PUPIL INFORMATICS: Pupil Response Mechanisms, Visual Performance & Clinical Applications

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1 PUPIL INFORMATICS: Pupil Response Mechanisms, Visual Performance & Clinical Applications Papers Abstracts Contribution of melanopsin-expressing retinal ganglion cells to pupillary pathway studied with a multi-primary illumination system S. Tsujimura, D.Ohama, K. Yunokuchi and A. Nuruki Department of Bioengineering, Kagoshima University, Kagoshima, Japan. Introduction: A recent study has shown that retinal ganglion cells containing the photopigment melanopsin, which are intrinsically photosensitive in primates, project to the lateral geniculate nucleus, in addition to the projection to the pupillary control centre in the pretectum. The aim of this study was to investigate how melanopsin-expressing retinal ganglion cells (mrgcs) contribute to the pupillary pathway. Methods: We designed and built a novel multi-primary stimulation system that allows independent control of the stimulation of the three cone types and mrgcs in the human eye. The illumination system has two integrating spheres in which four colours of light-emitting diodes (LEDs) were used as internal light sources. Luminance output of each LED was controlled by pulse width modulation units by adjusting a duty cycle of pulse train. The 2-deg test stimuli were presented superimposed in the steady background field of 20 deg in diameter. We calculated excitations of mrgcs and the other photoreceptors on the background and the test stimulus, expressed as a relative modulation between them. We measured pupillary responses for test stimuli modulating luminance and an excitation of mrgcs. Results & Conclusions: The pupillary response evoked by mrgcs had a sustained temporal property and the response to the luminance signals had a transient temporal property. The time to reach peak constriction to the stimuli modulating mrgcs was ca. 200 ms longer than that to the luminance stimuli. These results may reflect responses of mrgcs. The independent stimulation of mrgcs may therefore be useful for many applications in fundamental and clinical research. A tale of 3 blind mice; the mouse pupil as a tool for assessing visual function Ron Douglas Department of Optometry & Visual Science, City University, London, UK. Due to the ease with which their genome can be manipulated, mice are now the main tool for investigating many aspects of animal physiology. We have used pupillary constriction in genetically altered mice to produce 3 quite different advances in understanding mammalian vision in both health and disease. The eye is involved in more than forming an image of objects in the environment. It also monitors ambient light levels to, among other things, reset the bodies circadian clocks. Using the pupil response of rodless/coneless mice we characterised a novel photoreceptor (melanopsin-containing intrinsically-photosensitive retinal ganglion cells) that is used to assess overall light levels [1]. Degeneration of rods and cones results in irreversible blindness in millions of people every year. We have shown [2] that donor rod precursor cells implanted into the retina of mice with retinal degenerations form new photoreceptors in the host retina. Pupilometry shows that incorporation of as few as 200 new cells leads to a significant increase in visual sensitivity. We have recently begun work [3] on a mouse model of dominant optic atrophy, an inherited degenerative disease of retinal ganglion cells that starts in childhood and frequently results in blindness, which is associated with mutations in 2 genes (Opa1 and Opa3). Although

2 mice with mutations in these genes are by most measures of visual function significantly impaired, they maintain a robust, near normal, pupil response. This dissociation between pupillary function and visual perception implies that ganglion cells mediating visual perception are affected by Opa mutations but that those cells mediating the pupil response are spared. [1] Lucas, R.J., Douglas, R.H., & Foster, R.G. (2001) Characterisation of a novel ocular photopigment capable of driving pupillary constriction in mice. Nature Neuroscience 4(6), [2] MacLaren, R.E., Pearson, R.A., MacNeil, A., Douglas, R.H., Salt, T.E., Akimoto, M., Swaroop, A., Sowden, J.C. & Ali, R.R. (2006) Repair of degenerating retina by transplantation of mitotic rod precursors. Nature 444, [3] In collaboration with Dr Marcela Votruba, Dr Vanessa Davies & Jennifer Davies (School of Optometry & Vision Institute, Cardiff University) Melanopsin ganglion cells provide the primary route via which cone photoreceptors influence the pupil light reflex Guprit Lall 1, Samer Hattar 2, King-Wai Yau 3 and Robert Lucas 1 1 Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK 2 Departments of Biology and Neuroscience (JHMI), 227 Mudd Hall/3400 N.Charles St., Johns Hopkins University, Baltimore, MD 21218, USA. 3 Department of Neuroscience (JHMI), 227 Mudd Hall/3400 N.Charles St., Johns Hopkins University, Baltimore, MD 21218, USA. In mice, the magnitude of the dark adapted pupil light reflex is determined both by outer retinal (primarily cone) and inner retinal (melanopsin) ganglion cell photoreceptors. Melanopsin retinal ganglion cells (mrgcs) innervate the oliviary pretectal nuclei offering a direct route for melanopsin to influence pupillary responses. The pathways by which rod/cone signals reach pupillary centres are more uncertain. mrgcs receive synaptic inputs from the outer retina and could therefore provide a conduit for rod/cone signals. On the other hand this information could be routed via non-mrgcs which also innervate the pretectum. To distinguish between these possibilities we assessed pupillary responses in mice lacking mrgcs. We find that the dark adapted PLR is substantially impaired in these animals. This suggests that most rod/cone input to this response is routed via mrgcs and identifies these ganglion cells as the primary integration point for outer and inner retinal photoreception. Intrinsically-photoreceptive Retinal Ganglion Cells and Primate Pupillary Responses Paul Gamlin University of Alabama, Birmingham, USA. Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength sensitive cone photoreceptors in daylight. A parallel, non-rod, non-cone photoreceptive pathway, arising from a unique population of retinal ganglion cells, has been demonstrated in nocturnal rodents and, more recently, in primates. In primates, we have shown that this anatomically distinct population of melanopsinexpressing ganglion cells is intrinsically photosensitive and strongly activated by rods and cones. In rodents, these intrinsically-photoreceptive ganglion cells have been shown to serve the non-image-forming functions of circadian photoentrainment and pupil constriction. In primates, we have demonstrated that these cells play an important role both in light-evoked pupillary responses, and in the sustained pupil constriction that occurs after bright light cessation.

3 Relationship between pupil size and higher order aberrations Toshifumi Mihashi 1, Yoko Hirohara 1, Mariko Kobayashi 1, Naoyuki Maeda 2 and Takashi Fujikado 2, Howard Howland 3 1 R&D Center, Topcon Corp, Tokyo, Japan; 2 Osaka University; 3 Cornell University. We performed wavefront aberrometry on 30 normal eyes of 30 subjects (age 30.4±7.1 y mean ± SD, range 18 to 45 y) and 28 keratoconic (KC) eyes of 28 subjects (age 28.1±7.2 y mean ± SD, range 18 to 45 y). We measured pupil size simultaneously when we measured aberration. The higher order wavefront aberration (HOA) over 6-mm pupil of normal was 0.29 ± 0.01 (average ± SD) ìm and that of KC was 1.6 ± 0.62 ìm. The HOA of the keratoconic group was larger than that of the normal group (P < 0.01). The entrance pupil size of normal group was 6.6 ± 0.56 mm and that of KC group was 7.0 ±0.84 mm, the latter group being significantly larger (P < 0.05). This result did not suggest that the pupil size is smaller in an aberrated eye than that in a normal eye to form better images on the retina. We also performed dynamic wavefront aberrometry using our new binocular wavefront sensor on two normal subjects (age 32 and 35 y). We measured accommodation, aberrations, pupil size and vergence of two eyes in each subject while the subjects were observing a fixed visual stimulus under steady viewing condition. The measurement frequency was 24 Hz. We analyzed the observed small fluctuations in accommodation, pupil size and HOA. We found good correlation between the two eyes in accommodation fluctuations and in pupil size but not in HOA. We did not find a correlation between accommodation and pupil size fluctuations. This finding was not consistent with pupil contraction during accommodation and may be due to the much greater role the sympathetic innervation plays in pupillary control than in accommodation. The change of HOA may not be from the systematic control. Pupil Dilation Reflects Impacts of Fluid Intelligence on Resource Allocation and Task- Engagement Jan Ries, Judith Horn, Manja Foth, Elke van der Meer Department of Psychology, Humboldt University at Berlin, Germany. Cognition is biological work and involves the allocation of resources. The available pool of resources is assumed to be limited and to depend on neurotransmitter functioning, the various metabolic systems supporting the neural system, and the structural connectivity of the neural system (Just et al., 2003). Variation within these systems is one source of individual differences in cognition. We investigated the impact of fluid intelligence (superior vs. average) on allocation of cognitive resources in processing easy and difficult cognitive tasks. We measured speed and accuracy of processing, and pupil dilation which reflects an overall aggregate of mental resource allocation. (1) Individuals with superior fluid intelligence behaviourally outperformed individuals with average fluid intelligence. Further, they showed greater pupil dilations in the most difficult tasks. These results suggest that individuals with superior fluid intelligence have more resources available and thus can solve more demanding tasks. (2) There were striking group differences in pre-experimental and pre-trial pupil baselines. Individuals with superior fluid intelligence showed significantly greater pre-experimental pupil baselines. Towards the end of the experiment the pre-trial baselines of individuals with superior and average fluid intelligence did not differ. Recent research suggests that explorative distribution of attention goes along with increased tonic activity in locus coeruleus (LC) while higher task-engagement is accompanied by reduced tonic activity (Aston-Jones & Cohen, 2005). Furthermore, this LC activity is presumably highly correlated with pupil dilation (cf., Einhäuser et al., 2008). We interpret our results as evidence that the pupil baseline reveals initially more explorative behaviour in individuals with superior fluid intelligence. Over the course of the experiment and with increasing demand it changes in favour of a high task-engagement. As task-engagement is, in this theory, seen as a result of the presumed utility, individuals with superior fluid intelligence might perceive demanding tasks as more rewarding.

4 Accommodation responses to stereoscopic conflicted accommodation-convergence stimuli under increased depth-of-focus condition of retinal scan display Kazuhiko Ukai 1, Masahito Torii 1, Mitsuyoshi Watanabe 2 and Shoji Yamada 2 1 Waseda University, Japan; 2 Brother Industries, Ltd. Accommodation becomes small when the conflicted stereoscopic stimuli between accommodation and convergence are used, especially when the image is easily blurred by defocus. If higher spatial frequency components are removed from the image, accommodation responses are ruled by the convergence (Okada et al, Vision Res 2006). Similarly it is expected that the accommodative responses become free from the object distance (accommodative stimulus) and will be dominated by the convergence if the depthof-focus of the target is increased. To examine this, we measured accommodative responses as well as convergence and pupil responses of the observers of retinal scan stereoscopic displays using video-refraction unit. A pair of retinal scan displays made stereoscopic image by scanning retina of both eyes with fine beams. Effective diameter of the beams was around 2 mm. The produced image had large depth-of-focus equivalent to the image when pupil is constricted. However actual pupil size was kept non-constricted, so that position of the eye was not strictly fixed and eyes can move to converge. Further we could maintain pupil size enough large to measure accommodative responses. Target motion in depth was between 2D-2MA and 2D-3MA (D: diopters, MA: meter angle). For comparison, target motion between 2D-2MA and 3D-3MA was also used. Results obtained from 11 subjects show that accommodative responses were 0.89D for nonstereoscopic stimulus and 0.73D for stereoscopic stimulus while convergence responses were almost unity under both conditions. Amount of accommodative response was 80% of non-stereoscopic stimulation. This should be 0 if accommodative response was precise. According to the previous report, accommodative response was 40% when the pupil size of observers was larger, although it increased to 80% when the low-passed target was used. When the accommodative feedback loop becomes opened by any reasons (low-passed target or increased depth-offocus), accommodative responses are dominated by convergence. Effects of higher-order aberrations on visual performance as a function of pupil size and light level Dalimier E. 1, Dainty J. C. 1, Barbur J. L. 2 1 Applied Optics Group, Dpt. Of Experiment Physics, National University of Ireland, Galway; 2 Applied Vision Research Centre, City University, London, UK. The purpose of this study was to investigate the effects of higher-order (HO) ocular aberrations on functional vision in conditions encountered in everyday vision. We used an adaptive optics (AO) vision simulator comprising a Shack-Hartmann wavefront sensor, a 35 element bimorph mirror and visual displays. The system showed good correction of HO aberrations (i.e., less than 0.1 microns remaining rms wavefront error for a 6mm pupil, after static pre-correction of refractive errors with a Badal optometer and cylindrical lenses). Measurements of contrast acuity (Aviat. Space. Environ. Med., 74, , 2003) were carried out in a group of normal subjects over a range of light levels (from scotopic to photopic conditions) and pupil sizes (from 3 to 6 mm diameter), with and without correction of HO aberrations. At constant light level, the results showed that the visual benefit gained with the correction of HO was decreased with a decrease of pupil size, as expected. More interestingly, at constant pupil size, the visual benefit was decreased when the retinal illuminance was decreased. We can conclude that at low retinal illuminances, neural factors limit the effect that increased higher-order aberrations can have on visual performance. Measurements also provide an estimate of the AO benefit for functional vision expected under natural viewing conditions from low to high light levels.

5 Pupillary and vergence responses to the cognition of radial optic flow Atsuhiko Iijima 1,2, Kazuhiko Ukai 2, Sei-ichi Tsujimura 3, Masato Torii 2, Shota Hiramoto 2, Isao Hasegawa 1, Takehiko Bando 1 1 Integrative Physiology, Graduate school of Medical & Dental Sciences, Niigata University, Japan; 2 Department of Applied Physics, School of Science & Engineering, Waseda University, Japan; 3 Department of Biomedical Engineering, Faculty of Engineering, Kagoshima University, Japan. Objective: We investigated the relationship between pupillary response and vergence eye movement induced by radial expanding-contracting optic flow. We focused on (1) vergence and pupillary responses to the switch of stimulus direction and the change in the flow velocities, and (2) sustained vergence and pupillary responses to the stimuli. Methods: 12 participants watched a random dot radial optic flow pattern simulating oscillating translational motion in the anterior-posterior axis under four viewing conditions with fixation point at the focus of expansion: 1) contraction-stop pattern inducing backward and stop motion sensation; 2) contraction-expansion simulating backward and forward motion; 3) expansion-stop; and 4) expansion-contraction with three different frequencies of sinusoidal waves. Pupil size and vergence eye movement were measured with a video-oculography. Results: Pupil contraction was observed responding to the motion onset and to the switch of the stimulus direction while vergence eye movements showed convergence and divergence during forward and backward stimuli, respectively. Discussion: The pupil contraction may be connected to cognition of object motion changes and was supposed to be similar to the response elicited by translational coherent object motions [1] and this could not link to vergence eye movement. The continued vergence may be sustained component after the ultra-short latency vergence [2]. [1] Sahraie A and Barbur JL, Pupil response triggered by the onset of coherent motion., Graefes Arch Clin Exp Ophthalmol. 1997; 235(8): [2] Busettini C, Masson GS, Miles FA., Radial optic flow induces vergence eye movements with ultra-short latencies., Nature. 1997; 390(6659): Posters An investigation into the use of monocular pupillometry in the diagnosis and monitoring of optic nerve disease Mithu Storoni National Hospital of Neurology, Queens Square, London, UK. Objective: There were two aims of this study. The first was to compare the baseline results acquired with a custom built Maxwellian Pupillometer to baseline results published by other centres so far. The second was to examine the repeatability and spread of different parameters of the pupil light reflex. Methods: Thirty-five healthy volunteers were recruited for the study, ranging in age from 21 to 65, with a negative skew. Of these, twenty-six underwent a single episode of testing. Nine underwent repeated testing on five separate occasions. Testing was carried out with a custom-built infra-red Maxwellian-view pupillometer. Labview software was used to extract the pupil tracing and estimate values for the maximal amplitude of pupillary constriction, maximal constriction velocity and the change in pupil diameter between the point of maximal constriction velocity and the point of maximal constriction. Results: The relationship between age and dark diameter supported previous work, as did the decline of baseline diameter with repeated stimulation. The absolute amplitude was found to have the lowest spread. The spread of all the parameters was lower within an individual than between individuals, although significant differences in the response to repeated testing was demonstrable within an individual. An approximate correlation between pupillary diameter and maximal amplitude of constriction was found, particularly at a pupillary diameter of below 7mm. Conclusion: The custom-built infra-red Maxwellian view pupillometer is a suitable pupillometer to use for the testing of the pupillary light reflex as its baseline results are in accordance with results published by other centres thus far. There is a large variation of the

6 pupillary light reflex parameters, although this variation is smaller within an individual than between individuals. 95% confidence intervals were established in the relationship between maximal constriction amplitude and baseline diameter. Task-evoked pupil dilation in ageing and Alzheimer s disease Gillian Porter, Ute Leonards, Gordon Wilcock, Judy Haworth, Tom Troscianko and Andrea Tales University of Bristol, UK. There is often speculation that cognitive resource availability declines in older adults. Nevertheless, pupillary dilation, known to index effort or resource application, has rarely been applied in studies of healthy or pathological ageing. Here we compared patterns of task-evoked pupil dilation during performance of visual search tasks across young and healthy old participant groups, and patients with Alzheimer s disease (AD). Our search tasks involved difficult discriminations and were equally slow and inefficient. In the conjunction task, target and distractors differed in terms of a unique conjunction of features (shape and orientation), whereas in the feature task, a single feature dimension (orientation) defined the target. Visual reflexes were minimised and equated across task conditions, and trials were long enough to allow full task-evoked pupil responses to unfold. The manifestation of initial reflexes, in response to stimulus onset, differed between the groups, perhaps owing to slowed sympathetic reactivity in older and (especially) AD people. However, such differences were overcome within c.2 seconds. Task-evoked dilatory patterns as trials progressed were indistinguishable for young and healthy old groups and across tasks, suggesting that healthy ageing has no effect upon either resource availability or application. Unlike the healthy groups, AD patients showed a greater maximum pupillary dilation in conjunction than feature search, indicating an AD-specific deficit impacting upon the effort required to process information combined across multiple dimensions. However, peak pupil dilation was no less for patients than healthy controls overall. Although we need greater understanding of how pupillary control mechanisms are affected by AD, this tends to oppose the concept of general resource depletion in AD. Overall, the results indicate that effort expenditure during task performance, as indexed by pupil dilation, is maintained across the lifespan. They further demonstrate the potential applicability of this technique for identifying subtle differences in processing patterns across groups. Pupil constriction in teleost fish is related to camouflage not vision Ron Douglas Department of Optometry & Visual Science, City University, London, UK. The pupils of most vertebrates (mammals, birds, amphibian, reptiles & cartilaginous fish) constrict on increased illumination. However, the pupil of bony fish (teleosts) is generally thought to be immobile. Recent work by us and a review of the older literature, however, shows that some species of teleost (midshipman, suckermouth catfish, eels, stargazers, monkfish, toadfish, pearlfish and some flatfish) in fact have very extensive pupil movements. Why should some teleosts have mobile pupils while most do not? Arguably the main function of pupil constriction in most animals is to increase image quality by decreasing the amount of spherical aberration. However, the lenses of catfish, which have mobile pupils, and goldfish, whose pupils are fixed, show similar amounts of aberration, suggesting pupil mobility in fish does not serve such a visual function. Interestingly, most teleosts with extensive pupillary mobility are bottom dwellers with upwardly directed eyes that conceal themselves in the substrate. In such species large dark fixed pupils, as observed in most teleosts, would be very visible, and reveal their presence to both predators and prey. The lack of eyelids in fish makes this especially problematic. Furthermore, bottom dwelling teleosts cannot conceal their eyes using conspicuous stripes or spots in a similar way to free swimming species. Pupil constriction might thus serve to conceal the otherwise very prominent pupil with an iris that matches the bodily pigmentation.

7 Pupil studies in patients with congenital and acquired hemianopia P Jindahra 1, G T Plant 1, W Bi 2, J L Barbur 2, 1 Neuro-opthalmology, Institute of Neurology, University College London, London, UK.; 2 Applied Vision Research Centre, The Henry Wellcome Laboratories for Vision Sciences, City University, London, UK. Aim: To investigate possible differences in pupil response components to visual stimuli presented in the clinically blind regions of the visual field in patients with either congenital or acquired damage to the occipital cortex Methods: The P_SCAN system [1] was employed to generate appropriate visual stimuli and the corresponding pupil responses were in each eye. The viewing was binocular and the stimuli were presented both in the sighted and the cortically blind regions of the visual field. Two types of stimuli were employed to stimulate selectively either chromatic or luminance channels.the coloured stimuli were designed to activate only chromatic channels [2] and had no effect on rod photoreceptors in the eye [3]. This restriction limits the chromaticities that can be employed to two directions in the CIE (x,y) 1931 chromaticity diagram.these directions correspond perceptually to greenish and reddish colours. Two colour signal strengths were employed for the red stimulus (i.e., and 0.155) and only one colour signal strength was employed for the green stimulus (i.e., 0.1). The achromatic stimuli were of constant size, varied in luminance contrast (i.e., L/L=0.2, 1 or 4) and caused an increment in light flux on the retina. We report preliminary findings in normal subjects and in patients with either congenital or acquired homonymous hemianopia (only 10 subjects have been examined so far and the findings are therefore preliminary. Results: Pupil responses measured in the blind hemifield of patients with acquired cortical damage are in general of reduced amplitude when compared to those measured in the corresponding regions of the sighted field.the differences between the blind and sighted regions of the visual filed are particularly strong for small stimuli of low luminance contrast. The patient with congenital loss of visual field sensitivity (studied so far) does not show the pattern of pupil response loss measured in patients with acquired hemianopia. The results so far reveal significantly larger pupil responses in the blind hemifield in this patient when compared to the normal, sighted field. Conclusion: This observation suggests that in the absence of normal functioning of the direct genicolostriate projection, other projections to midbrain nuclei or to extrastriate regions of the brain (that may bypass the primary visual cortex) are enhanced and these include the pupillary pathways. It remains to be shown that these findings can be generalised to patients with congenital hemianopia. [1] J. L. Barbur, W. D. Thomson, and P. M. Forsyth. A new system for the simultaneous measurement of pupil size and two-dimensional eye movements. Clinical Vision Science 2: , [2] J. L. Barbur. 'Double-blindsight' revealed through the processing of color and luminance contrast defined motion signals. Prog.Brain Res.144: , [3] J. L. Barbur, L. Weiskrantz, and J. A. Harlow. The unseen color aftereffect of an unseen stimulus: insight from blindsight into mechanisms of color afterimages. Proc.Natl.Acad.Sci.U.S.A. 96 (20): , 1999.