Pupillary Constriction In Response Research Articles

Orexin-A Intensifies Mouse Pupillary Light Response by Modulating Intrinsically Photosensitive Retinal Ganglion Cells.

We show for the first time that the neuropeptide orexin modulates pupillary light response, a non-image-forming visual function, in mice of either sex. Intravitreal injection of the orexin receptor (OXR) antagonist TCS1102 and orexin-A reduced and enhanced pupillary constriction in response to light, respectively. Orexin-A activated OX1Rs on M2-type intrinsically photosensitive retinal ganglion cells (M2 cells), and caused membrane depolarization of these cells by modulating inward rectifier potassium channels and nonselective cation channels, thus resulting in an increase in intrinsic excitability. The increased intrinsic excitability could account for the orexin-A-evoked increase in spontaneous discharges and light-induced spiking rates of M2 cells, leading to an intensification of pupillary constriction. Orexin-A did not alter the light response of M1 cells, which could be because of no or weak expression of OX1Rs on them, as revealed by RNAscope in situ hybridization. In sum, orexin-A is likely to decrease the pupil size of mice by influencing M2 cells, thereby improving visual performance in awake mice via enhancing the focal depth of the eye's refractive system.SIGNIFICANCE STATEMENT This study reveals the role of the neuropeptide orexin in mouse pupillary light response, a non-image-forming visual function. Intravitreal orexin-A administration intensifies light-induced pupillary constriction via increasing the excitability of M2 intrinsically photosensitive retinal ganglion cells by activating the orexin receptor subtype OX1R. Modulation of inward rectifier potassium channels and nonselective cation channels were both involved in the ionic mechanisms underlying such intensification. Orexin could improve visual performance in awake mice by reducing the pupil size and thereby enhancing the focal depth of the eye's refractive system.

The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

PurposeHuman and animal studies suggest that light-mediated dopamine release may underlie the protective effect of time outdoors on myopia development. Melanopsin-containing retinal ganglion cells may be involved in this process by integrating ambient light exposure and regulating retinal dopamine levels. The study evaluates this potential involvement by examining whether melanopsin-driven pupillary responses are associated with adult refractive error.MethodsSubjects were 45 young adults (73% female, 24.1 ± 1.8 years) with refractive errors ranging from –6.33 D to +1.70 D. The RAPDx (Konan Medical) pupillometer measured normalized pupillary responses to three forms of square-wave light pulses alternating with darkness at 0.1 Hz: alternating long wavelength (red, peak at 608 nm) and short wavelength (blue, peak at 448 nm), followed by red only and then blue only.ResultsNon-myopic subjects displayed greater pupillary constriction in the blue-only condition and slower redilation following blue light offset than subjects with myopia (P = 0.011). Pupillary responses were not significantly different between myopic and non-myopic subjects in the red-only condition (P = 0.15). More hyperopic/less myopic refractive error as a continuous variable was linearly related to larger increases in pupillary constriction in response to blue-only stimuli (r = 0.48, P = 0.001).ConclusionsRepeated light exposures to blue test stimuli resulted in an adaptation in the pupillary response (more constriction and slower redilation), presumably due to increased melanopsin-mediated input in more hyperopic/less myopic adults. This adaptive property supports a possible role for these ganglion cells in the protective effects of time outdoors on myopia development.

Cross-species convergence in pupillary response: understanding human anxiety via non-human primate amygdala lesion.

Few studies have used matched affective paradigms to compare humans and non-human primates. In monkeys with amygdala lesions and youth with anxiety disorders, we examined cross-species pupillary responses during a saccade-based, affective attentional capture task. Given evidence of enhanced amygdala function in anxiety, we hypothesized that opposite patterns would emerge in lesioned monkeys and anxious participants. A total of 53 unmedicated youths (27 anxious, 26 healthy) and 8 adult male rhesus monkeys (Macaca mulatta) completed matched behavioral paradigms. Four monkeys received bilateral excitotoxic amygdala lesions and four served as unoperated controls. Compared to healthy youth, anxious youth exhibited increased pupillary constriction in response to emotional and non-emotional distractors (F(1,48) = 6.28, P=0.02, η2p= 0.12). Pupillary response was associated significantly with anxiety symptoms severity (F(1,48) = 5.59, P=0.02, η2p= 0.10). As hypothesized, lesioned monkeys exhibited the opposite pattern i.e. decreased pupillary constriction in response to distractors, compared to unoperated control monkeys (F(1,32) = 24.22, P<0.001, η2= 0.33). Amygdala lesioned monkeys and youth with anxiety disorders show opposite patterns of pupil constriction in the context of an affective distractor task. Such findings suggest the presence of altered amygdala circuitry functioning in anxiety. Future lesion and human neuroimaging work might examine the way in which specific amygdala sub-nuclei and downstream circuits mediate these effects.

Tropicamide has limited clinical effect on cycloplegia and mydriasis when combined with cyclopentolate and phenylephrine

To examine the cycloplegic and mydriatic effect of tropicamide omission from a common pediatric eye drop combination. Consecutive children examined at the Ann & Robert H. Lurie Children's Hospital of Chicago from June 8, 2017 to September 6, 2017 were enrolled prospectively. Tropicamide, cyclopentolate, and phenylephrine (TCP) was instilled in one eye; cyclopentolate and phenylephrine (CP), in the other. Spherical equivalent, maximum pupil size, and pupillary constriction in response to photostimulation were measured before and 30minutes after instillation using an autorefractor and pupillometer. Iris pigmentation was examined as a between-subjects variable. A total of 75 children 4-11years of age were included. Mean differences in spherical equivalent between TCP and CP were not statistically significant (P=0.95). Significant interactions between eye drop regimen and iris pigmentation were observed for pupil size (P=0.001) and constriction percentage (P=0.02). Among only patients with dark irides, TCP yielded slightly larger pupils (7.70 vs 7.31mm [P<0.001]) that were less responsive to light (5.75% vs 8.07% [P=0.002]). All pupils dilated to ≥6.0mm, with equivalent proportions achieving ≥7.0mm for TCP and CP (P=0.18). TCP and CP elicited equivalent cycloplegic effects. Mydriatic differences between the regimens, although statistically significant in dark irides, were of limited clinical magnitude, and all pupils achieved sufficient dilation for funduscopy.

An Anatomic Characterization of the Midbrain Near Response Neurons in the Macaque Monkey.

PurposeThese experiments were designed to reveal the location of the premotor neurons that have previously been designated physiologically as the midbrain near response cells controlling vergence, lens accommodation, and pupillary constriction in response to target distance.MethodsTo identify this population, the fixed N2c strain of rabies virus was injected into the ciliary body of seven Macaca fascicularis monkeys. The virus was trans-synaptically transported to the brain. Following a 58- to 76-hour survival, animals were perfused with formalin fixative. After frozen sectioning, tissue was reacted to reveal the location of the infected populations by use of a monoclonal anti-rabies antibody. Another series of sections was processed to determine which of the rabies-positive cells were cholinergic motoneurons by use of an antibody to choline acetyl transferase.ResultsAt earlier time points, only cholinergic cells in the preganglionic Edinger-Westphal nucleus ipsilateral to the injection were labeled. At later time points, an additional population of noncholinergic, premotor cells was present. These were most numerous at the caudal end of the supraoculomotor area, where they formed a bilateral band, oriented mediolaterally immediately above the oculomotor nucleus. Rostral to this, a smaller bilateral population was located near the midline within the supraoculomotor area.ConclusionsMost lens preganglionic motoneurons are multipolar cells making up a continuous column within the Edinger-Westphal nucleus. A population of premotor cells that likely represents the midbrain near response cells is located in the supraoculomotor area. These cells are bilaterally distributed relative to the eye they control, and are most numerous caudally.

EVER Lecture ‐ and is delivered by the Past President: The Pupil: A marker of visual and non‐visual light sensitivity

SummaryThe well‐recognized, rapid pupillary constriction in response to an abrupt increase in illuminatino is largely mediated by rods and cones and pupillary size trends with the rapid adaptation function of these photoreceptors. The melanopsin‐mediated light response of intrinsically photosensitive retinal ganglion cells (ipRGCs) displays unique features whose influence on pupillary movement can be best differentiated in the post‐illumination phase of the pupil light reflex. Even the longterm adaptation to cyclic environmental light is reflected in the pupil response. As such, our understanding of ”deficit” in patients with ophthalmological disorders is no longer limited to visual perception and has broadened to consider non‐visual light functions directly or indirectly mediated by melanopsin.

Pupillary response abnormalities in depressive disorders.

Depressive disorders lack objective physiological measurements to characterize the affected population and facilitate study of relevant mechanisms. The melanopsin-mediated light signaling pathway may contribute to seasonal variation and can be measured non-invasively by pupillometry. We prospectively studied changes in melanopsin-mediated pupillary constriction in 19 participants with major depressive disorder (MDD) and 10 control across the summer and winter solstices. The melanopsin-mediated response, as measured by the pupil's sustained constriction six s after a high intensity blue light stimulus, was marginally attenuated in those with MDD relative to controls (p=0.071). The participants with MDD unexpectedly showed a significantly reduced transient pupillary response to low intensity red (p=0.011) and blue light (p=0.013), but not high intensity red and blue light. Sustained pupillary constriction in response to high intensity blue light was more pronounced with increasing daylight hours (p=0.037) and was more strongly related to objectively measured versus estimated light exposure. Melanopsin-mediated impairments in pupil response may serve as a biological marker for vulnerability to depression in low light conditions. Assessment of these and other responses to light stimuli, such as response to low intensity light, may be useful for the study of the neurobiology of MDD and related mood disorders.

Intracranial Causes of Ophthalmoplegia: The Visual Reflex Pathways

The gathering of visual information is a complex process that relies on concerted movements of the eyes, and cranial nerves II-VIII are at least partially involved in the visual system. The cranial nerves do not function in isolation, however, and there are multiple higher-order cortical centers that have input into the cranial nerves to coordinate eye movement. Among the functions of the cortical reflex pathways are (a) controlling vertical and horizontal gaze in response to vestibular input to keep the eyes focused on an object as the head moves through space, and (b) controlling rapid, coordinated eye movement to a new visual target (saccades). There are also reflex pathways connecting the cranial nerves involved in vision that produce consensual blinking of the eyes in response to corneal stimulation of one eye and consensual pupillary constriction in response to light input on one pupil. A variety of intracranial pathologic conditions, including benign and malignant neoplasms, infection, trauma, autoimmune diseases, vascular anomalies, degenerative diseases, and inherited-congenital disorders, can disrupt the cranial nerves and visual reflex pathways. This disruption can manifest in myriad ways-for example, as extraocular muscle paresis, afferent pupillary defect, oculosympathetic paresis (Horner syndrome), internuclear ophthalmoplegia, dorsal midbrain (Parinaud) syndrome, or loss of the corneal reflex. Knowledge of the function and anatomy of the cranial nerves and visual reflex pathways, coupled with selection of the proper magnetic resonance pulse sequence, will allow the radiologist to order appropriate imaging of the involved cranial nerve or visual reflex pathway based on the patient's symptoms and thereby play an essential role in establishing the diagnosis and planning appropriate therapy.

Duration of pupillary constriction in response to a photographic flash

We read with interest the recent article by Twa et al.1 concerning the clinical measurement of pupil diameter (PD) using digital flash photography. Although not explicitly stated, it appears that the authors' intention was to measure the dark-adapted pupil diameter (DAPD) at <1 lux and at 5 lux. Digital photography was performed with the Nikon CoolPix 990 camera using the auto-flash setting at 17 cm. First, a 10-second infrared video clip was taken followed by a flash photograph; the subject was allowed to readapt for 2 minutes, and then another examiner repeated the video and photograph. It is unlikely that the second digital photograph was taken exactly 2 minutes and 10 seconds after the first one, but the interval between them was not measured. We were concerned that incomplete dark adaptation at the time of the second photograph might be a source of experimental error. Two of us (J.C.B., A.M.K.) conducted the following experiment: After dark adaptation at 5 lux for 5 minutes, an infrared still digital photograph of 1 eye was taken with an infrared-capable digital video camera using our customary technique2; following this, a Nikon CoolPix 990 camera was held 17 cm from the subject and an auto-flash photograph was taken, although no effort was made to focus it. At 2, 5, and 10 minutes after the flash, infrared photographs were repeated (Figure 1).Figure 1.: Pupil diameter plotted as a function of the timing of the infrared photograph after the digital camera flash. Neither pupil returned to baseline by 10 minutes. The measurement errors induced by incomplete readaptation at 5 minutes were 0.18 mm and 0.35 mm. Multiple flashes (required in 4% of subjects tested by Twa et al.) would exacerbate the problem. Baseline = dark adaptation at 5 lux for 5 minutes.In Twa et al., 2 investigators tested subjects in an “arbitrary” examiner order and the results of examiner 1 versus examiner 2 were statistically analyzed. Analysis of the first versus the second examination for each test would be interesting. If the examiner order was not randomized, a test performed by examiner 1 might frequently also be examination 1, which could induce systematic inter-examiner errors related to the unrecognized duration of the flash-induced PD reduction (Figure 2).Figure 2.: Measured mean pupil diameter plotted in the (speculative) test sequence, in which examiner 1 performed a nonrandom majority of the photographic testing before examiner 2. For measurements taken at 0.63 lux, a steady downward trend can be identified. Measurements at 5 lux do not show this trend, but they would if the examiners had reversed order so examiner 2 was more frequently performing the examination first (data from Table 3, Twa et al.1).This is speculative analysis, but it deserves further consideration by the authors because it illustrates 2 major sources of test artifact when measuring the DAPD: incomplete retinal dark adaptation, especially after brief exposure to a bright light source, and involuntary accommodation or psychogenic awareness of near. Along the same line, might the consistently smaller Colvard pupillometer measurements of examiner 2 be due to residual accommodative miosis induced by the first pupillometer measurement? Although the authors took pains to discourage accommodation, randomized examiner sequence is the only way to rule out accommodation as a confounding variable. We encourage the authors to analyze and report their data based on the examination sequence and also to repeat the Colvard pupillometer measurements with a randomized examiner order. Sandra M. Brown MD Jay C. Bradley MD Arshad M. Khanani MD Lubbock, Texas, USA

Duration of pupillary constriction in response to a photographic flash

Reply: We are pleased to receive insightful comments on our work by Brown and coauthors. They raise several important methodology issues with respect to studies of pupil measurement that deserve further discussion and wider consideration. Brown and coauthors suggest that our study was intended to measure the pupil under dark-adapted conditions. This, however, was not our intent. We make a strict distinction between the dark-room conditions described in our study and true dark adaptation, which we reserve for the unique physiological state of rod-driven retinal sensitivity occurring after approximately 35 minutes of complete darkness in the normal eye.1 Brown and coauthors are rightly concerned that the time interval between the first flash exposure and subsequent measurements by the second examiner could have been insufficient for full pupil recovery. If the order of examiner was not randomized, this would lead to a sequence effect whereby the second examiner would measure a consistently smaller pupil size. They provide a plot of pupil size as a function of time in 2 eyes photographed using their recently published technique2 to illustrate this point. In our original publication, we reported that examiner order was arbitrary. In fact, 1 examiner was first in all but 2 cases. This provided an opportunity to test Brown and coauthors' hypothesis. Using a 2-way repeated measures analysis of variance (ANOVA) model, we compared the mean pupil size measured at each light level across examiners and also tested for an interaction between examiner and light level for the digital photographic method of measurement. If the concerns expressed by Brown and coauthors were a factor in our experiments, we would expect to find a significant interaction between these 2 variables. We found no interaction between light level and examiner (Figure 1; P=.09) and no difference between the 2 examiners in pupil size measurements (P=.20).Figure 1.: Mean measured pupil diameter by examiner as a function of light level for the photographic measurement method.Because any observed differences in pupil size could be due to examiner effects or sequence effects, we further explored their concern by testing for differences between examiners in mean pupil diameter with a 2-way ANOVA comparing light level across methods of measurement for each examiner sequence (examiner 1 then examiner 2; examiner 2 then examiner 1). We did not find a significant sequence effect on pupil size when we compared light levels by method interactions or method of measurement for either test sequence and show the comparison of pupil size by light level for each examiner (Figure 1). These findings should satisfy the concerns expressed by Brown and coauthors. Although the concern about an examiner sequence effect is valid and they identify a methodological weakness of our design, it did not influence our reported results. Brown and coauthors suggest that the time between photographs was not controlled or measured. Although we elected not to report these data, they were recorded and provide further evidence to allay their concerns. We show the difference between examiners for pupil diameter measurements as a function of time (Figure 2). The slope of this function was not significantly different than zero by linear regression (−0.018 mm/min; 95% confidence interval −0.050 to +0.014). The time between pupil measurements was 3.5 minutes at the medium light level (5 lux) and 4.3 minutes at the low light level (<0.63 lux).Figure 2.: Difference in measured pupil diameter between examiner 1 and examiner 2 as a function of the time difference between the 2 measurements. Number = 45 (×3 light levels); r 2 = 0.00, P = .98, Y = (0.130)X. The slope of this function was not statistically different than zero.A second hypothesis proposed by Brown and coauthors is that the variations observed in pupil size measurements with the Colvard pupillometer were possibly due to a prolonged tonic proximal accommodative response, and they suggest that we repeat our study with a randomized examiner order to address this issue. This raises another important concern of any pupil measurement study; namely, control of accommodation. The normal time course of pupil recovery from a convergent accommodative stimulus is seconds.3 Given that more than 2 minutes had passed between each examiner's measurements, the pupil should have had sufficient time to completely recover from an accommodative stimulus. We are grateful for the comments of Brown and coauthors and appreciate the opportunity to respond to their concerns. Michael Twa OD Melissa Bailey OD, PhD Mark Bullimore MCOptom, PhD John Hayes PhD

Real-time optical coherence tomography of the anterior segment at 1310 nm.

Recent advances in high-speed scanning technology have enabled a new generation of optical coherence tomographic (OCT) systems to perform imaging at video rate. Here, a handheld OCT probe capable of imaging the anterior segment of the eye at high frame rates is demonstrated for the first time. To demonstrate real-time OCT imaging of anterior segment structures. Survey of anterior segment structures in normal human subjects. Laboratory. Achieving real-time imaging of the anterior segment, satisfactory image quality, and convenience of a handheld probe. Optical coherence tomographic imaging of the anterior segment of the eyes of human subjects was performed using 1310-nm wavelength light with an image rate of 8 frames per second. Imaging trials demonstrated clear resolution of corneal epithelium and stroma, sclerocorneal junction, sclera, iris pigment epithelium and stroma, and anterior lens capsule. The anterior chamber angle was clearly visualized. Limited imaging of the ciliary body was performed. Real-time imaging of pupillary constriction in response to light stimulus was also performed. High-speed OCT at 1310-nm wavelength is a potentially useful technique for noninvasive assessment of anterior segment structures. Our results suggest that real-time OCT has potential applications in glaucoma evaluation and refractive surgery.

An Open Future

isoelectric EEG and yet live for many years. Dr. White seems to be implying that we should simply ignore the frequent finding of intact neurohormonal function in patients diagnosed as brain dead. If regulation of the body's fluid and electrolyte balance within a narrow tolerance does not represent intricate brain functioning, then what should we think of such relatively simple reflexes as pupillary constriction in response to light? No one can survive without osmotic homeostasis, while the absence of pupillary constriction is at most an inconvenience. And if

Pupillary constriction in response to light in rodents, which does not depend on central neural pathways

We show here that the widely held belief that reflex constriction of the mammalian pupil in response to light depends exclusively upon neural pathways between eye and brain is in need of revision. We investigated the response of the pupil to light in dark-adapted rodents (golden hamsters; hooded rats; albino rats) subjected to a variety of surgical and pharmacological interventions designed to destroy or block all of the neural pathways and structures through which the reflex could be mediated. The interventions included bilateral intraorbital optic nerve section, or unilateral intracranial optic nerve section with enucleation of the contralateral eye, combined in some cases with bilateral removal of the superior cervical ganglia and/or pinealectomy; topical application of atropine; intraocular injection of tetrodotoxin (TTX). Golden hamsters and hooded rats, but not albino rats, retained an effective constriction of the pupil in response to light after all of these interventions, although the constriction was less and slower than in normal animals. These findings show that hamsters and hooded rats have both a neurally mediated fast light reflex that can be eliminated by severing connections between eye and brain, by blockade of cholinergic transmission to iris smooth muscle, and by blockade of action potentials by TTX; and a local, slower constriction in response to light, which remains after all these procedures. We have also confirmed previous observations of Bito and Turansky (1975) that pupillary constriction in response to light occurs in isolated in vitro anterior chamber preparations of hamster and hooded rat eyes. However, we were not able to demonstrate constriction in identical preparations of albino rat eyes. The data suggest on the basis of both in vivo and in vitro studies, that the hamster and hooded rat, but not the albino rat, possess an autonomous local mechanism for controlling pupillary diameter that is completely independent of the retina or the brain.

Autonomic denervation hypersensitivity in the primary glaucomas.

Autonomic denervation hypersensitivity of the iris was assessed in 44 patients with primary closed-angle glaucoma, 20 patients with primary open-angle glaucoma, and 40 age- and sex-matched control subjects. Significantly increased pupillary constriction in response to 2.5% methacholine chloride, indicating parasympathetic denervation hypersensitivity, was present in both closed-angle (p less than 0.02) and open-angle glaucoma patients (p less than 0.001), compared with the control group. Significantly increased pupillary dilatation in response to 0.5 per cent phenylephrine hydrochloride, indicating sympathetic denervation hypersensitivity of the iris, was also present in both closed-angle glaucoma (p less than 0.01) and open-angle glaucoma patients (p less than 0.05). The association between autonomic neuropathy and the primary glaucomas is discussed, with particular reference to the potential effects of autonomic dysfunction on aqueous dynamics.

639 UNILATERAL OPTIC NERVE DISEASE, A COMPLICATION OF CHEMOTHERAPY OF ACUTE LYMPHATIC LEUKEMIA (ALL)

Ocular complications are not uncommon with the use of vincristine (VCR) but usually consist of ophthalmoplegias. A single case of optic neuropathy, presumably caused by VCR, has been previously reported in a patient with Hodgkin's disease (Am. J. Ophthal. 81:146, 1976). We have observed this complication in two subjects with ALL. In each case, severe unilateral retrobulbar pain occurred 5-7 days following the administration of VCR (2.0 mg/m2) during maintenance therapy. In the first subject, an 8 yr. old, eye exam several months after the onset of ocular symptoms revealed a visual acuity of 20/80 in the affected eye which failed to improve with refraction. A positive Marcus Gunn pupil, defective color vision and a central scotoma were noted. Fundoscopy was normal. Eye exam prior to the onset of symptoms had been unremarkable. In the second case, a 6 yr. old, acuity was 20/40 in the affected eye unimproved by refraction. Pupillary constriction in response to light was followed by rapid dilatation. Color vision was normal but a paracentral scotoma was present. A vitritis localized over the optic disc caused the disc to appear pale and indistinct. In each subject the contralateral eye exam was normal. In both cases repeated spinal fluid cytologies have been negative. Optic nerve disease in these cases is presumably related to the use of VCR. Retrobulbar or eye pain following the administration of VCR calls for careful ophthalmologic examination.