Recent advances in modeling sleep: from the clinic to society and disease

Abstract

In the past few decades, advances in understanding sleep-wake neurophysiology have occurred hand-in-hand with advances in mathematical modeling of sleep and wake. In this review, we summarize recent updates in modeling the timing and durations of sleep and wake, the underlying neurophysiology of sleep and wake, and the application of these models in understanding cognition and disease. Throughout, we highlight the role modeling has played in developing our understanding of sleep and its underlying mechanisms. We present open questions and controversies in the field and propose the utility of individualized models of sleep for precision sleep medicine.

Keywords: circadian rhythm; cognition; mathematical modeling; precision medicine; sleep.

Figure 1:

Approach to modeling sleep and circadian rhythms. Experimentation and modeling of sleep and circadian rhythms are iterative processes: experimental results can be used to develop and refine models and models can be used to design experiments. This experimental plus modeling process yields translational results that may be brought into the clinic for further testing and evaluation.

Figure 2:

Integration of arousal circuitry (top) and molecular basis of circadian rhythms (bottom) with the Two-Process Model and its biomarkers (center). The detail in a model largely depends upon its intended use, and so a more detailed model may not be “better” as many detailed models involve assumptions that are challenging to prove conclusively. The arousal circuitry model for the transition between sleep and wake was adapted from the bihemispheric model in [71], where arrows represent excitation and straight lines represent inhibition. Abbreviations of neuronal populations: VLPO: ventrolateral preoptic area, ACh: acetyl choline, Orx: orexin, MA: monoaminergic. Note that the bihemispheric model does not intend to describe the sleep homeostat (which is a component of the model itself), but simply the mechanistic transition between states for sleep. Thus, it informs the Two-Process Model but does not supplant it. The simplified clock diagram reflects the ODE model used in [66], where arrows represent upregulation of transcription or translation and straight lines represent repression of transcription. Like the sleep-wake switch model, the mechanistic circadian model informs the structure of Process C, but does not aim to replace it.