Pupillary Light Response Research Articles

Keeping a large-pupilled eye on high-level visual processing

The pupillary light response has long been considered an elementary reflex. However, evidence now shows that it integrates information from such complex phenomena as attention, contextual processing, and imagery. These discoveries make pupillometry a promising tool for an entirely new application: the study of high-level vision.

A Positive Association Between Intrinsically Photosensitive Retinal Ganglion Cells and Retinal Nerve Fiber Layer Thinning in Glaucoma

To assess the integrity of intrinsically photosensitive retinal ganglion cells (ipRGCs) using the pupillary light reflex in glaucoma patients. A cross-sectional study was conducted, including 76 eyes from 38 patients with primary open-angle glaucoma and 36 eyes from 18 control subjects. The patients were tested in the dark with light stimuli using the Ganzfeld system, and the pupil diameter was measured with the assistance of an eye tracker consisting of two infrared cameras fit to an eyeglass frame. To preferentially stimulate ipRGCs, we used a 1-second 470-nm flash with a luminance of 250 cd/m(2). To stimulate different retinal photoreceptors (cones and rods), we used a 1-second 630-nm flash with a luminance of 250 cd/m(2). Standard automated perimetry (SAP), matrix frequency-doubling technology (FDT), and high-definition optical coherence tomography (Cirrus HD-OCT) were also performed. The correlation between the ipRGC-mediated sustained response following the pupillary light reflex and the structural and functional changes in glaucoma patients was analyzed using generalized estimating equation. An association was observed between the average retinal nerve fiber layer (RNFL) thickness, as measured by Cirrus HD-OCT, and the sustained pupillary response to the blue flash (P = 0.024). The severity of glaucoma, based on the mean deviation of SAP (Hodapp-Anderson-Parrish system), was also associated with the sustained response to the blue flash (P = 0.006). This study showed a correlation between the mean RNFL thickness and the pupillary light response. A decrease in the number of ipRGCs is potentially related to the reduced RNFL thickness.

Opponent melanopsin and S-cone signals in the human pupillary light response.

In the human, cone photoreceptors (L, M, and S) and the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are active at daytime light intensities. Signals from cones are combined both additively and in opposition to create the perception of overall light and color. Similar mechanisms seem to be at work in the control of the pupil's response to light. Uncharacterized however, is the relative contribution of melanopsin and S cones, with their overlapping, short-wavelength spectral sensitivities. We measured the response of the human pupil to the separate stimulation of the cones and melanopsin at a range of temporal frequencies under photopic conditions. The S-cone and melanopsin photoreceptor channels were found to be low-pass, in contrast to a band-pass response of the pupil to L- and M-cone signals. An examination of the phase relationships of the evoked responses revealed that melanopsin signals add with signals from L and M cones but are opposed by signals from S cones in control of the pupil. The opposition of the S cones is revealed in a seemingly paradoxical dilation of the pupil to greater S-cone photon capture. This surprising result is explained by the neurophysiological properties of ipRGCs found in animal studies.

Discovering irregular pupil light responses to chromatic stimuli using waveform shapes of pupillograms.

BackgroundThe waveforms of the pupillary light reflex (PLR) can be analyzed in a diagnostic test that allows for differentiation between disorders affecting photoreceptors and disorders affecting retinal ganglion cells, using various signal processing techniques. This procedure has been used on both healthy subjects and patients with age-related macular degeneration (AMD), as a simple diagnostic procedure is required for diagnosis.ResultsThe Fourier descriptor technique is used to extract the features of PLR waveform shapes of pupillograms and their amplitudes. To detect those patients affected by AMD using the extracted features, multidimensional scaling (MDS) and clustering techniques were used to emphasize stimuli and subject differences. The detection performance of AMD using the features and the MDS technique shows only a qualitative tendency, however. To evaluate the detection performance quantitatively, a set of combined features was created to evaluate characteristics of the PLR waveform shapes in detail. Classification performance was compared across three categories (AMD patients, aged, and healthy subjects) using the Random Forest method, and weighted values were optimized using variations of the classification error rates. The results show that the error rates for healthy pupils and AMD-affected pupils were low when the value of the coefficient for a combination of PLR amplitudes and features of waveforms was optimized as 1.5. However, the error rates for patients with age-affected eyes was not low.ConclusionsA classification procedure for AMD patients has been developed using the features of PLR waveform shapes and their amplitudes. The results show that the error rates for healthy PLRs and AMD PLRs were low when the Random Forest method was used to produce the classification. The classification of pupils of patients with age-affected eyes should be carefully considered in order to produce optimum results.Electronic supplementary materialThe online version of this article (doi:10.1186/s13637-014-0018-x) contains supplementary material, which is available to authorized users.

Temporal lobe abnormalities in neurosyphilis

A 28-year-old woman presented with a 5-month history of cognitive and behavioural disturbances. Her past history was unremarkable, and she had no family history of neurological disorders. On examination, she...

The pupillary light response reflects eye-movement preparation

The pupillary light response reflects eye-movement preparation

Visual dysfunction and pupillary responses are dissociated in the Opa3 mutant mouse with retinal degeneration

AbstractPurpose To assess the affect of the missense mutation p.L122P in a mouse model of 3‐methylglutaconic aciduria (MGA‐III), a neuro‐metabolic syndrome which presents with retinal and optic atrophy and neurological impairment.Methods Visual acuity was quantified in an optokinetic nystagmus drum by increasing the spatial frequency of the grating until an optomotor response could not be elicited. Pupillary light responsiveness was assessed by video pupillometry. Time course and phenotype of retinal degeneration was examined using haematoxylin and eosin and terminal dUTP transferase nick end labelling.Results Opa3+/+ and Opa3+/‐ mice showed normal visual acuity by tracking a 2° grating. However, Opa3‐/‐ mice displayed no optomotor response at any grating frequency. Despite this, their pupil response was little affected. Pupil response/intensity curves of Opa3‐/‐ and Opa3+/+ mice diverged somewhat at lower intensities although they only differed significantly at two irradiance levels. At 50% constriction Opa3‐/‐ mice were only 0.61 log units less sensitive than wildtypes. Histology showed panretinal degeneration in adult Opa3‐/‐ mice and TUNEL revealed increased cell death in postnatal and adult Opa3‐/‐ retinae.Conclusion The Opa3‐/‐ mouse is a useful model of the human disease. Retinal atrophy in Opa3‐/‐ animals is associated with widespread retinal thinning. However, dissociation between visual perception and pupillary function implies that the intrinsically photosensitive retinal ganglion cells (ipRGCs) subserving pupillary function may be less susceptible to damage by mutations of Opa3 than the retinogeniculate fibres underlying visual perception.

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep.

Using siRNA to define functional interactions between melanopsin and multiple G Protein partners.

Melanopsin expressing photosensitive retinal ganglion cells (pRGCs) represent a third class of ocular photoreceptors and mediate a range of non-image forming responses to light. Melanopsin is a G protein coupled receptor (GPCR) and existing data suggest that it employs a membrane bound signalling cascade involving Gnaq/11 type G proteins. However, to date the precise identity of the Gα subunits involved in melanopsin phototransduction remains poorly defined. Here we show that Gnaq, Gna11 and Gna14 are highly co-expressed in pRGCs of the mouse retina. Furthermore, using RNAi based gene silencing we show that melanopsin can signal via Gnaq, Gna11 or Gna14 in vitro, and demonstrate that multiple members of the Gnaq/11 subfamily, including Gna14 and at least Gnaq or Gna11, can participate in melanopsin phototransduction in vivo and contribute to the pupillary light responses of mice lacking rod and cone photoreceptors. This diversity of G protein interactions suggests additional complexity in the melanopsin phototransduction cascade and may provide a basis for generating the diversity of light responses observed from pRGC subtypes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-014-1664-6) contains supplementary material, which is available to authorized users.

Outcome in patients with bacterial meningitis presenting with a minimal Glasgow Coma Scale score.

Objective:In bacterial meningitis, a decreased level of consciousness is predictive for unfavorable outcome, but the clinical features and outcome in patients presenting with a minimal score on the Glasgow Coma Scale are unknown.Methods:We assessed the incidence, clinical characteristics, and outcome of patients with bacterial meningitis presenting with a minimal score on the Glasgow Coma Scale from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012.Results:Thirty of 1,083 patients (3%) presented with a score of 3 on the Glasgow Coma Scale. In 22 of 30 patients (73%), the minimal Glasgow Coma Scale score could be explained by use of sedative medication or complications resulting from meningitis such as seizures, cerebral edema, and hydrocephalus. Systemic (86%) and neurologic (47%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (77%). However, 12 of 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as a score of 5 on the Glasgow Outcome Scale. Patients presenting with a minimal Glasgow Coma Scale score on admission and bilaterally absent pupillary light responses, bilaterally absent corneal reflexes, or signs of septic shock on admission all died.Conclusions:Patients with community-acquired bacterial meningitis rarely present with a minimal score on the Glasgow Coma Scale, but this condition is associated with high rates of morbidity and mortality. However, 1 out of 5 of these severely ill patients will make a full recovery, stressing the continued need for aggressive supportive care in these patients.

Pupil size and social vigilance in rhesus macaques.

Complex natural environments favor the dynamic alignment of neural processing between goal-relevant stimuli and conflicting but biologically salient stimuli like social competitors or predators. The biological mechanisms that regulate dynamic changes in vigilance have not been fully elucidated. Arousal systems that ready the body to respond adaptively to threat may contribute to dynamic regulation of vigilance. Under conditions of constant luminance, pupil diameter provides a peripheral index of arousal state. Although pupil size varies with the processing of goal-relevant stimuli, it remains unclear whether pupil size also predicts attention to biologically salient objects and events like social competitors, whose presence interferes with current goals. Here we show that pupil size in rhesus macaques both reflects the biological salience of task-irrelevant social distractors and predicts vigilance for these stimuli. We measured pupil size in monkeys performing a visual orienting task in which distractors—monkey faces and phase-scrambled versions of the same images—could appear in a congruent, incongruent, or neutral position relative to a rewarded target. Baseline pupil size under constant illumination predicted distractor interference, consistent with the hypothesis that pupil-linked arousal mechanisms regulate task engagement and distractibility. Notably, pupil size also predicted enhanced vigilance for social distractors, suggesting that pupil-linked arousal may adjust the balance of processing resources between goal-relevant and biologically important stimuli. The magnitude of pupil constriction in response to distractors closely tracked distractor interference, saccade planning and the social relevance of distractors, endorsing the idea that the pupillary light response is modulated by attention. These findings indicate that pupil size indexes dynamic changes in attention evoked by both the social environment and arousal.

Pupillary light response in guinea pigs and swine exposed to organophosphate agents (1143.5)

Here we report a study to more precisely define and quantify the relationship between organophosphate agent exposure, including pesticides and nerve agents, with cholinesterase inhibition and the ocular biomarkers that are induced. A thorough investigation of these relationships was conducted to subsequently refine pupillary algorithms for the automated detection of organophosphate exposures with greater specificity regarding level of exposure, the extent of cholinesterase inhibition, and the temporal presentation and persistence of the ocular biomarkers. A guinea pig model was exposed to varying concentrations of parathion (pesticide), soman and VX (nerve agents) to methodically detail both the temporal and quantitative occurrence of pupillary deficits (anticholinesterase biomarkers) to determine the most sensitive, accurate diagnostic algorithms in these animal models. Dose‐response curves and temporal‐response curves for both pupillary deficits and generalized symptoms were developed for each agent used. Based upon previous studies dose ranges were conducted from the LD50 to 3000‐fold below the LD50 to incorporate lethal and sub‐lethal exposures without decreasing the potential sensitivity of the ocular biomarkers. In addition, cholinesterase assays were performed at various time points post‐exposure. The key finding of this study was that after exposure to organophosphates changes in pupillary response were detected prior to changes in acetylcholine esterase levels in guinea pigs. This opens the possibility of early detection to organophosphate exposure in a non‐invasive manner that does not require the use of enzyme markers. We are in the process of duplicating these studies in swine and swine data will be presented.Grant Funding Source: Supported by Defense Threat Reduction Agency

Monochromatic Pupillometry in Unilateral Glaucoma Discloses no Adaptive Changes Subserved by the ipRGCs

Purpose: To detect signs of a possible adaptive mechanism of the intrinsically photosensitive ganglion cells in unilateral glaucoma.Method: Eleven patients with unilateral glaucoma, classified by automated perimetry (glaucoma: mean deviation <0), were studied by monochromatic pupillometry, employing red (660 nm) or blue (470 nm) light, and by optical coherence tomography of the peripapillary retinal nerve fiber layer. The main outcome measure in pupillometry, the area under the curve (AUC), i.e., the product of pupillary contraction amplitude and time, was determined during and after light exposure in glaucomatous and unafflicted fellow eyes and compared to the AUCs of a healthy, age-matched control group.Results: The AUC to stimulation with blue light was significantly reduced in glaucomatous eyes, both during and after stimulus, compared with that of fellow, unafflicted eyes (p ≤ 0.014). The AUC to red light stimulation was reduced during (p = 0.035), but not after (p ≥ 0.072), exposure in glaucomatous eyes. In the unafflicted fellow eyes, the pupillary response to blue light did not differ from that of healthy controls.Conclusion: The pupillary response to blue light was decreased in the glaucomatous eyes of unilateral glaucoma. No difference was detected between the pupillary light response of the unafflicted fellow eyes and that of a healthy, age-matched control group. Thus no sign of an adaptive mechanism was detected, neither in the glaucomatous nor in the unafflicted fellow eyes, and consequently glaucoma appears to differ from non-arteritic anterior ischemic optic neuropathy.

The pupillary light response reveals the focus of covert visual attention.

The pupillary light response is often assumed to be a reflex that is not susceptible to cognitive influences. In line with recent converging evidence, we show that this reflexive view is incomplete, and that the pupillary light response is modulated by covert visual attention: Covertly attending to a bright area causes a pupillary constriction, relative to attending to a dark area under identical visual input. This attention-related modulation of the pupillary light response predicts cuing effects in behavior, and can be used as an index of how strongly participants attend to a particular location. Therefore, we suggest that pupil size may offer a new way to continuously track the focus of covert visual attention, without requiring a manual response from the participant. The theoretical implication of this finding is that the pupillary light response is neither fully reflexive, nor under complete voluntary control, but is instead best characterized as a stereotyped response to a voluntarily selected target. In this sense, the pupillary light response is similar to saccadic and smooth pursuit eye movements. Together, eye movements and the pupillary light response maximize visual acuity, stabilize visual input, and selectively filter visual information as it enters the eye.

Association between melanopsin gene polymorphism (I394T) and pupillary light reflex is dependent on light wavelength

BackgroundOur aim was to determine the association between melanopsin gene polymorphism and pupillary light reflex under diverse photic conditions, including different intensities and wavelengths.MethodsA total of 195 visually corrected subjects volunteered for investigation of the melanopsin gene of single nucleotide polymorphism (SNP) of rs1079610 (I394T). The genotype groups were TT (n = 126), TC (n = 55), and CC (n = 8), and 75 of the subjects, including subjects with TT (n = 34), TC (n = 33), and CC (n = 8) participated in our experiment. Three monochromatic lights with peak wavelengths of 465 nm (blue), 536 nm (green), and 632 nm (red) were prepared, and each light was projected to the subjects with five intensities, 12, 13, 14, 14.5 and 15 log photons/(cm2 s), for one minute. The pupil size of the left eye was measured under each light condition after a 1-minute adaptation.ResultsThe pupils of the TC + CC genotypes (n = 38) were significantly smaller than those of the TT genotype (n = 31) under a blue (463 nm) light condition with 15 log photons/(cm2 s) (P < 0.05). In contrast, there were no significant differences under green (536 nm) and red (632 nm) light conditions. Conversely, relative pupil constrictions of the TC + CC genotypes were greater than those of the TT genotype under both blue and green conditions with high intensities (14.5 and 15 log photons/(cm2 s)). In contrast, there were no significant differences between genotype groups in pupil size and relative pupilloconstriction under the red light conditions.ConclusionsOur findings suggest that the melanopsin gene polymorphism (I394T) functionally interacts with pupillary light reflex, depending on light intensity and, particularly, wavelength, and that under a light condition fulfilling both high intensity and short wavelength, the pupillary light response of subjects with the C allele (TC + CC) is more sensitive to light than that of subjects with the TT genotype.

SIRT1 Promotes RGC Survival and Delays Loss of Function Following Optic Nerve Crush

Activation of SIRT1 deacetylase prevents retinal ganglion cell (RGC) loss in experimental optic neuritis, an inflammatory optic neuropathy. While mechanisms of this effect are not known, evidence suggests it involves reduction of oxidative stress. We hypothesized that SIRT1 reduces RGC loss due to oxidative stress in noninflammatory optic neuropathies, and examined effects following traumatic injury. Optic nerve crush injury was induced in wild-type C57BL/6 mice, mice overexpressing SIRT1, and mice with conditional deletion of SIRT1 in neurons. Wild-type mice were treated daily with vehicle or 250 mg/kg resveratrol, a naturally occurring polyphenol that activates SIRT1. RGC function was assessed by pupillometry and optokinetic responses (OKR), and RGC survival was measured. Superoxide levels were measured to assess oxidative stress. Significant decreases in pupillary light responses, OKR and RGC survival occurred 1 week after optic nerve crush, with progressive worsening at 2 to 4 weeks. Resveratrol treatment and SIRT1 overexpression delayed RGC loss and loss of pupillary light responses following optic nerve crush, although no change in RGC loss occurred in neuronal SIRT1-deficient mice. A significant accumulation of superoxide was detected in wild-type optic nerves following crush, and was reduced in mice overexpressing SIRT1 or treated with resveratrol. SIRT1 delays RGC loss following traumatic injury. Effects are associated with reduced oxidative stress. Results suggest SIRT1-activating drugs may have a specific role in preventing traumatic optic nerve damage, and suggest a broader role for this strategy in treating a variety of optic neuropathies that may include a component of oxidative stress.

End-of-Life and Brain Death in Acute Coma and Disorders of Consciousness

Consulting neurologists are often asked to evaluate patients in acute nontraumatic coma. The authors review prognostication of functional outcomes, determining brain death, and managing end-of-life care. Prognostication of outcome after cardiac arrest in comatose patients is a frequently encountered scenario with high-stakes implications. However, current guidelines are limited by a failure to address the use of therapeutic hypothermia and thus may lead to overly pessimistic outcome prediction. Pupillary light responses and corneal reflexes remain highly predictive clinical signs of a poor prognosis. Motor responses have a high false-positive rate for predicting a poor outcome, especially in patients treated with therapeutic hypothermia. Ancillary testing with electroencephalography, somatosensory evoked potentials, serum neuron-specific enolase, and neuroimaging is often useful in predicting outcomes. Brain death is a clinical condition of irreversible coma of known cause with absent brainstem reflexes and apnea. An understanding of the value of confirmatory testing and the potential for confounding factors is essential in making a correct diagnosis. As coma carries a high mortality rate, neurologists must be capable of guiding goals of care, discussing end-of-life issues, and understanding organ-procurement procedures.

Prognostic Assessment Always Requires Several Parameters

An important point of criticism regarding the cited studies is the fact that the prognostic parameters under investigation are further used in decisions about stopping therapy. This entails the possibility of a self-fulfilling prophecy. In the study by Bouwes et al., for example, therapy was immediately ended or limited in 40 out of 42 patients with lacking somatosensory evoked potentials (SEP) (1). We have repeatedly cared for patients who woke up again in spite of concentrations of neuron-specific enolase (NSE) >97 µg/L. The biggest impression was left by the case of a patient with a neuroendocrine tumor, whose NSE rose to >1000 µg/L. In assessing the NSE, malignant tumors should be regarded as confounders. In our opinion, the key message “Elevated serum concentrations of neuron-specific enolase have to be above 97 µg/L to serve as a safe indicator of an unfavorable prognosis” is therefore problematic in this abbreviated form. We think that the factually equating the bilateral absence of the pupillary light response or the corneal reflex with reliable indicators of a poor prognosis is equally problematic, because of possible examiner bias. Especially absent corneal reflexes should be assessed with a great deal of caution. Bouwes and Samaniego described 2 of 23, and 2 of 22, patients whose outcome was good in spite of absent corneal reflexes (1, 3). A high degree of certainty in the prognostic assessment is possible only by basing it on several parameters, rather than a single one. We treat most patients for seven days before we limit their treatment according to an interdisciplinary prognostic algorithm, on the basis of several consistent parameters for a poor prognosis (2).

Melanopsin Gene Polymorphism I394T Is Associated with Pupillary Light Responses in a Dose-Dependent Manner

BackgroundMelanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) play an important role in non-image forming responses to light, such as circadian photoentrainment, light-induced melatonin suppression, and pupillary light response. Although it is known that there are some single nucleotide polymorphisms (SNPs) in the melanopsin (OPN4) gene in humans, the associations of the SNPs with non-image forming responses to light remains unclear. In the present study, we examined the associations of melanopsin gene polymorphisms with pupillary light response.MethodsJapanese university students (mean age: 21.0±1.7 years) with the genotypes of TT (n = 38), TC (n = 28) and CC (n = 7) at rs1079610 (I394T) located in the coding region participated in the present study. They were matched by age and sex ratio. Dark-adapted pupil size (<1 lx) was first measured. Then steady-state pupil size was measured during exposure to five lighting conditions (10 lx, 100 lx, 1000 lx, 3000 lx, 6000 lx in the vertical direction at eye level).ResultsSignificant interaction between the genotype of I394T (TT versus TC+CC) and luminance levels was found in pupil size. Under high illuminance levels (1000 lx, 3000 lx and 6000 lx), pupil sizes in subjects with the C allele were significantly smaller than those in subjects with the TT genotype. On the other hand, pupil size in subjects with the C allele under low illuminance (<1 lx) was significantly larger than that in subjects with the TT genotype. Percentages of pupil constriction under high illuminance levels were significantly greater in subjects with the C allele than in subjects with the TT genotype.ConclusionsHuman melanopsin gene polymorphism I394T interacted with irradiance in association with pupil size. This is the first evidence suggesting a functional connection between melanopsin gene polymorphism and pupillary light response as an index of non-image forming response to light.

MEDIUM-GRADE ASTROCYTOMA IN A COUGAR (PUMA CONCOLOR)

A 17-year-old, male castrated cougar (Puma concolor) was presented minimally responsive and severely depressed, with bilateral mydriasis and absent pupillary light response. On gross examination of the brain, there was a tan-to-gray, invasive mass with a central cavitation on the ventral aspect in the left cerebral hemisphere, rostral to the caudate nucleus. On histopathologic examination, the mass was composed of sheets of medium-sized, round-to-polygonal cells that were multifocally separated by islands of neuropil. Approximately 80% of the neoplastic cells showed strong cytoplasmic labeling for glial fibrillary acidic protein. These findings were consistent with a medium-grade astrocytoma. To the authors' knowledge, neoplastic disease of the central nervous system has not been previously reported in cougars.