A Model-Based Approach to Optimizing Ultradian Forced Desynchrony Protocols for Human Circadian Research.

The human circadian system regulates internal 24-h rhythmicity and plays an important role in many aspects of human health and behavior. To investigate properties of the human circadian pacemaker such as intrinsic period and light sensitivity, experimental researchers have developed forced desynchrony (FD) protocols in which manipulations of the light-dark (LD) cycle are used to desynchronize the intrinsic circadian rhythm from the rest-activity cycle. FD protocols have typically been based on exposure to long LD cycles, but recently, ultradian FD protocols with short LD cycles have been proposed as a new methodology for assessing intrinsic circadian period. However, the effects of ultradian FD protocol design, including light intensity or study duration, on estimates of intrinsic circadian period have not, to our knowledge, been systematically studied. To address this gap, we applied a light-sensitive, dynamic mathematical model of the human circadian pacemaker to simulate ultradian FD protocols and analyze the effects of protocol design on estimates of intrinsic circadian period. We found that optimal estimates were obtained using protocols with low light intensities, at least 10 d of exposure to ultradian cycling, and a 7-h LD cycle duration that facilitated uniform light exposure across all circadian phases. Our results establish a theoretical framework for ultradian FD protocols that can be used to provide insights into data obtained under existing protocols and to optimize protocols for future experiments.