Pupillometric Complexity and Symmetricity Follow Inverted-U Curves Against Baseline Diameter Due to Crossed Locus Coeruleus Projections to the Edinger-Westphal Nucleus.

In addition to photic reflex function, the temporal behavior of the pupil diameter reflects levels of arousal and attention and thus internal cognitive neural activity. Recent studies have reported that these behaviors are characterized by baseline activity, temporal complexity, and symmetricity (i.e., degree of symmetry) between the right and left pupil diameters. We hypothesized that experimental analysis to reveal relationships among these characteristics and model-based analysis focusing on the newly discovered contralateral projection from the locus coeruleus (LC) to the Edinger-Westphal nucleus (EWN) within the neural system for controlling pupil diameter could contribute to another dimension of understanding of complex pupil dynamics. In this study, we aimed to validate our hypothesis by analyzing the pupillary hippus in the healthy resting state in terms of sample entropy (SampEn), to capture complexity, and transfer entropy (TranEn), to capture symmetricity. We also constructed a neural model embedded with the new findings on neural pathways. The following results were observed: first, according to surrogate data analysis, the complexity and symmetricity of pupil diameter changes reflect a non-linear deterministic process. Second, both the complexity and the symmetricity are unimodal, peaking at intermediate pupil diameters. Third, according to simulation results, the neural network that controls pupil diameter has an inverted U-shaped profile of complexity and symmetricity vs. baseline LC activity; this tendency is enhanced by the contralateral synaptic projections from the LCs to the EWNs. Thus, we characterized the typical relationships between the baseline activity and the complexity and symmetricity of the pupillometric data in terms of SampEn and TranEn. Our evaluation method and findings may facilitate the development of estimation and diagnostic tools for exploring states of the healthy brain and psychiatric disorders based on measurements of pupil diameter.