Pupil Size as a Window on Neural Substrates of Cognition.

Relationships between Pupil Diameter and Neuronal Activity in the Locus Coeruleus, Colliculi, and Cingulate Cortex

Background. The pupillary light reflex is the main mechanism that regulates the pupillary diameter; it is controlled by the autonomic system and mediated by subcortical pathways. In addition, cognitive and emotional processes influence pupillary function due to input from cortical innervation, but the exact circuits remain poorly understood. We performed a systematic review to evaluate the mechanisms behind pupillary changes associated with cognitive efforts and processing of emotions and to investigate the cerebral areas involved in cortical modulation of the pupillary light reflex. Methodology. We searched multiple databases until November 2018 for studies on cortical modulation of pupillary function in humans and non-human primates. Of 8808 papers screened, 252 studies were included. Results. Most investigators focused on pupillary dilatation as an index of cognitive and emotional processing, evaluating how changes in pupillary diameter reflect levels of attention and arousal. Only few tried to correlate specific cerebral areas to pupillary changes, using either cortical activation models (employing micro-stimulation of cortical structures in non-human primates) or cortical lesion models (e.g. investigating patients with stroke and damage to salient cortical and/or subcortical areas). Results suggest involvement of several cortical regions, including the insular cortex, the frontal eye field and the prefrontal cortex, and of subcortical structures such as the locus coeruleus and the superior colliculus. Conclusions. Pupillary dilatation occurs with many kinds of mental or emotional processes, following sympathetic activation or parasympathetic inhibition. This phenomenon is controlled by several subcortical and cortical structures that are directly or indirectly connected to the brainstem pupillary innervation system.

Changes in pupil size induced by phacoemulsification and posterior chamber lens implantation: Consequences for multifocal lenses

Pupil size variations have been associated with changes in brain activity patterns related with specific cognitive factors, such as arousal, attention, and mental effort. The locus coeruleus (LC), a key hub in the noradrenergic system of the brain, is considered to be a key regulator of cognitive control on pupil size, with changes in pupil diameter corresponding to the release of norepinephrine (NE). Advances in eye-tracking technology and open-source software have facilitated accurate pupil size measurement in various experimental settings, leading to increased interest in using pupillometry to track the nervous system activation state and as a potential biomarker for brain disorders. This review explores pupillometry as a non-invasive and fully translational tool for studying cortical plasticity starting from recent literature suggesting that pupillometry could be a promising technique for estimating the degree of residual plasticity in human subjects. Given that NE is known to be a critical mediator of cortical plasticity and arousal, the review includes data revealing the importance of the LC-NE system in modulating brain plasticity and pupil size. Finally, we will review data suggesting that pupillometry could provide a quantitative and complementary measure of cortical plasticity also in pre-clinical studies.

IntroductionAssessment of the pupillary light reflex (PLR) is key in intensive care monitoring of neurosurgical patients, particularly for monitoring intracranial pressure (ICP). Quantitative pupillometry using a handheld pupillometer is a reliable method for PLR assessment. However, many variables are derived from such devices. We therefore aimed to assess the performance of these variables at monitoring ICP. MethodsSedated patients admitted to neurocritical care in a tertiary neurosurgical centre with invasive ICP monitoring were included. Hourly measurement of ICP, subjective pupillometry (SP) using a pen torch device, and quantitative pupillometry (QP) using a handheld pupillometer were performed. Results561 paired ICP, SP and QP pupillary observations from nine patients were obtained (1122 total pupillary observations). SP and QP had a moderate concordance for pupillary size (κ=0.62). SP performed poorly at detecting pupillary size changes (sensitivity=24%). In 40 (3.6%) observations, SP failed to detect a pupillary response whereas QP did. Moderate correlations with ICP were detected for maximum constriction velocity (MCV), dilation velocity (DV), and percentage change in pupillary diameter (%C). Discriminatory ability at an ICP threshold of >22 mmHg was moderate for MCV (AUC=0.631), DV (AUC=0.616), %C (AUC=0.602), and pupillary maximum size (AUC=0.625). ConclusionQP is superior to SP at monitoring pupillary reactivity and changes to pupillary size. Although effect sizes were moderate to weak across assessed variables, our data indicates MCV and %C as the most sensitive variables for monitoring ICP. Further study is required to validate these findings and to establish normal range cut-offs for clinical use.

Brimonidine and pupillary diameter

Night Driving After LASIK

Dynamic non-luminance-mediated changes in pupil diameter have frequently been shown to be a reliable index for the level of arousal, mental effort, and activity in the locus coeruleus, the brainstem's noradrenergic arousal center. While pupillometry has most commonly been used to assess the level of arousal in particular psychological states or the level of engagement in cognitive tasks, some recent studies have found a relationship between average resting-state (i.e. baseline) pupil sizes and individuals' working memory capacity (WMC), indicating that individuals with higher WMC on average have larger pupils than individuals with relatively lower WMC. In the present study, we measured pupil size continuously in 212 participants during rest (i.e. while fixating) and estimated WMC in all participants by administering the Letter-Number Sequencing (LNS) task from WAIS-III. We were unable to replicate the relation between average pupil size and WMC. However, the novel finding was that higher WMC was associated with higher variability in resting-state pupil size. The present results are relevant for the current debate on the role of noradrenergic activity on working memory capacity.

This paper investigates the relationship between semantic processing of words and modifications in pupil size. Variations in pupil diameter reflect cognitive processing, as has been widely demonstrated in literature. We designed an experiment in which semantic association between words was manipulated in order to disclose potential differences in cognitive processing. Moreover, we measured the concurrent pupil diameter changes. Results showed faster pupil dilation in trials in which words were semantically associated. As changes in pupil diameter do not occur under voluntary control, they could reflect processing of preconscious information. We believe that a better symbiotic relationship between humans and machines is achievable once systems are able to make us aware of these “involuntary” changes.KeywordsPupil diameterSemantic associationSymbiotic relationship

It has been hypothesized that central and peripheral refraction, in eyes treated with myopic overnight orthokeratology, might vary with changes in pupil diameter. The aim of this work was to evaluate the axial and peripheral refraction and optical quality after orthokeratology, using ray tracing software for different pupil sizes. Zemax-EE was used to generate a series of 29 semi-customized model eyes based on the corneal topography changes from 29 patients who had undergone myopic orthokeratology. Wavefront refraction in the central 80 degrees of the visual field was calculated using three different quality metrics criteria: Paraxial curvature matching, minimum root mean square error (minRMS), and the Through Focus Visual Strehl of the Modulation Transfer Function (VSMTF), for 3- and 6-mm pupil diameters. The three metrics predicted significantly different values for foveal and peripheral refractions. Compared with the Paraxial criteria, the other two metrics predicted more myopic refractions on- and off-axis. Interestingly, the VSMTF predicts only a marginal myopic shift in the axial refraction as the pupil changes from 3 to 6 mm. For peripheral refraction, minRMS and VSMTF metric criteria predicted a higher exposure to peripheral defocus as the pupil increases from 3 to 6 mm. The results suggest that the supposed effect of myopic control produced by ortho-k treatments might be dependent on pupil size. Although the foveal refractive error does not seem to change appreciably with the increase in pupil diameter (VSMTF criteria), the high levels of positive spherical aberration will lead to a degradation of lower spatial frequencies, that is more significant under low illumination levels.

BackgroundThe pupillary light reflex is the main mechanism that regulates the pupillary diameter; it is controlled by the autonomic system and mediated by subcortical pathways. In addition, cognitive and emotional processes influence pupillary function due to input from cortical innervation, but the exact circuits remain poorly understood. We performed a systematic review to evaluate the mechanisms behind pupillary changes associated with cognitive efforts and processing of emotions and to investigate the cerebral areas involved in cortical modulation of the pupillary light reflex.MethodologyWe searched multiple databases until November 2018 for studies on cortical modulation of pupillary function in humans and non-human primates. Of 8,809 papers screened, 258 studies were included.ResultsMost investigators focused on pupillary dilatation and/or constriction as an index of cognitive and emotional processing, evaluating how changes in pupillary diameter reflect levels of attention and arousal. Only few tried to correlate specific cerebral areas to pupillary changes, using either cortical activation models (employing micro-stimulation of cortical structures in non-human primates) or cortical lesion models (e.g., investigating patients with stroke and damage to salient cortical and/or subcortical areas). Results suggest the involvement of several cortical regions, including the insular cortex (Brodmann areas 13 and 16), the frontal eye field (Brodmann area 8) and the prefrontal cortex (Brodmann areas 11 and 25), and of subcortical structures such as the locus coeruleus and the superior colliculus.ConclusionsPupillary dilatation occurs with many kinds of mental or emotional processes, following sympathetic activation or parasympathetic inhibition. Conversely, pupillary constriction may occur with anticipation of a bright stimulus (even in its absence) and relies on a parasympathetic activation. All these reactions are controlled by subcortical and cortical structures that are directly or indirectly connected to the brainstem pupillary innervation system.

Attentional effort relates to the allocation of limited-capacity attentional resources to meet current task demands and involves the activation of top-down attentional systems in the brain. Pupillometry is a sensitive measure of this intensity aspect of top-down attentional control. Studies relate pupillary changes in response to cognitive processing to activity in the locus coeruleus (LC), which is the main hub of the brain's noradrenergic system and it is thought to modulate the operations of the brain's attentional systems. In the present study, participants performed a visual divided attention task known as multiple object tracking (MOT) while their pupil sizes were recorded by use of an infrared eye tracker and then were tested again with the same paradigm while brain activity was recorded using fMRI. We hypothesized that the individual pupil dilations, as an index of individual differences in mental effort, as originally proposed by Kahneman (1973), would be a better predictor of LC activity than the number of tracked objects during MOT. The current results support our hypothesis, since we observed pupil-related activity in the LC. Moreover, the changes in the pupil correlated with activity in the superior colliculus and the right thalamus, as well as cortical activity in the dorsal attention network, which previous studies have shown to be strongly activated during visual tracking of multiple targets. Follow-up pupillometric analyses of the MOT task in the same individuals also revealed that individual differences to cognitive load can be remarkably stable over a lag of several years. To our knowledge this is the first study using pupil dilations as an index of attentional effort in the MOT task and also relating these to functional changes in the brain that directly implicate the LC-NE system in the allocation of processing resources.

Event Abstract Back to Event Pupillometric evidence for a role of locus coeruleus in dynamic belief updating Matthew Nassar1*, Robert C. Wilson2, Rishi Kalwani1, Benjamin Heasly1 and Joshua Gold1 1 University of Pennsylvania, United States 2 Princeton University, United States Many decisions are based on subjective beliefs about the probability and utility of potential outcomes. These beliefs are typically adjusted upon observation of a new outcome. One biologically supported rule for this belief-updating process is the delta rule, according to which a belief is updated by some fraction of the error made in predicting an outcome. The fractional term, the learning rate, regulates the influence of incoming information on a stored belief and is often set as a constant. However, theoretical and experimental work suggests that the brain does not use a constant learning rate but instead adaptively regulates the influence of new outcomes [A.J.Yu and P.Dayan NIPS 157-164,2002; T.E.J.Behrens et.al. Nature Neuroscience 10:1214-1221,2007]. Little is known about the underlying neural mechanisms. Here we identify a physiological correlate of this adaptive regulation process involving changes in pupil diameter, which are thought to reflect the activity of the norepinephrine-locus coeruleus (NE-LC) system. Human subjects performed a novel inference task that required them to make predictions about a random quantity whose value fluctuated from trial to trial because of either noise or changepoints in the statistics of the generative process. A computationally tractable reduction of the ideal-observer model for this task is a form of delta rule in which the learning rate depends on the number of outcomes that occurred since the most recent changepoint (run length) and the probability that a changepoint occurred on the current trial (changepoint probability). The model can predict trial-to-trial changes in subject learning rates. Such rational adaptation of learning rate has been proposed to involve the NE-LC and other neuromodulatory systems [A.J.Yu and P.Dayan Neuron 46:681-692,2005]. To test this idea, we measured pupil diameter in subjects performing a version of the task with an isoluminant display, a condition under which pupil diameter is correlated with the activity of LC neurons R.Kalwani, unpublished data. We found that pupil diameter changed relative to task events on multiple timescales. Transient changes in pupil diameter occurred on each trial after the presentation of a new outcome. The magnitude of these phasic responses was correlated with model estimates of changepoint probability and subject learning rates. More gradual changes in pupil diameter occurred on the timescale of many trials. This baseline pupil diameter was greatest 1-2 trials after a changepoint and correlated inversely with run-length estimates produced by the model. To examine whether LC plays a causal role in setting the learning rate we used a salient, but task irrelevant, auditory stimulus to evoke phasic pupil (and thus, presumably, LC) responses. Despite knowing that these stimuli were irrelevant to the task, subjects increased their learning rates after stimuli that caused large phasic pupil responses. Together, these data suggest that the NE-LC system helps to dynamically regulate the influence of new outcomes based on information about run length and changepoint probability. Conference: Computational and Systems Neuroscience 2010, Salt Lake City, UT, United States, 25 Feb - 2 Mar, 2010. Presentation Type: Oral Presentation Topic: Oral presentations Citation: Nassar M, Wilson RC, Kalwani R, Heasly B and Gold J (2010). Pupillometric evidence for a role of locus coeruleus in dynamic belief updating. Front. Neurosci. Conference Abstract: Computational and Systems Neuroscience 2010. doi: 10.3389/conf.fnins.2010.03.00043 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Feb 2010; Published Online: 18 Feb 2010. * Correspondence: Matthew Nassar, University of Pennsylvania, Philadelphia, United States, mattnassar@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Matthew Nassar Robert C Wilson Rishi Kalwani Benjamin Heasly Joshua Gold Google Matthew Nassar Robert C Wilson Rishi Kalwani Benjamin Heasly Joshua Gold Google Scholar Matthew Nassar Robert C Wilson Rishi Kalwani Benjamin Heasly Joshua Gold PubMed Matthew Nassar Robert C Wilson Rishi Kalwani Benjamin Heasly Joshua Gold Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Several commercial pilocarpine preparations have been compared for their efficacy of drug delivery as evaluated by changes in pupil diameter, and return to base-line pupil size, in rabbits and squirrel monkeys. Adsorbocarpine, Isoptocarpine, Pilocar, all at 2%, and Pilopine HS gel, 4%, were used. In albino rabbits the order of efficacy, as judged by area under the curve, or maximal pupil diameter change, was Pilopine greater than Isoptocarpine = Adsorbocarpine greater than Pilocar = saline (prepared in this laboratory). In general, greater areas under the curve were associated with greater changes in pupil diameter. Pupil diameter had returned to normal by a maximum of 5 hours after drop instillation. In squirrel monkeys, the maximum pupillary change was statistically (P greater than 0.05) the same for all preparations, as was the percentage change in pupil diameter at 6 hours since pupils were still somewhat constricted at this time after drop instillation. The differences in area under the curve were minor. The greater response in primates compared to rabbits may be due to differences in pigment, intraocular kinetics and a far more active ciliary muscle in primates. Also studied were newly developed, non-surfactant containing, preservative-free polymer- and microparticle-based vehicles. Some of the vehicles, based on cyanoacrylate, modified hyaluronate, anionic copolymers, polyvinyl-pyrrolidone, cross-linked gelatin and microparticles showed greater pupillary changes and areas under the curve in rabbits compared to saline vehicle. When compared to commercial preparations in the monkey eye cyanoacrylate block copolymer and modified hyaluronate showed an increase in efficacy. Polyvinylpyrrolidone, anionic copolymer and cross-linked gelatin were equal to the commercial preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute mild exercise has been observed to facilitate executive function and memory. A possible underlying mechanism of this is the upregulation of the ascending arousal system, including the catecholaminergic system originating from the locus coeruleus (LC). Prior work indicates that pupil diameter, as an indirect marker of the ascending arousal system, including the LC, increases even with very light-intensity exercise. However, it remains unclear whether the LC directly contributes to exercise-induced pupil-linked arousal. Here, we examined the involvement of the LC in the change in pupil dilation induced by very light-intensity exercise using pupillometry and neuromelanin imaging to assess the LC integrity. A sample of 21 young males performed 10 min of very light-intensity exercise, and we measured changes in the pupil diameters and psychological arousal levels induced by the exercise. Neuromelanin-weighted magnetic resonance imaging scans were also obtained. We observed that pupil diameter and psychological arousal levels increased during very light-intensity exercise, which is consistent with previous findings. Notably, the LC contrast, a marker of LC integrity, predicted the magnitude of pupil dilation and psychological arousal enhancement with exercise. These relationships suggest that the LC-catecholaminergic system is a potential a mechanism for pupil-linked arousal induced by very light-intensity exercise.