Development of a Unified Cardiovascular-Pupillary Model for Interpreting Pupil Size Variability as an Autonomic Marker.

Background: Pupil size variability (PSV) has emerged as a potential non-contact indicator of autonomic nervous system (ANS) function; however, its physiological origins remain unclear. This study aims to develop a computational model to investigate the physiological foundations of PSV and assess how frequency-domain indices reflect cardiovascular autonomic balance. Methods: We integrated a well-established cardiovascular regulation model with a biomechanical pupillary muscle plant. The model simulates PSV alongside heart rate variability (HRV) by transmitting respiratory and baroreflex inputs through an indirect neural pathway to the pupillary muscles. Frequency-domain analyses were conducted to compare simulated PSV and HRV across different autonomic states. Results: Simulations suggest that PSV arises from respiratory and baroreceptor inputs, with its classical range-nonlinearity (RNL) property emerging naturally from iris biomechanics. The model reproduces key physiological behaviors, including inspiration-linked dilation and parasympathetic modulation. Frequency-domain analyses reveal low- and high-frequency components in PSV that are similar to those found in HRV. However, the magnitudes of these PSV components depend heavily on the underlying autonomic state and the mean pupil size. Conclusion: These findings provide a mechanistic framework for interpreting PSV as a cardiovascular autonomic biomarker. This ultimately supports the development of non-invasive, wearable, and eye-based ANS monitoring systems.