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Chromatic Pupillometry, used to assess Pupil Light Reflex (PLR) to a coloured light stimulus, has regained interest since the discovery of melanopsin in the intrinsically photosensitive Retinal Ganglion Cells (ipRGCs). This technique has shown the potential to be used as a screening tool for neuro-ophthalmological diseases; however, most of the pupillometers available are expensive and not portable, making it harder for them to be used as a widespread screening tool. In this study, we developed a smartphone-based system for chromatic pupillometry that allows targeted stimulation of the ipRGCs. Using a smartphone, this system is portable and accessible and takes advantage of the location of the ipRGCs in the perifovea. The system incorporates a 3D-printed support for the smartphone and an illumination system. Preliminary tests were carried out on a single individual and then validated on eleven healthy individuals with two different LED intensities. The average Post-Illumination Pupil Light Response 6 s after the stimuli offsets (PIPR-6s) showed a difference between the blue and the red stimuli of 9.5% for both intensities, which aligns with the studies using full-field stimulators. The results validated this system for a targeted stimulation of the ipRGCs for chromatic pupillometry, with the potential to be a portable and accessible screening tool for neuro-ophthalmological diseases.

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Light triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates.

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Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications.SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.

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PURPOSE: To explore the pupil redilation during persistent light exposure (pupillary escape phenomenon) at the macula and periphery with monochromatic light stimuli. METHODS: Forty healthy subjects aged 18-64 years (24 females) were examined by chromatic pupil campimetry (CPC) using red and blue 4-s stimuli of 10° radius at the center and 20°-peripheral locations one per quadrant. One glaucoma patient and one achromatopsia patient served as disease models. For statistical analyses, linear mixed-effects models were performed followed by post hoc t-tests. RESULTS: A distinct pupillary escape could be demonstrated peripherally (blue 0.099%*s, red 0.153%*s); at the central healthy retina, there was no relevant escape, neither for blue nor red stimulation. Comparing central versus peripheral stimulation revealed highly significant differences in the escape (difference blue 0.100 ± 0.013, red 0.144 ± 0.013, < 0.0001, respectively). In the periphery, the escape was significantly more pronounced for red compared with blue stimulation (difference 0.054 ± 0.013; p = 0.0001). Enhanced pupillary escape outside of the 95% confidence interval of the linear mixed-effects model of the healthy population could be exemplarily shown in a patient with glaucomatous ganglion cell damage. In the achromatopsia example, no relevant escape was found for blue stimulation, but for red stimulation in the periphery in a comparable range to healthy controls. CONCLUSION: The results emphasize that an intact inner retinal network of nerve fibers arising from the central macular region is necessary for maintaining pupillary constriction during a bright 4-s light stimulus and preventing increase of pupillary escape. Increasing receptive field sizes towards the periphery on the level of retinal ganglion cells and less input from central 1:1 connections could be one of the driving mechanisms for pupillary escape.

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Purpose: To compare if the kinetic pupillary changes differs between high myopia (HM) and low/moderate myopia by Pentacam. Setting: Chinese People's Liberation Army (PLA) General Hospital, Beijing, China. Design: Comparative study. Methods: In this cross-sectional retrospective study, 44 eyes of 44 patients were recruited in the Refractive Surgery Center of Chinese PLA General Hospital. Eyes were divided into two groups according to the refractive error: low/moderate myopia (22 eyes; -2.99 ± 1.09 D) and HM (22 eyes, -12.93 ± 3.44 D). At the beginning of the experiment, we made trials of scanning one false pupil by Pentacam. All patients underwent the Pentacam examination three times. Pupillary diameters (PD) during the scan process and other parameters were measured using the Pentacam. Coefficient variations of PD (CV) during the different scanning periods were analyzed comparatively between the two groups. Results: Pentacam once time output 25 Scheimpflug images, with 13 ones during the period from 1st to 1.5th s and 12 ones during the period from 2.5th to 3rd s after the scanning onset. For the spatial order on all the 25 meridians, 13 Scheimpflug images came out when the Pentacam rotated from 60° to 153°meridians and the remaining 12 Scheimpflug images from 161° to 245° meridians. Among pupillary parameters, no statistical significance existed in PD25, PD13, and PD12 (pupil diameter's mean from all, former 13 and remaining 12 of 25 Scheimpflug images, respectively) (P > 0.05) between the two groups. However, there were statistically significant differences in CV25 and CV13 (coefficient variation of the pupil diameters from all and former 13 of 25 images, respectively) (P < 0.001), with no statistical significance in CV12 (coefficient variation of the pupil diameters from remaining 12 of 25 images) between both groups. Conclusion: Twenty-five Scheimpflug images on Pentacam had the temporal and the spatial orders. CV in eyes with HM was lower than that in eyes with low/moderate myopia in a certain period of the Pentacam scan. Kinetic pupillary size in HM changed more slowly than that in low/moderate myopia during some scanning period analogous to the phasic response of the pupil reflex.

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Objective:recently, pupil oscillations synchronized with steady visual stimuli were used as input for an interface. The proposed system, inspired by a brain-computer interface based on steady-state visual evoked potentials, does not require contact with the participant. However, the pupil oscillation mechanism limits the stimulus frequency to 2.5 Hz or less, making it hard to enhance the information transfer rate (ITR).Approach:here, we compared multiple conditions for stimulation to increase the ITR of the pupil vibration-based interface, which were called monocular-single, monocular-superposed, and binocular-independent conditions. The binocular-independent condition stimulates each eye at different frequencies respectively and mixes them by using the visual stereoscopic perception of users. The monocular-superposed condition stimulates both eyes by a mixed signal of two different frequencies. We selected the shape of the stimulation signal, evaluated the amount of spectral leakage in the monocular-superposed and binocular-independent conditions, and compared the power spectrum density at the stimulation frequency. Moreover, 5, 10, and 15 patterns of stimuli were classified in each condition.Main results:a square wave, which causes an efficient pupil response, was used as the stimulus. Spectral leakage at the beat frequency was higher in the monocular-superposed condition than in the binocular-independent one. The power spectral density of stimulus frequencies was greatest in the monocular-single condition. Finally, we could classify the 15-stimulus pattern, with ITRs of 14.4 (binocular-independent, using five frequencies), 14.5 (monocular-superimposed, using five frequencies), and 23.7 bits min-1(monocular-single, using 15 frequencies). There were no significant differences for the binocular-independent and monocular-superposed conditions.Significance:this paper shows a way to increase the number of stimuli that can be simultaneously displayed without decreasing ITR, even when only a small number of frequencies are available. This could lead to the provision of an interface based on pupil oscillation to a wider range of users.

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Two largely separate lines of research have documented altered pupillary dynamics in individuals diagnosed with schizophrenia. An older set of studies has demonstrated reductions in the pupillary light reflex (PLR) in individuals with schizophrenia; however, clinical and cognitive correlates of this blunted PLR have been relatively unexplored. More recently, a large body of work has demonstrated reductions in pupillary dilation in response to cognitive demands in individuals with schizophrenia, and the degree of this blunted pupil dilation has been related to more severe cognitive deficits and motivational negative symptoms. These clinically relevant alterations in the cognitive modulation of pupil size have been interpreted as reflecting insufficient information processing resources or inappropriate effort allocation. To begin to bridge these two lines of work, we investigated the PLR in 34 individuals with schizophrenia and 30 healthy controls and related the amplitude of the PLR to motivational negative symptoms and cognitive performance. Consistent with prior work, we found that the PLR was reduced in individuals with schizophrenia, and furthermore, that these measurements were highly reliable across individuals. Blunted constriction was associated with more severe motivational negative symptoms and poorer working memory among individuals with schizophrenia. These observed correlates provide a bridge between older literature documenting an altered PLR and more recent work reporting associations between negative symptoms, cognition, and blunted pupillary dilation in response to cognitive demands in individuals with schizophrenia. We provide possible mechanistic interpretations of our data and consider a parsimonious explanation for reduced cognitive- and light-related modulation of pupil size.

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Mammalian retinas contain three specialized photoreceptors: the rods and cones in the outer retina, whose primary function is to support visual perception in dim and bright environments, respectively, and a small subset of retinal ganglion cells ("intrinsically photosensitive" retinal ganglion cells; ipRGCs), which are directly light-responsive owing to their expression of the photopigment melanopsin. Melanopsin photoreception is optimized to encode low-frequency changes in the light environment and, as a result, extends the temporal and spatial range over which light is detected by the retina. ipRGCs innervate many brain areas, and this allows melanopsin light responses to be used for diverse purposes, ranging from the synchronization of the circadian clock with the solar day to light's regulation of mood, alertness, and neuroendocrine and cognitive functions. In this review, we discuss the methods and findings that have contributed to our understanding of melanopsin across biology. We particularly focus on the approaches that allow melanopsin to be studied at a systems/whole animal level and how these methods have illuminated the role of melanopsin in diverse physiological outputs.

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Saccadic eye movements are directed to the objects of interests and enable high-resolution visual images in the exploration of the visual world. There is a trial-to-trial variation in saccade dynamics even in a simple task, possibly attributed to arousal fluctuations. Previous studies have showed that an increase of fatigue level over time, also known as time-on-task, can be revealed by saccade peak velocity. In addition, pupil size, controlled by the autonomic nervous system, has long been used as an arousal index. However, limited research has been done with regards to the relation between pupil size and saccade behavior in the context of trial-to-trial variation. To investigate fatigue and arousal effects on saccadic and pupillary responses, we used bright and emotional stimuli to evoke pupillary responses in tasks requiring reactive and voluntary saccade generation. Decreased voluntary saccade peak velocities, reduced tonic pupil size and phasic pupillary responses were observed as time-on-task increased. Moreover, tonic pupil size affected saccade latency and dynamics, with steeper saccade main sequence slope as tonic pupil size increased. In summary, saccade dynamics and tonic pupil size were sensitive to fatigue and arousal level, together providing valuable information for the understanding of human behavior.

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The stall-housing system is commonly used in the modern swine industry in many countries; however, long-term space restrictions can cause affective and physiological abnormalities in sows. The pupil light reflex (PLR) can reflect the psychological and neurological changes in animals, and confined sows show higher pupillary rigidity. However, the PLR differs between same-parity sows, suggesting differences in behaviors and affective states between parity groups. We subjected confined Yorkshire × Landrace sows of parity 0, 2, and 5 to a PLR test and accordingly assigned them to the weak PLR (WR) group (n = 20) or the strong PLR (SR) group (n = 22). We then observed the sows' behaviors and performed a sucrose/quinine response test and novel object test (NOT) to assess the differences in their affective states. The standing and lateral lying behaviors of the sows were less frequent in WR than in SR (p < 0.05), whereas ventral lying and sitting behaviors was more frequent in WR than in SR (p < 0.05). No changes in chewing behaviors and sucrose/quinine responses were observed (p > 0.05); however, the numbers and duration of novel object contact were lower and the novel object response latency time was longer in WR than in SR (p < 0.05). Regarding parity, standing and lateral lying behaviors were less frequent and ventral lying and sitting behaviors were more frequent at parity 5 than at parity 0 (p < 0.05). Bar-biting, rooting, trough-biting, and sucrose response score were lower at parity 5 than at parity 0 (p < 0.05), and vacuum chewing behavior and quinine response score were higher in sows of parity 5 than in those of parity 0 (p < 0.05). NOT showed that the number of contacts and contact duration in sows decreased with increasing parity (p < 0.05), and the response latency time was longer in sows of parity 5 than in those of lower parity (p < 0.05). In conclusion, the behavioral expression and responses of confined sows to novel objects differed between PLRs. The evaluation of the affective state of sows also revealed marked differences with increasing parity. Thus, confined sows with WR and high parity apparently suffer from more severe psychological problems, and PLR may be a potent indicator for evaluating the affective state of confined sows.

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When the pupil dilates, the amount of light that falls onto the retina increases. However, in daily life, this does not make the world look brighter. Here we asked whether pupil size (resulting from active pupil movement) influences subjective brightness in the absence of indirect cues that, in daily life, support brightness constancy. We measured the subjective brightness of a tester stimulus relative to a referent as a function of pupil size during tester presentation. In Experiment 1, we manipulated pupil size through a secondary working-memory task (larger pupils with higher load and after errors). We found some evidence that the tester was perceived as darker, rather than brighter, when pupils were larger. In Experiment 2, we presented a red or blue display (larger pupils following red displays). We again found that the tester was perceived as darker when pupils were larger. We speculate that the visual system takes pupil size into account when making brightness judgments. Finally, we highlight the challenges associated with manipulating pupil size. In summary, the current study (as well as a recent pharmacological study on the same topic by another team) is intriguing first steps towards understanding the role of pupil size in brightness perception.

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The pupil responds to a salient stimulus appearing in the environment, in addition to its modulation by global luminance. These pupillary responses can be evoked by visual or auditory stimuli, scaled with stimulus salience, and enhanced by multisensory presentation. In addition, pupil size is modulated by various visual stimulus attributes, such as color, area, and motion. However, research that concurrently examines the influence of different factors on pupillary responses is limited. To explore how presentation of multiple visual stimuli influences human pupillary responses, we presented arrays of visual stimuli and systematically varied their luminance, color, and set size. Saliency level, computed by the saliency model, systematically changed with set size across all conditions, with higher saliency levels in larger set sizes. Pupillary constriction responses were evoked by the appearance of visual stimuli, with larger pupillary responses observed in larger set size. These effects were pronounced even though the global luminance level was unchanged using isoluminant chromatic stimuli. Furthermore, larger pupillary constriction responses were obtained in the blue, compared to other color conditions. Together, we argue that both cortical and subcortical areas contribute to the observed pupillary constriction modulated by set size and color.

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AIMS: The evidence relating the pupil light reflex (PLR) and cognition have been inconsistent. In this cross-sectional study, we evaluated the association between the PLR and cognition in community-dwelling middle-aged and older individuals. METHODS: Pupil reactivity was recorded in a subgroup of 403 participants (mean age 60.7 years, 57.3% females) in an epidemiologic study of aging. Ten pupil parameters were calculated to describe pupil constriction to light stimuli. A principal component analysis (PCA) score was used to calculate an overall performance over four cognitive testings. Linear regression was used to assess the association between pupil parameters and PCA scores, adjusting for age, sex, education, medications, health-related quality of life questionnaire, and systemic and ocular comorbidities. RESULTS: The PCA scores decreased by 0.039 [95% CI (- 0.050, - 0.028)] per year increase in age and were lower in males than females by 0.76 [95% CI (- 0.96, - 0.55)] (p < 0.001). Pupil constriction amplitude in millimeters and the duration from stimulus onset to maximal constriction velocity were significantly associated with cognition after adjusting for (1) age and sex and (2) age, sex, and multiple covariates (p < 0.05). CONCLUSIONS: In this study, we provided moderate evidence suggesting the association between PLR and neuropsychological cognitive measures. The findings suggest the potential of pupil reactivity to serve as a biomarker of brain aging and warrant further longitudinal study to assess if changes in the PLR can predict cognitive decline over time.

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The autonomic nervous system (ANS) confers neural control of the entire body, mainly through the sympathetic and parasympathetic nerves. Several studies have observed that the physiological functions of the eye (pupil size, lens accommodation, ocular circulation, and intraocular pressure regulation) are precisely regulated by the ANS. Almost all parts of the eye have autonomic innervation for the regulation of local homeostasis through synergy and antagonism. With the advent of new research methods, novel anatomical characteristics and numerous physiological processes have been elucidated. Herein, we summarize the anatomical and physiological functions of the ANS in the eye within the context of its intrinsic connections. This review provides novel insights into ocular studies.

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The pupil light reflex (PLR), a marker of neuronal response to light, is a well-studied index of autonomic functioning. Studies have found that autistic children and adults have slower and weaker PLR responses compared to non-autistic peers, suggesting lower autonomic control. Altered autonomic control has also been associated with increased sensory difficulties in autistic children. With autistic traits varying in the general population, recent studies have begun to examine similar questions in non-autistic individuals. The current study looked at the PLR in relation to individual differences in autistic traits in non-autistic children and adults, asking how differences in the PLR could lead to variation in autistic traits, and how this might change across development. Children and adults completed a PLR task as a measure of sensitivity to light and autonomic response. Results showed that, in adults, increased levels of restricted and repetitive behaviors (RRB) were associated with a weaker and slower PLR. However, in children, PLR responses were not associated with autistic traits. Differences in PLR were also found across age groups, with adults showing smaller baseline pupil diameter and stronger PLR constriction as compared with children. The current study expanded on past work to examine the PLR and autistic traits in non-autistic children and adults, and the relevance of these findings to sensory processing difficulties is discussed. Future studies should continue to examine the neural pathways that might underlie the links between sensory processing and challenging behaviors.

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The size of our pupils changes continuously in response to variations in ambient light levels, a process known as the pupillary light reflex (PLR). The PLR is not a simple reflex as its function is modulated by cognitive brain function and any long-term changes in brain function secondary to injury should cause a change in the parameters of the PLR. We performed a retrospective clinical review of the PLR of our patients using the BrightLamp Reflex iPhone app. The PLR variables of latency, maximum pupil diameter (MaxPD), minimum pupil diameter (MinPD), maximum constriction velocity (MCV), and the 75% recovery time (75% PRT) were associated with significant differences between subjects who had suffered a concussion and those that had not. There were also significant differences in PLR metrics over the life span and between genders and those subjects with and without symptoms. The differences in PLR metrics are modulated not only by concussion history but also by gender and whether or not the person has symptoms associated with a head injury. A concussive injury to the brain is associated with changes in the PLR that persist over the life span, representing biomarkers that might be used in clinical diagnosis, treatment, and decision making.

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Microsaccade is a type of fixational eye movements that is modulated by various sensory and cognitive processes, and impact our visual perception. Although studies in monkeys have demonstrated a functional role for the superior colliculus and frontal eye field (FEF) in controlling microsaccades, our understanding of the neural mechanisms underlying the generation of microsaccades is still limited. By applying continuous theta-burst stimulation (cTBS) over the right FEF and the vertex, we investigated the role of the FEF in generating human microsaccade responses evoked by salient stimuli or by changes in background luminance. We observed higher microsaccade rates prior to target appearance, and larger rebound in microsaccade occurrence following salient stimuli, when disruptive cTBS was applied over FEF compared to vertex stimulation. Moreover, the microsaccade direction modulation after changes in background luminance was disrupted with FEF stimulation. Together, our results constitute the first evidence of FEF modulation in human microsaccade responses.

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Saccades are rapid eye movements that are used to move the high acuity fovea in a serial manner in the exploration of the visual scene. Stimulus contrast is known to modulate saccade latency and metrics possibly via changing visual activity in the superior colliculus (SC), a midbrain structure causally involved in saccade generation. However, the quality of visual signals should also be modulated by the amount of lights projected onto the retina, which is gated by the size of the pupil. Although absolute pupil size should modulate visual signals and in turn affect saccade responses, research examining this relationship is very limited. Besides, pupil size is associated with motor preparation. However, the role of pupil dilation in saccade metrics remains unexplored. Through varying peripheral background luminance level and target visual contrast in the saccade task, we investigated the role of absolute pupil size and baseline-corrected pupil dilation in saccade latency and metrics. Higher target detection accuracy was obtained with lower background luminance level, and larger absolute pupil diameter correlated with smaller saccade amplitude and higher saccade peak velocities. More interestingly, the comparable modulation between pupil dilation and stimulus contrast was obtained, showing larger pupil dilation (or higher contrast stimuli) correlating with faster saccade latencies, larger amplitude, higher peak velocities, and smaller endpoint deviation. Together, our results demonstrated the influence of absolute pupil size induced by global luminance level and baseline-corrected pupil dilation associated with motor preparation on saccade latency and metrics, implicating the role of the SC in this behavior.

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BACKGROUND: We investigated the effectiveness of automated pupillometry on monitoring cardiopulmonary resuscitation (CPR) and predicting return of spontaneous circulation (ROSC) in a swine model of cardiac arrest (CA). METHODS: Sixteen male domestic pigs were included. Traditional indices including coronary perfusion pressure (CPP), end-tidal carbon dioxide (ETCO2), regional cerebral tissue oxygen saturation (rSO2) and carotid blood flow (CBF) were continuously monitored throughout the experiment. In addition, the pupillary parameters including the initial pupil size before constriction (Init, maximum diameter), the end pupil size at peak constriction (End, minimum diameter), and percentage of change (%PLR) were measured by an automated quantitative pupillometer at baseline, at 1, 4, 7 min during CA, and at 1, 4, 7 min during CPR. RESULTS: ROSC was achieved in 11/16 animals. The levels of CPP, ETCO2, rSO2 and CBF were significantly greater during CPR in resuscitated animals than those non-resuscitated ones. Init and End were decreased and %PLR was increased during CPR in resuscitated animals when compared with those non-resuscitated ones. There were moderate to good significant correlations between traditional indices and Init, End, and %PLR (|r| = 0.46-0.78, all P < 0.001). Furthermore, comparable performance was also achieved by automated pupillometry (AUCs of Init, End and %PLR were 0.821, 0.873 and 0.821, respectively, all P < 0.05) compared with the traditional indices (AUCs = 0.809-0.946). CONCLUSION: The automated pupillometry may serve as an effective surrogate method to monitor cardiopulmonary resuscitation efficacy and predict ROSC in a swine model of cardiac arrest.

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The appearance of a salient stimulus evokes a series of orienting responses including saccades and pupil size to prepare the body for appropriate action. The midbrain superior colliculus (SC) that receives critical control signals from the frontal eye field (FEF) is hypothesized to coordinate all components of orienting. It has shown recently that the FEF, together with the SC, is also importantly involved in the control of pupil size, in addition to its well-documented role in eye movements. Although the role of the FEF in pupil size is demonstrated in monkeys, its role in human pupil responses and the coordination between pupil size and saccades remains to be established. Through applying continuous theta-burst stimulation over the right FEF and vertex, we investigated the role of the FEF in human pupil and saccade responses evoked by a salient stimulus, and the coordination between pupil size and saccades. Our results showed that neither saccade reaction times (SRT) nor pupil responses evoked by salient stimuli were modulated by FEF stimulation. In contrast, the correlation between pupil size and SRTs in the contralateral stimulus condition was diminished with FEF stimulation, but intact with vertex stimulation. Moreover, FEF stimulation effects between saccade and pupil responses associated with salient stimuli correlated across participants. This is the first transcranial magnetic stimulation (TMS) study on the pupil orienting response, and our findings suggest that human FEF was involved in coordinating pupil size and saccades, but not involved in the control of pupil orienting responses.