whether this relationship between performance and body temperature reflects the regulation of both the internal biological timekeeping system and/or the influence of body temperature on performance independent of circadian phase. Fourteen subjects participated in a forced desynchrony protocol allowing assessment of the relationship between body temperature and performance while controlling for circadian phase and hours awake. Most neurobehavioral measures varied as a function of internal biological time and duration of wakefulness. A number of performance measures were better when body temperature was elevated, including working memory, subjective alertness, visual attention, and the slowest 10% of reaction times. These findings demonstrate that an increased body temperature, associated with and independent of internal biological time, is correlated with improved performance and alertness. These results support the hypothesis that body temperature modulates neurobehavioral function in humans.     

Endogenous opioids, circadian rhythms, nutrient deprivation, eating and drinking

Immunoreactive (ir) beta-endorphin (b-END) and dynorphin (DYN) in rat brain and pituitary were measured after food and water deprivation and from brains taken during either day or night. In other rats, eating and drinking were measured following lesions in the arcuate n. Ir-DYN levels are higher in hypothalamus and lower in pituitary at night. Deprivation, particularly water deprivation, increases hypothalamic, day-time ir-DYN. Water deprivation decreases pituitary levels of ir-DYN. Arcuate-lesions, depleting both ir-b-END and ir-DYN, do not modify total daily intake of water or food but does modify circadian rhythmicity of eating and drinking. These data support the conclusion that b-END and DYN are involved in maintaining day-night patterns of eating and drinking.