Intrinsic Phase Difference between Cone and Melanopsin Signals in the Pupillary Pathway

Humans have adapted to a light environment with natural light in the course of evolution. A novel light environment control system is needed to address the problems of inadequate adaptation to the modern artificial light environment. For a long time, only cone and rod cells were thought to be photoreceptors in the retina (i.e. light sensors in human), but a new photoreceptor was discovered around 2000. These photoreceptors are called melanopsin ganglion cells (ipRGCs: intrinsically photoreceptive retinal ganglion cells). However, at present, the understanding of the functions of melanopsin cells is extremely limited and little is known. For example, many people are getting more sunlight in the morning to improve their sleep quality, wearing blue light-cutting glasses or using the Night Shift function in iOS, suggesting that it is important to activate or inhibit melanopsin cells depending on the light environment, but it is necessary to understand the function of melanopsin cells in order to make appropriate decisions on when to activate or inhibit melanopsin cells. Melanopsin cells have a slower response than cones. They receive signals from classical photoreceptors, indicating that cone and melanopsin signals are integrated at the retina. In the present study, we measured the intrinsic phase difference between cone and melanopsin signals in the pupillary pathway using a silent-substitution technique. The goal of the present study was to investigate how these signals are temporally integrated. We used three different test stimuli: (i) varying melanopsin stimulation without changing L-, M-, and S-cone stimulation (melanopsin stimulus); (ii) varying L-, M-, and Scone stimulation only, without changing melanopsin stimulation (cone stimulus); and (iii) varying the radiant flux of the stimuli, without changing the spectral composition, which reduces or increases the radiant flux uniformly at all wavelengths (lightflux stimulus). Consistent with previous studies, we found a delayed pupillary response to the melanopsin stimulus. The cone signal leads the melanopsin signal by approximately 100 ms in onset constriction of the pupil response. In addition, we measured pupillary responses to the light-flux stimulus, consisting of cone and melanopsin stimuli. The timings of the melanopsin stimuli were set at variable physical phases. When we estimated the intrinsic phase difference from the first harmonic component of the pupil trace, the melanopsin signal leads the cone signal by approximately 32° and the contribution of cone signals is approximately five times greater than that of melanopsin signals at a temporal frequency of 0.5 Hz; this could be accounted for by a linear summation model of cone and melanopsin signals. These results suggest that the intrinsic phase difference between the cone and melanopsin signals is not a simple latency difference between photoreceptors at the retina. The difference in onset time of pupil constriction could be explained by the simple latency difference between cone and melanopsin photoreception, whereas the intrinsic phase difference could be explained by an integration process in the melanopsin receptive field.