Blue Light and Melanopsin Contribution to the Pupil Constriction

in the Blind-spot, Parafovea and Periphery

Tim Schilling

, Mojtaba Soltanlou

2,3

, Yeshwanth Seshadri

, Hans-Christoph Nuerk

2,3

and Hamed Bahmani

1,4,5

Dopavision GmbH, Berlin, Germany

Department of Psychology, University of Tübingen, Tübingen, Germany

LEAD Research Network, University of Tübingen, Tübingen, Germany

Max Planck Institute for Biological Cybernetics, Physiology of Cognitive Processes, Tübingen, Germany

Bernstein Center for Computational Neuroscience, Tübingen, Germany

Keywords: Melanopsin, Blind-spot, Optic Disc, Pupil.

Abstract: Retinal photoreceptors modulate the pupil diameter to regulate retinal illumination. At early stage the pupil-

response is formed by intrinsically-photosensitive-Retinal-Ganglion-Cells (ipRGCs) expressing melanopsin,

activated by blue light. ipRGCs’ axons pass through the optic nerve head, corresponding to the blind-spot. No

photoreceptors except melanopsin appear to exist in the blind-spot. Contributions of melanopsin to pupil

constriction in absence of classical photoreceptors in the blind-spot is not fully understood. We investigated

how blue light in the blind-spot changes melanopsin-pupil-response compared to parafovea and periphery.

The Post-Illumination-Pupil-Response (PIPR) amplitude reflecting melanopsin was analyzed for standardized

time windows (1s<1.7s, 1s>1.8s and 2–6s) and expressed as pupillary-change. Bayesian analysis showed a

BF>3 that PIPR>1.8s for blind-spot and periphery is not different. At times 2s–6s, a t-test comparison in the

blind-spot condition showed a significantly larger PIPR to blue compared to red light, confirming a

melanopsin-pupil-response in the blind-spot. Taken together, equivalent stimulation in the blind-spot and

periphery revealed comparable PIPR, although there are no rods and cones in the blind-spot. In absence of

classical photoreceptors in the blind-spot, melanopsin seems to be responsible for pupil constriction in similar

manner as in the periphery, which supports the presence of melanopsin on the axons of ipRGCs.

1 INTRODUCTION

In the human eye, the retina contains a peripheral

region without rods and cones where ganglion-cell

axons bundle in the optic nerve. The head of the optic

nerve is called the optic disc which corresponds to the

blind-spot. Although light illumination in the blind-

spot is reported to be invisible, but reduces the

brightness perception of a white light outside the

blind-spot (Saito, Miyamoto, Uchiyama, &

Murakami, 2018), this does not mean that the optic

disc is insensitive to light.

Melanopsin-expressing retinal ganglion cells

(RGCs) are intrinsically photosensitive (ipRGCs) and

receive extrinsic input from rods and cones in

primates (Dacey et al., 2005; Gamlin et al., 2007).

ipRGCs form the afferent pupil pathway to regulate

the pupil response (Gamlin et al., 2007).

Pupil size dynamics are controlled by melanopsin

containing ipRGCs (Fu et al., 2005; Hattar et al.,

2003; Lucas et al., 2003), whose axons pass through

the optic disc of the human eye. It has been shown in

rats that melanopsin is expressed in cell bodies,

dendrites, and proximal axonal segments of this

subset of RGCs (Hattar, Liao, Takao, Berson, & Yau,

2002). Melanopsin is sensitive to shorter wavelengths

centered around 480 nm (Berson, Dunn, & Takao,

2002; Hattar et al., 2002). In contrast to the short-

wave blue spectrum, red light consists of higher

wavelengths over 600 nm, which barely overlaps with

the sensitivity spectrum of melanopsin.

Light of different wavelengths have been shown

to modulate pupil response differently. When the

whole retina is stimulated, it has been shown that

short-wavelength blue light (467 ± 10 nm) induces a

larger change in pupil size, whereas global long-

482

Schilling, T., Soltanlou, M., Seshadri, Y., Nuerk, H. and Bahmani, H.

Blue Light and Melanopsin Contribution to the Pupil Constriction in the Blind-spot, Parafovea and Periphery.

DOI: 10.5220/0008972404820489

In Proceedings of the 13th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2020) - Volume 5: HEALTHINF, pages 482-489

ISBN: 978-989-758-398-8; ISSN: 2184-4305

wavelength red light (640 ± 17 nm) leads to a smaller

change (Park et al., 2011).

In the beginning of the 19th century, Hess found

a pupil contraction when he focused light on the

blind-spot (Hess, 1908). Later, stimuli of different

wavelengths were delivered to the blind-spot and the

spectral response curve was assumed to be a modified

rod curve originating from scattered light (Alpern &

Campbell, 1962). Alpern and Campbell speculated on

whether the deviation from the rod curve derives from

the activity of another photosensitive visual substance

in addition to rhodopsin. Their postulated visual

substance might be melanopsin, which was shown to

be present on ipRGCs’ axons a few decades later

(Hattar et al., 2002).

Melanopsin-expressing ipRGCs have been

documented as playing a role in the pupil light

response, contributing to it a sluggish recovery

component; an extended response primarily mediated

by melanopsin activation that persists for some time

after stimulus light termination - referred to as Post-

Illumination or Post-Stimulus Pupillary Response

(PIPR or PSPR respectively; Münch, Léon, Crippa, &

Kawasaki, 2012). There is evidence that melanopsin

drives the PIPR, which is a sustained pupil

constriction after stimulus offset, produced by the

intrinsic response of ipRGCs (Adhikari, Zele, &

Feigl, 2015; Dacey et al., 2005; Gamlin et al., 2007).

While both rods and ipRGCs have been shown to

provide input to the pupil light response, hence

rhodopsin and melanopsin contribute largely to PIPR

<1.7 s (Adhikari, Feigl, & Zele, 2016), it was reported

that melanopsin dominates all phases of PIPR and

solely contributes to the PIPR after 1.7 s (Adhikari et

al., 2016).

Miyamoto and Murakami studied the effects of

light stimulation inside the blind-spot on pupillary

light reflex with additional stimulus outside the blind-

spot (Miyamoto & Murakami, 2015). A sole

stimulation of the blind-spot and its effect on PIPR

has not been investigated to date, as far as we know.

We conducted experiments to examine the PIPR in

the blind-spot as well as periphery and parafovea to

have comparable conditions outside the blind-spot.

We tested the hypothesis that blue light constricts the

pupil more than red light in the blind-spot, when

elicited by melanopsin. The purpose of the study was

to compare melanopsin-induced PIPR when

illuminating the retina with a stimulus a) fitting in the

blind-spot and b) of equivalent size on parafovea and

periphery.

2 METHODS

2.1 Participants

The study contains data from 15 participants with

normal or corrected to normal vision. Visual acuity

was assessed before the experiment with FrACT

(Bach, 2006) to be greater or equal to 0.0 logMAR.

All experiments were approved by the Ethics

Committee for Psychological Research at the

Department of Psychology of the University of

Tuebingen and conducted in accordance with the

tenets of the Declaration of Helsinki. After explaining

the experiment, written informed consent was

obtained from all participants.

2.2 Stimulus

The stimulus consists of red or blue circular discs

presented in three different locations of the retina: in

the parafovea, in the peripheral retina and in the

blind-spot. The monitor (FUJITSU Display B24-8 TS

Pro, Fujitsu Technology Solutions GmbH, Munich,

Germany) was placed 50 cm in front of the

participant’s head, which was stabilized in a chin rest.

The right eye was covered with an eye patch while

the left eye dynamics were captured by an eye tracker

(EyeLink 1000 Eye Tracking system, SR Research

Ltd., Ottawa, Ontario, Canada), after the inbuilt

calibration procedure was completed.

The blind-spot of the left eye was mapped using

the following calibration procedure: the participant

looked at a fixation target and adjusted a disc on the

screen within the position and radius of the blind-

spot. The fixation target consisted of four points

around the center - above, below, left, and right -

connected circularly with a thin line (see Fig. 1). The

stimulus size and stimulus position had to be adjusted

by the participant with a keyboard until the stimulus

was invisible for the participant when fixating at all

four surrounding fixation points and the centered

fixation target. For the parafovea condition the

stimulus was in the parafoveal region, meaning

outside the fixation target in the horizontal direction

towards the corresponding blind-spot, 1.2° inferior

and 3.4° lateral leftwards to the fixation resulting in a

total distance of 3.4° visual angle from the fixation

target. The peripheral stimulus was in the same

direction as parafoveal and blind-spot in the visual

field, 12.4° distant from the fixation target, located at

4.6° superior and 11.9° lateral leftwards to the

fixation target. Stimulus diameter varied among

individuals for the blind-spot condition and was 1.25°

for parafovea condition and periphery condition.

Blue Light and Melanopsin Contribution to the Pupil Constriction in the Blind-spot, Parafovea and Periphery

483

Blue stimulus was composed of short-wavelength

blue light with a peak at 450 nm (CIE color

coordinates: x = 0.15, y = 0.06) whereas the red

stimulus consisted of long-wavelength red light with

a peak at 610 nm (CIE color coordinates: x = 0.65,

y = 0.34) stimulus measured with i1 studio (x-rite

Incorporated, Kentwood, Michigan, USA) and the

software f.luxometer™ LLC (Los Angeles,

California, USA). Both stimuli had a luminance of

11.8 cd/m², measured with a luminance meter

(Konica Minolta LS-110, Konica Minolta, Inc.,

Tokyo, Japan). The background of the monitor was

set to black. Participants were asked to passively view

the fixation target while the stimuli were presented to

the target locations. Gaze position was monitored

during the experiment to ensure a fixation on the

target.

Figure 1: A screenshot of the display during the calibration

phase. Stimulus color was green for calibration phase.

The experiment consisted of one block of four

trials with two red and blue stimuli, separately (see

Fig. 2). The red disc was always shown first to

account for the bi-stability factor (Mure et al., 2009).

Each block was presented separately for blind-spot

condition, parafovea condition, and periphery

condition. One block (47.32 s) began with a 23 s

baseline, followed by an 80 ms stimulus four times

and a 6 s inter-stimulus-interval (ISI). The stimulus

length of 80 ms was chosen as it is over the minimal

duration for a pupillary light reflex (Webster, 1969)

and secondly, to reduce the chance that eye fixation

was outside the fixation target.

A 6 s window is recommended when using short

pulse (Adhikari et al., 2015).

Figure 2: One block consists of a 23 s baseline and an 80 ms

stimulus four times followed by a 6 s inter-stimulus-interval

(ISI).

2.3 Analysis

Data was preprocessed by down-sampling the signal

to 10 Hz, removing blinks and interpolating the

signal. Pupil response was corrected to the 500 ms

pre-stimulus baseline. Furthermore, the pupillary

change was calculated as a percentage relative to the

pre-stimulus baseline, as recommended by Kelbsch

and colleagues to obtain relative pupil constriction

amplitude (Kelbsch et al., 2019). For the Area Under

the Curve (AUC) analysis, the pupil response values

were calculated to a 100% pre-stimulus baseline,

whereas for pupillary change, the baseline was

adapted to 0% by subtracting 100%.

The pupillary change was analyzed along

different time windows. Following the standards of

pupillography, combined rhodopsin and melanopsin

contribution was analyzed in a 1 s time window

before 1.7 s, and sole melanopsin contribution was

analyzed in a 1 s time window after 1.8 s (Kelbsch et

al., 2019). Additionally, the AUC from 2 s to 6 s PIPR

was calculated, which is until the end of the ISI,

which was adapted from the standard AUC of 2 s to

10 s (Kelbsch et al., 2019) because our ISI was not

longer than 6 s.

For statistical analysis repeated measure ANOVA

for the factor stimulus location and color with post-

hoc test Tukey correction was conducted.

Additionally, to test the a priori hypothesis, a paired

one-sided t-test was performed on AUC.

Furthermore, Bayesian inference statistics was used

in order to test the absence of a difference (null

hypothesis). Therefore, the Bayes factors were

calculated to evaluate evidence in favor of the null

hypothesis (BF

). Bayes factors were categorized to

the degrees of evidence by Kass and Raftery (Kass &

Raftery, 1995) i.e. BF

= 1-3 is interpreted as weak

evidence, BF

= 3-20 is interpreted as positive

evidence, BF

= 20-150 is interpreted as strong

evidence and BF

> 150 is interpreted as very strong

evidence.

For statistical analysis JASP (Version 0.10.2.0,

JASP Team, 2019) was used. The rest of the pupil

signal processing and preprocessing was done with

Octave (John W. Eaton, David Bateman, Søren

Hauberg, 2018).

3 RESULTS

We analyzed PIPR for melanopsin contribution in

different stimulus locations using three standardized

time windows, separately: times < 1.7 s for rhodopsin

and melanopsin contribution, and times > 1.8 s for

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melanopsin contributions, and 2 s – 6 s for

melanopsin contributions, see shaded gray box for

different time windows in Fig. 3.

Figure 3: Mean and standard error of the mean (SEM) of

pupillary change in % to blue and red stimulus for blind-

spot, parafovea and periphery over time in ms. Stimulus

onset is at 0 ms.

3.1 Melanopsin and Rhodopsin at

Times < 1.7 s

A repeated ANOVA revealed a significant main

effect for color (p < 0.001) and stimulus location

(p < 0.05), but not for their interaction (p = 0.20), see

Table 1.

Table 1: ANOVA of PIPR at times < 1.7 s in detail.

df F p η²

Stimulus

location

2.28 3.60 0.04 0.06

Color

1.14 17.42 < 0.001 0.19

Stimulus

location

✻ Color

2.28 1.71 0.20 0.01

Regarding stimulus location, post-hoc tests

corrected with Tukey showed that pupil response to

the parafovea is larger than blind-spot condition

(p < 0.05), but no significant difference appeared

between the blind-spot condition and periphery

condition (p = 0.25) and the parafovea condition and

periphery condition (p = 0.50), see Fig. 4.

Regarding color, post-hoc tests corrected with

Tukey showed that pupil response to blue light is

significantly larger than the red light condition

(p < 0.001).

Figure 4: Mean and SEM of pupillary change in % at times

< 1.7 s for blind-spot, parafovea and periphery stimulus

location separated into blue and red light conditions.

3.2 Melanopsin at Times > 1.8 s

The repeated ANOVA revealed a significant main

effect for color (p < 0.01), but not for stimulus

location (p = 0.48) and their interaction (p = 0.39),

see Table 2.

Table 2: ANOVA of PIPR at times > 1.8 s in detail.

df F p η²

Stimulus

location

2.28 0.75 0.48 0.02

Color

1.14 11.93 < 0.01 0.12

Stimulus

location ✻

Color

2.28 0.96 0.39 0.01

Regarding color, post-hoc tests corrected with

Tukey showed that pupil response to blue light is

significantly larger than for the red light condition

(p < 0.01), see Fig. 5.

In the red light condition for the parafovea

condition and periphery condition, an overshoot after

pupil constriction shortly before 2 s can be observed,

which is not in the blind-spot condition, see Fig. 3.

Therefore, PIPR at times 1 s > 1.8 s was analyzed

only in blue light conditions in the following analysis.

In order to test the hypothesis for no difference

between blind-spot and periphery conditions,

Bayesian analysis was conducted. Positive evidence

(i.e., BF

= 3.2, error = 0.003%) was observed

comparing blind-spot and periphery at times

1 s > 1.8 s. An overlapping PIPR at times after 1.8 s

is visible in Fig. 6 between blind-spot and periphery.

Blue Light and Melanopsin Contribution to the Pupil Constriction in the Blind-spot, Parafovea and Periphery

485

Figure 5: Mean and SEM of pupillary change in % for

sustained pupillary response Melanopsin at times > 1.8 s for

blind-spot, parafovea and periphery stimulus location

separated into blue and red light conditions.

Figure 6: Pupillary change for blind-spot (solid line) and

periphery (dotted line) condition for blue light condition.

Stimulus onset is at 0 ms.

3.3 Melanopsin at Times 2 s – 6 s

For the AUC at times 2 s – 6 s, Bayesian analysis was

conducted in order to test for no difference in PIPR

after blue light stimulus between the blind-spot and

periphery. Positive evidence (i.e., BF

= 3.81,

error = 0.003% was observed when comparing the

blind-spot and periphery conditions.

Lastly, to test our hypothesis, due to no overshoot

in blind-spot red light condition, a paired one-sided t-

test comparison in the blind-spot condition showed a

significantly larger pupillary change to blue light as

compared to red light (t(14) = -1.9, p = 0.043,

d = -0.48).

4 DISCUSSION

We characterized pupil responses after blue light

stimulation in the blind-spot to investigate

melanopsin contributions in the blind-spot compared

to parafovea condition and periphery condition.

Miyamoto and Murakami found that stimulation

inside the blind-spot enhances, but does not trigger,

the pupillary light reflex (Miyamoto & Murakami,

2015). A photo-sensitive mechanism inside the optic

disk, which most likely involves melanopsin, has

been suggested to provide a reference for calibrating

the perceived brightness of visual objects (Saito et al.,

2018). In this study, we further explored the presence

of melanopsin in the blind-spot by investigating the

sustained response of pupil constriction regarding

melanopsin contribution to PIPR when stimulating

the blind-spot solely.

At both times < 1.7 s and times > 1.8 s pupillary

change in blue light conditions were larger than in the

red light conditions independent of the stimulus

location. This independency was indicated by the

absence of a significant interaction between the two

factors color and stimulus location. Therefore, we

assume that melanopsin contributes to the sustained

pupil response in the blind-spot, parafovea and

periphery. This is consistent with previous work that

described sustained pupil constriction by the spectral

sensitivity of melanopsin (Gamlin et al., 2007).

However, the difference between the blue and red

light could also be explained by greater than a 0%

pupillary change in the red light conditions, which

could come from a dilating pupil, while the pupillary

change was only slightly below 0% in blue light

conditions.

The time window of 1 s before times < 1.7 s is

reported to be influenced by the contribution of

rhodopsin and melanopsin (Adhikari et al., 2016).

Due to the absence of rods and cones in the optic disc,

blind-spot stimulation is influenced less by rhodopsin

than parafovea region is, which could explain the

observed difference between the blind-spot condition

and parafovea condition at times < 1.7 s.

Furthermore, this difference between blind-spot and

parafovea can be explained by the finding that red

light does not trigger the pupil constriction in the

blind-spot because of the absence of cones in the

blind-spot, as shown before (Miyamoto & Murakami,

2015).

For the blind-spot condition, we would mainly

expect the pupillary response to be influenced by

melanopsin, whereas the periphery would be

influenced by both rhodopsin and melanopsin.

Even when the light is focused exactly on the

optic disc, there could be light hitting the retina on

other locations than the target area due to light

scattering. Small particles in the compartments of the

eye, such as cornea and crystalline lens, and the

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486

spectacles - if worn - can scatter light away from the

target (van den Berg, Franssen, Kruijt, & Coppens,

2013), which would activate photoreceptors on the

retina. Therefore, we implemented two control

conditions in the periphery and parafovea. The

scattered light profile is similar in blind-spot and

periphery due to comparable location and similar

stimulus characteristics. If scattering was the reason

for blind-spot PIPR, we would have expected a larger

PIPR in the periphery as compared to the blind-spot

due to the extra rhodopsin contribution which is not

present in the blind-spot; but both conditions have

similar PIPRs. Earlier works have provided further

arguments to rule out a substantial influence by

scattered light when stimulating the blind-spot (Saito

et al., 2018). Still, we cannot completely exclude that

the remaining scattered light may stimulate rods to

modulate the pupil response in our experiment.

There are a few reasons for choosing the

parafoveal location. First, in the central fovea there

are no RGCs between the entering light and the

photoreceptor layer. To have comparable condition to

the blind-spot and periphery, the stimulus was placed

at the outer edge of the parafoveal region, where

RGCs project away from the fovea. Secondly,

potential filtering by the macular pigment is expected

to be reduced when moving from the center towards

the periphery as compared to the central fovea.

Finally, no cells containing melanopsin have been

reported in the central retina (Dacey et al., 2005; Liao

et al., 2016; Nasir-Ahmad, Lee, Martin, & Grünert,

2019); therefore, to target melanopsin containing

cells, we stimulated near the fovea in the parafovea

region.

Previous studies have shown that pupil response

can be induced by purely activating melanopsin, for

example see (Woelders et al., 2018). Furthermore,

pupil response is intact in cone-less and rod-less mice

with a peak sensitivity at 479 nm (Lucas et al., 2001).

Nevertheless, there was no difference between

periphery and blind-spot, which could be explained

by the presence of melanopsin in the blind-spot,

because the pupil response in the periphery should be

driven by both rhodopsin and melanopsin. To date,

we are not aware of any systematic comparison

between melanopsin concentration in the blind-spot

and other regions, but it has been shown that the

concentration of melanopsin cells is higher near the

human fovea when compared to the periphery (Nasir-

Ahmad et al., 2019). Such a difference between

parafovea and periphery was not evidenced in our

data, probably because our peripheral condition was

not far enough in the periphery. We would expect a

decrease in the sustained pupil response with a more

eccentric peripheral condition that can be subject to

future studies.

Looking only at blue light conditions, the

Bayesian analysis provided support for the null

hypothesis that there is no difference between blind-

spot and periphery PIPR; indicating an equal

contribution of melanopsin in both conditions. One

explanation for the similarity in the sustained signal

among all stimulus location for the blue light

condition could be that blind-spot contains as much

melanopsin as the parafovea and periphery.

The limitation of this comparison among the blue

light conditions is that BF

was uncorrected and no

strong or very strong evidence was found, however it

showed positive evidence for the absence of a

difference in PIPR between the blind-spot and

periphery. One possible explanation would be that

only two trials per stimulus condition were recorded

and no trials were excluded. Furthermore, we looked

closer at the blue light conditions only at times

1 s > 1.8 s for the following reason: the red light

condition in blind-spot seems to increase pupil size

continuously, because no input triggered the pupil

size change and the pupil was not dark adapted and

therefore not stable. Moreover, an overshoot after

pupil constriction was noticeable in the red light

conditions, except in the blind-spot condition, likely

because there was no pupil constriction. This

overshoot could affect the calculation of the

melanopsin response at times 1 s > 1.8 s, if the red

light condition was the reference.

However, this overshoot in the red light condition

was not visible for the blind-spot. Therefore, it allows

a comparison between blue and red light in the blind-

spot. This comparison confirmed our hypothesis that

blue light constricts the pupil more than red light

when shone in the blind-spot. To our knowledge, this

sustained pupil constriction in the blind-spot is a

novel finding and suggests the presence of

melanopsin in the blind-spot.

Previous work found that pupil response is

enhanced by blue light as compared to red light inside

the blind-spot, when outside blind-spot was also

illuminated (Miyamoto & Murakami, 2015).

Miyamoto and Murakami speculated that this is

modulated by melanopsin in the blind-spot. Our

results provide further support for the presence of

melanopsin in the blind-spot. Similarly, the AUC

between 2 s – 6 s showed that blue light stimulation

in the blind-spot keeps the pupil constricted for a

longer time as compared to red light; which suggests

a contribution of blind-spot melanopsin to the PIPR.

Blue Light and Melanopsin Contribution to the Pupil Constriction in the Blind-spot, Parafovea and Periphery

487

5 CONCLUSIONS

In conclusion blue light stimulation inside blind-spot

and outside blind-spot in the peripheral retina

revealed a comparable PIPR, although there are no

rods and cones in the optic disc. In the absence of

classical photoreceptors, melanopsin seems to be

responsible for pupil constriction when light is shone

in the blind-spot. This supports the presence of

melanopsin on the axons of ipRGCs at the head of

optic nerve, which can constitute potential

applications of stimulating melanopsin with visible

light, although invisible to the observer.

ACKNOWLEDGEMENTS

This work was supported by the Federal Ministry of

Education and Research, Industrie-in-Klinik-

Plattform Program BMBF, Germany (FKZ:

13GW0256). MS was supported by the DFG grant

[NU 265/3-1] to HCN. MS and HCN are members of

the LEAD Research Network [GSC1028], which is

funded within the framework of the Excellence

Initiative of the German federal and state

governments. We would like to thank Zoë Kirste for

language proofreading.

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