Editorial: the pupil: behavior, anatomy, physiology and clinical biomarkers

Editorial on the Research Topic
The Pupil: Behavior, Anatomy, Physiology and Clinical Biomarkers

The pupil response is more than a simple light evoked reflex ( 1 ). At any moment, pupil diameter reflects the activity of complex neurological pathways to changes in the environmental illumination and autonomic activity through parasympathetic and sympathetic innervations ( 2 ). A mobile pupil also modulates retinal illumination and enhances visual performance by affecting the depth of focus and optical aberrations. This special issue brings together 110 co-authors from 17 countries across 24 original research articles and reviews, that together highlight the latest research on the afferent and efferent pupil control pathways in humans and animals and the influence of non-photic control factors on the pupil response, including cognition and attention, sleepiness, and circadian processing. It includes a significant focus on the non-invasive measurement of the pupil as a clinically important neurological marker of autonomic, midbrain, and central brain function. The publications are organized in this eBook according to studies describing the cognitive/sleep-related and light-evoked behavior of the pupil, the anatomy and physiology of pupillary responses, and clinical pupil biomarkers, and begins with the international Standards in Pupillography.

Standards in Pupillography: Kelbsch et al.

The widespread application of pupillometry in basic and clinical measurements of humans and animals in ophthalmology, neurology, neuroscience, psychology, and chronobiology has necessitated the demand to introduce a set of recommendations and general standards. With this in mind, experts convened at the 32nd International Pupil Colloquium (IPC) in Morges Switzerland to discuss and prepare the first iteration of an international standard for pupillography ( Kelbsch et al. ). This living standard considers the procedures relating to data collection, processing and a minimum set of variables for reporting in publications. The guidelines cover specific applications, including the afferent pupil light response and conditions for differentiating the pupil light reflex initiated by rhodopsin-driven rod responses, opsin-driven cone responses, and/or melanopsin-driven ipRGC responses, the efferent pupillary pathway, pharmacological effects on the pupil, pupillography in psychology and psychiatry, and methods for evaluating sleepiness-related pupillary oscillations. The standard is applicable to measurements of the pupil in humans and animals and designed to facilitate its correct application and improve the comparability between studies.

The Pupil: Light-Evoked Responses

In the past 20 years, it has been recognized that the pupillary light reflex is driven predominantly by a unique subset of intrinsically-photosensitive retinal ganglion cells (ipRGCs) that contain melanopsin and project to the pretectum, specifically the olivary pretectal nucleus ( 3 , 4 ). Further, ipRGCs are strongly influenced by rod and cone inputs in addition to their slower, melanopsin-driven intrinsic responses ( 5 , 6 ). Thus light-evoked pupillary responses are dependent on both spectral and temporal stimulus characteristics as well as on stimulus intensity ( 7 ).

2. McDougal DH, Gamlin PD. Autonomic control of the eye. Compr Physiol.(2015) 5: 439–73. doi: 10. 1002/cphy. c140014

3. Berson DM. Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci.(2003) 26: 314–20. doi: 10. 1016/S0166-2236(03)00130-9

4. Gamlin PD. The pretectum: connections and oculomotor-related roles. Prog Brain Res.(2006) 151: 379–405. doi: 10. 1016/S0079-6123(05)51012-4

5. Dacey DM, Liao HW, Peterson BB, Robinson FR, Smith VC, Pokorny J, et al. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature.(2005) 433: 749–54. doi: 10. 1038/nature03387

6. Gooley JJ, Ho Mien I, St Hilaire MA, Yeo SC, Chua EC, van Reen E, et al. Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans. J Neurosci.(2012) 32: 14242–53. doi: 10. 1523/JNEUROSCI. 1321-12. 2012

7. Adhikari P, Zele AJ, Feigl B. The post-illumination pupil response (PIPR). Invest Ophthalmol Vis Sci.(2015) 56: 3838–49. doi: 10. 1167/iovs. 14-16233

8. Estévez O, Spekreijse H. The “ silent substitution” method in visual research. Vision Res.(1982) 22: 681–91. doi: 10. 1016/0042-6989(82)90104-3

9. Binda P, Gamlin PD. Renewed attention on the pupil light reflex. Trends Neurosci.(2017) 40: 455–7. doi: 10. 1016/j. tins. 2017. 06. 007

10. Güler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao HW, et al. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature.(2008) 453: 102–5. doi: 10. 1038/nature06829

11. Feigl B, Zele AJ. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease. Optom Vis Sci.(2014) 91: 894–903. doi: 10. 1097/OPX. 0000000000000284

12. Markwell EL, Feigl B, Zele AJ. Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm. Clin Exp Optom.(2010) 93: 137–49. doi: 10. 1111/j. 1444-0938. 2010. 00479. x

13. Lucas RJ, Douglas RH, Foster RG. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci.(2001) 4: 621–6. doi: 10. 1038/88443

14. Gamlin PD, McDougal DH, Pokorny J, Smith VC, Yau KW, Dacey DM. Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells. Vision Res.(2007) 47: 946–54. doi: 10. 1016/j. visres. 2006. 12. 015

15. Hannibal J, Kankipati L, Strang CE, Peterson BB, Dacey D, Gamlin PD. Central projections of intrinsically photosensitive retinal ganglion cells in the macaque monkey. J Comp Neurol.(2014) 522: 2231–48. doi: 10. 1002/cne. 23555

16. Kankipati L, Girkin CA, Gamlin PD. Post-illumination pupil response in subjects without ocular disease. Invest Ophthalmol Vis Sci.(2010) 51: 2764–9. doi: 10. 1167/iovs. 09-4717

17. Adhikari P, Pearson CA, Anderson AM, Zele AJ, Feigl B. Effect of age and refractive error on the melanopsin mediated post-illumination pupil response (PIPR). Sci Rep.(2015) 5: 17610. doi: 10. 1038/srep17610

18. Zele AJ, Feigl B, Adhikari P, Maynard ML, Cao D. Melanopsin photoreception contributes to human visual detection, temporal and colour processing. Sci Rep.(2018) 8: 3842. doi: 10. 1038/s41598-018-22197-w

19. LeGates TA, Altimus CM, Wang H, Lee HK, Yang S, Zhao H, et al. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature.(2012) 491: 594–8. doi: 10. 1038/nature11673

20. Kawasaki A, Kardon RH. Intrinsically photosensitive retinal ganglion cells. J Neuroophthalmol.(2007) 27: 19. doi: 10. 1097/WNO. 0b013e31814b1df9