Real-world uptake of an innovative pupil expander device for cataract surgery: Implementation lessons learnt.

Cataract surgery in the eyes, where the pupil does not dilate despite using eye drops, is fraught with vision-threatening complications. About 11 per cent of eyes undergoing cataract surgery have non-dilating, small pupils. The increasing prevalence of benign prostatic hyperplasia (BPH), hypertension, diabetes and medications used for the same are the contributing factors. The recent Food and Drug Administration (FDA) approval for the use of miotic agents in the treatment of presbyopia will lead to a further rise in the number of non-dilating pupils. While pharmacological agents and other methods have been used, mechanical pupil expander devices are the only fail safe option. However, available devices had a steep learning curve and limitations which made them difficult to use, unpredictable and unsafe. With its patented single plane, hexagonal, notches and flanges design, the US FDA registered B-HEX Pupil Expander (Med Invent Devices Pvt. Ltd., India) overcame these limitations and fulfilled an unmet need. The B-HEX is machinable, rapidly produced, consistent, easy to use, safe, and affordable. Despite such advantages, implementation hurdles have restricted its availability to healthcare systems worldwide. Peer acceptance has been steadily growing, with the B-HEX becoming the market leader in India, as evidenced by numerous publications, videos and papers presented at international conferences and comments from opinion leaders endorsing its use. However, impractical regulatory requirements and resource constraints remain a great impediment to the global distribution of this novel invention. This has denied many patients the benefits of a superior and more affordable option. Though value continues to be added to the B-HEX by maintaining a strong intellectual property portfolio with internationally granted Patents and Trademark, increasing its user base, and garnering support from key opinion leaders, only a collaboration with the right partner will help scale up the global reach and make it a leader in the global market.

Alpha-adrenergic antagonists and iris dynamics: Challenges and solutions in cataract surgery.

BACKGROUND: Alpha-1 adrenergic receptor antagonists (α1-ARAs) are frequently used in treatment of Hypertension and symptomatic benign prostatic hypertrophy (BPH). Numerous studies have demonstrated the association between α1-ARAs like Tamsulosin and increased surgical risks for patients undergoing cataract surgery. This study aims to identify and study the effects of α1-ARAs on iris parameters and the subsequent operative challenges encountered during cataract surgery. METHODS: A cross-sectional, prospective study involving 30 patients on α1-ARAs planned for cataract surgery and equal number of age and sex matched controls were subjected to evaluation of changes on iris parameters and subsequent challenges in cataract surgery. RESULTS: The study group had statistically significant lesser pupil diameter. Iris thickness at sphincter muscle region (SMR) was similar between groups (P = 0.53). Significantly lower values of iris thickness at dilator muscle region (DMR) found in treated subjects (P = < 0.001). There was statistically significant difference between DMR/SMR ratio of two groups (P < 0.001). Multiple regression analysis revealed longer duration of α1-ARAs treatment correlated with reduced DMR/SMR ratio (P = 0.001; r = 0.47). CONCLUSION: α1-ARAs have implications for pupil size regulation and surgical procedures involving the eye. Tamsulosin is more potent than alfuzosin in inducing IFIS. Systemic α1-ARAs lower values of DMR thickness, DMR/SMR ratio and reduces pupillary diameter. Therefore, ophthalmologists, primary care physicians, urologists, and patients should be aware of the potential difficulties that these drugs pose for cataract surgery.

Ocular Accommodative and Pupillary Responses During Fixation on Augmented Reality With a Maxwellian Display.

Purpose: This study aimed to investigate the changes in ocular refraction and pupillary diameter during fixation on augmented reality (AR) images using a Maxwellian display. Methods: Twenty-two healthy young volunteers (average age, 20.7 ± 0.5 years) wore a Maxwellian display device in front of their right eye and fixated on an asterisk displayed on both a liquid-crystal display (real target) and a Maxwellian display (AR target) for 29 seconds (real as a baseline for 3 seconds, AR for 13 seconds, and real for 13 seconds) at distances of 5.0, 0.5, 0.33, and 0.2 meters. A binocular open-view autorefractometer was used to measure the ocular refraction and pupillary diameter of the left eye. Results: Accommodative (5.0 meters, 0.28 ± 0.29 diopter [D]; 0.5 meter, -0.12 ± 0.35 D; 0.33 meter, -0.43 ± 0.57 D; 0.2 meter, -1.20 ± 0.82 D) and pupillary (5.0 meters, 0.07 ± 0.22 mm; 0.5 meter, -0.08 ± 0.17 mm; 0.33 meter, -0.16 ± 0.20 mm; 0.2 meter, -0.25 ± 0.24 mm) responses were negative when the real target distances were farther away. The accommodative response was significantly and positively correlated with the pupillary response during fixation on the AR target (R2 = 0.187, P < 0.001). Conclusions: Fixating on AR images using a Maxwellian display induces accommodative and pupillary responses. Accommodative responses depend on the distance between real objects. Overall, the Maxwellian display does not completely eliminate accommodation in real space.

The effects of emotional arousal on pupil size depend on luminance.

Pupillometry is widely used to measure arousal states. The primary functional role of the pupil, however, is to respond to the luminance of visual inputs. We previously demonstrated that cognitive effort-related arousal interacted multiplicatively with luminance, with the strongest pupillary effects of arousal occurring at low-to-mid luminances (< 37 cd/m2), implying a narrow range of conditions ideal for assessing cognitive arousal-driven pupillary differences. Does this generalize to other forms of arousal? To answer this, we assessed luminance-driven pupillary response functions while manipulating emotional arousal, using well-established visual and auditory stimulus sets. At the group level, emotional arousal interacted with the pupillary light response differently from cognitive arousal: the effects occurred primarily at much lower luminances (< 20 cd/m2). Analyses at the individual-participant level revealed qualitatively distinct patterns of modulation, with a sizable number of individuals displaying no arousal response to the visual or auditory stimuli, regardless of luminance. Together, our results suggest that effects of arousal on pupil size are not monolithic: different forms of arousal exert different patterns of effects. More practically, our findings suggest that lower luminances create better conditions for measuring pupil-linked arousal, and when selecting ambient luminance levels, consideration of the arousal manipulation and individual differences is critical.

Olfaction modulates cortical arousal independent of perceived odor intensity and pleasantness.

Throughout history, various odors have been harnessed to invigorate or relax the mind. The mechanisms underlying odors' diverse arousal effects remain poorly understood. We conducted five experiments (184 participants) to investigate this issue, using pupillometry, electroencephalography, and the attentional blink paradigm, which exemplifies the limit in attentional capacity. Results demonstrated that exposure to citral, compared to vanillin, enlarged pupil size, reduced resting-state alpha oscillations and alpha network efficiency, augmented beta-gamma oscillations, and enhanced the coordination between parietal alpha and frontal beta-gamma activities. In parallel, it attenuated the attentional blink effect. These effects were observed despite citral and vanillin being comparable in perceived odor intensity, pleasantness, and nasal pungency, and were unlikely driven by semantic biases. Our findings reveal that odors differentially alter the small-worldness of brain network architecture, and thereby brain state and arousal. Furthermore, they establish arousal as a unique dimension in olfactory space, distinct from intensity and pleasantness.

Visuomotor predictors of interception.

Intercepting moving targets is a fundamental skill in human behavior, influencing various domains such as sports, gaming, and other activities. In these contexts, precise visual processing and motor control are crucial for adapting and navigating effectively. Nevertheless, there are still some gaps in our understanding of how these elements interact while intercepting a moving target. This study explored the dynamic interplay among eye movements, pupil size, and interceptive hand movements, with visual and motion uncertainty factors. We developed a simple visuomotor task in which participants used a joystick to interact with a computer-controlled dot that moved along two-dimensional trajectories. This virtual system provided the flexibility to manipulate the target's speed and directional uncertainty during chase trials. We then conducted a geometric analysis based on optimal angles for each behavior, enabling us to distinguish between simple tracking and predictive trajectories that anticipate future positions of the moving target. Our results revealed the adoption of a strong interception strategy as participants approached the target. Notably, the onset and amount of optimal interception strategy depended on task parameters, such as the target's speed and frequency of directional changes. Furthermore, eye-tracking data showed that participants continually adjusted their gaze speed and position, continuously adapting to the target's movements. Finally, in successful trials, pupillary responses predicted the amount of optimal interception strategy while exhibiting an inverse relationship in trials without collisions. These findings reveal key interactions among visuomotor parameters that are crucial for solving complex interception tasks.

[Differences in anterior segment structure and pupillary diastolic characteristics of eyes with primary angle closure suspects under light and shade environments].

Objective: To investigate the anatomical structure changes of the anterior segment and dynamic pupil changes in eyes with suspected primary angle-closure (PACS) under light and dark conditions, and their correlation with the occurrence of acute primary angle-closure (APAC). Methods: This cross-sectional study collected data from 37 PACS patients (66 eyes) who visited the ophthalmology clinic of the Second Affiliated Hospital of Harbin Medical University between September 2019 and March 2021. The patients included 12 males and 25 females, with an average age of (61.27±7.35) years. Of the 66 eyes, 58 had no history of APAC in the contralateral eye, while 8 had a history of APAC in the contralateral eye. Patients without a history of APAC in both eyes underwent the dark room prone provocative test (DRPPT), and the eyes were divided into three groups: DRPPT- (44 eyes), DRPPT+ (14 eyes), and APAC (8 eyes). The DRPPT+ and APAC groups were combined into the APAC+ group. All patients underwent ultrasound biomicroscopy (UBM) to measure the changes in various parameters under light and dark conditions, including anterior chamber angle 500 (ACA500Δ) and 1000 (ACA1000Δ), angle opening distance 500 (AOD500Δ) and 1000 (AOD1000Δ), and iris thickness 500 (IT500Δ) and 1000 (IT1000Δ). Anterior segment analysis was performed to capture the pupil changes under light and dark conditions, recording pupil diameter, maximum dilation speed (Vmax), maximum constriction speed (Vmin), and average speed (Vm). Results: There was no significant difference in the parameters between DRPPT+ group and APAC group (P>0.05). In the difference analysis, it was found that the Vm value of DRPPT- group [(0.17±0.07) mm/s] was higher than that of APAC+ group [(0.13±0.06)mm/s], and the difference was statistically significant (P<0.05). There was no significant difference in other parameters (P>0.05). Vmax was positively correlated with temporal ACA1000Δ and temporal AOD1000Δ in all patients with PACS (r=0.302, 0.260; P<0.05), Vmin was negatively correlated with temporal ACA1000Δ and temporal AOD1000Δ (r=-0.338, -0.330; P<0.05). Conclusions: The dynamic changes in the anterior segment and pupil under different lighting conditions provide insights into the risk factors and potential predictive indicators for the occurrence of APAC in PACS patients.

Pupillary responses for social versus non-social stimuli in autism: A systematic review and meta-analysis.

Pupillometry has gained attention as a valuable tool for assessing autonomic nervous system activity and studying phasic changes in pupil size to comprehend underlying neurocognitive mechanisms. However, knowledge regarding pupillary responses to social processing in autism is limited. We conducted a systematic review and meta-analysis, examining research studies on pupil size changes that compare social and non-social stimuli in autism. Electronic searches were performed for articles up to September 2023 and relevant studies were evaluated following PRISMA guidelines. Out of 284 articles screened, 14 studies were eligible for systematic review. The results indicated that non-autistic individuals showed larger pupil size for social compared to non-social stimuli (g = 0.54; 95 % CI [0.25, 0.82]), whereas autistic individuals seemed to exhibit no differences between the two conditions. However, high heterogeneity was observed between studies in autistic populations, compromising interpretability. Despite such limitations, pupillary responses may constitute an objective physiological marker of social processing in autism. This review emphasizes the need for further investigations into pupillary responses in autism across different life stages.

Pupillometry reveals effects of pitch manipulation within and across words on listening effort and short-term memory.

For individuals with hearing loss, even successful speech communication comes at a cost. Cochlear implants transmit degraded information, specifically for voice pitch, which demands extra and sustained listening effort. The current study hypothesized that abnormal pitch patterns contribute to the additional listening effort, even in non-tonal language native speaking normally hearing listeners. We manipulated the fundamental frequency (F0) within and across words, while participants listen and repeat (simple intelligibility task), or listen, repeat, and later recall (concurrent encoding task) the words. In both experiments, the F0 manipulations resulted in small changes in intelligibility but no difference in free recall or subjective effort ratings. Pupillary metrics were yet sensitive to these manipulations: pupil dilations were larger when words were monotonized (flat contour) or inverted (the natural contour flipped upside-down), and larger when successive words were organized into a melodic pattern. The most likely interpretation is that the natural or expected F0 contour of a word contributes to its identity and facilitate its matching and retrieval from the phonological representation stored in long-term memory. Consequently, degrading words' F0 contour can result in extra listening effort. Our results call for solutions to improve pitch saliency and naturalness in future development of cochlear implants' signal processing strategies, even for non-tonal languages.

Exploring the Impact of Math Anxiety and Task Difficulty on Pupil Dilation in Adults and Young Children.

We investigated the relations between self-reported math anxiety, task difficulty, and pupil dilation in adults and very young children during math tasks of varying difficulty levels. While task difficulty significantly influenced pupillary responses in both groups, the association between self-reported math anxiety and pupil dilation differed across age cohorts. The children exhibited resilience to the effects of math anxiety, hinting at additional influential factors such as formal math education experiences shaping their relations to mathematics and their impact on cognitive processes over time. Contrary to expectations, no significant association between self-reported math anxiety and pupil dilation during task anticipation was found in either group. In adults, math anxiety influenced pupil dilation exclusively during the initial phase of task processing indicating heightened cognitive load, but this influence diminished during sustained task processing. Theoretical implications emphasize the need for exploring individual differences, cognitive strategies, and the developmental trajectory of math anxiety in very young children.

Iris Morphological and Biomechanical Factors Influencing Angle Closure During Pupil Dilation.

Purpose: To use finite element (FE) analysis to assess what morphologic and biomechanical factors of the iris and anterior chamber are more likely to influence angle narrowing during pupil dilation. Methods: The study consisted of 1344 FE models comprising the cornea, sclera, lens, and iris to simulate pupil dilation. For each model, we varied the following parameters: anterior chamber depth (ACD = 2-4 mm) and anterior chamber width (ACW = 10-12 mm), iris convexity (IC = 0-0.3 mm), iris thickness (IT = 0.3-0.5 mm), stiffness (E = 4-24 kPa), and Poisson's ratio (v = 0-0.3). We evaluated the change in (△∠) and the final dilated angles (∠f) from baseline to dilation for each parameter. Results: The final dilated angles decreased with a smaller ACD (∠f = 53.4° ± 12.3° to 21.3° ± 14.9°), smaller ACW (∠f = 48.2° ± 13.5° to 26.2° ± 18.2°), larger IT (∠f = 52.6° ± 12.3° to 24.4° ± 15.1°), larger IC (∠f = 45.0° ± 19.2° to 33.9° ± 16.5°), larger E (∠f = 40.3° ± 17.3° to 37.4° ± 19.2°), and larger v (∠f = 42.7° ± 17.7° to 34.2° ± 18.1°). The change in angles increased with larger ACD (△∠ = 9.37° ± 11.1° to 15.4° ± 9.3°), smaller ACW (△∠ = 7.4° ± 6.8° to 16.4° ± 11.5°), larger IT (△∠ = 5.3° ± 7.1° to 19.3° ± 10.2°), smaller IC (△∠ = 5.4° ± 8.2° to 19.5° ± 10.2°), larger E (△∠ = 10.9° ± 12.2° to 13.1° ± 8.8°), and larger v (△∠ = 8.1° ± 9.4° to 16.6° ± 10.4°). Conclusions: The morphology of the iris (IT and IC) and its innate biomechanical behavior (E and v) were crucial in influencing the way the iris deformed during dilation, and angle closure was further exacerbated by decreased anterior chamber biometry (ACD and ACW).

Strategic stabilization of arousal boosts sustained attention.

Arousal and motivation interact to profoundly influence behavior. For example, experience tells us that we have some capacity to control our arousal when appropriately motivated, such as staying awake while driving a motor vehicle. However, little is known about how arousal and motivation jointly influence decision computations, including if and how animals, such as rodents, adapt their arousal state to their needs. Here, we developed and show results from an auditory, feature-based, sustained-attention task with intermittently shifting task utility. We use pupil size to estimate arousal across a wide range of states and apply tailored signal-detection theoretic, hazard function, and accumulation-to-bound modeling approaches in a large cohort of mice. We find that pupil-linked arousal and task utility both have major impacts on multiple aspects of task performance. Although substantial arousal fluctuations persist across utility conditions, mice partially stabilize their arousal near an intermediate and optimal level when task utility is high. Behavioral analyses show that multiple elements of behavior improve during high task utility and that arousal influences some, but not all, of them. Specifically, arousal influences the likelihood and timescale of sensory evidence accumulation but not the quantity of evidence accumulated per time step while attending. In sum, the results establish specific decision-computational signatures of arousal, motivation, and their interaction in attention. So doing, we provide an experimental and analysis framework for studying arousal self-regulation in neurotypical brains and in diseases such as attention-deficit/hyperactivity disorder.

Tunnel motion: Pupil dilations to optic flow within illusory dark holes.

We showed to the same observers both dynamic and static 2D patterns that can both evoke distinctive perceptions of motion or optic flow, as if moving in a tunnel or into a dark hole. At all times pupil diameters were monitored with an infrared eye tracker. We found a converging set of results indicating stronger pupil dilations to expansive growth of shapes or optic flows evoking a forward motion into a dark tunnel. Multiple regression analyses showed that the pupil responses to the illusory expanding black holes of static patterns were predicted by the individuals' pupil response to optic flows showing spiraling motion or "free fall" into a black hole. Also, individuals' pupil responses to spiraling motion into dark tunnels predicted the individuals' sense of illusory expansion with the static, illusory expanding, dark holes. This correspondence across individuals between their pupil responses to both dynamic and static, illusory expanding, holes suggests that these percepts reflect a common perceptual mechanism, deriving motion from 2D scenes, and that the observers' pupil adjustments reflect the direction and strength of motion they perceive and the expected outcome of an increase in darkness.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Muscarinic M3 Receptor-Positive Allosteric Modulator ASP8302 Following Single and Multiple Ascending Oral Doses in Healthy Volunteers.

ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.

Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

The effect of cycloplegia in the accuracy of autorefraction, keratometry and axial length using the Myopia Master.

BACKGROUND: Assessing refractive errors under cycloplegia is recommended for paediatric patients; however, this may not always be feasible. In these situations, refraction has to rely on measurements made under active accommodation which may increase measurements variability and error. Therefore, evaluating the accuracy and precision of non-cycloplegic refraction and biometric measurements is clinically relevant. The Myopia Master, a novel instrument combining autorefraction and biometry, is designed for monitoring refractive error and ocular biometry in myopia management. This study assessed its repeatability and agreement for autorefraction and biometric measurements pre- and post-cycloplegia. METHODS: A prospective cross-sectional study evaluated a cohort of 96 paediatric patients that underwent ophthalmologic examination. An optometrist performed two repeated measurements of autorefraction and biometry pre- and post-cycloplegia. Test-retest repeatability (TRT) was assessed as differences between consecutive measurements and agreement as differences between post- and pre-cycloplegia measurements, for spherical equivalent (SE), refractive and keratometric J0/J45 astigmatic components, mean keratometry (Km) and axial length (AL). RESULTS: Cycloplegia significantly improved the SE repeatability (TRT, pre-cyclo: 0.65 D, post-cyclo: 0.31 D). SE measurements were more repeatable in myopes and emmetropes compared to hyperopes. Keratometry (Km) repeatability did not change with cycloplegia (TRT, pre-cyclo: 0.25 D, post-cyclo:0.27 D) and AL repeatability improved marginally (TRT, pre-cyclo: 0.14 mm, post-cyclo: 0.09 mm). Regarding pre- and post-cycloplegia agreement, SE became more positive by + 0.79 D, varying with refractive error. Myopic eyes showed a mean difference of + 0.31 D, while hyperopes differed by + 1.57 D. Mean keratometry, refractive and keratometric J0/J45 and AL showed no clinically significant differences. CONCLUSIONS: Refractive error measurements, using the Myopia Master were 2.5x less precise pre-cycloplegia than post-cycloplegia. Accuracy of pre-cycloplegic refractive error measurements was often larger than the clinically significant threshold (0.25 D) and was refractive error dependent. The higher precision compared to autorefraction measurements, pre- and post-cycloplegia agreement and refractive error independence of AL measurements emphasize the superiority of AL in refractive error monitoring.

Case report: Topical pilocarpine ameliorated the accommodation loss and pupillary dilation after micropulse transscleral laser treatment.

BACKGROUND: The present study elucidates a common significant postoperative complication of micropulse transscleral laser treatment (mTLT) and explores its potential management strategies for younger patients with good central vision. CASE PRESENTATION: Three younger Chinese glaucoma patients with good central vision maintained high intraocular pressures (IOPs) (36, 25, and 30 mmHg) on maximally tolerated topical anti-glaucoma medications. All patients were treated with mTLT because of a higher risk of complications with filtering surgery. After the procedure, their best-corrected visual acuities were not significantly changed, IOPs were significantly decreased, and the number of topical anti-glaucoma medicines was gradually decreased. However, all patients complained about reduced near visual acuity (NVA) for 1-5 months. Slit-lamp examination revealed pupillary dilation, and binocular accommodative function examination indicated accommodation loss. After treatment with 2% topical pilocarpine, all patients reported an improvement in NVA. Among them, we could observe pupillary constriction, recovery of accommodation function, and improved NVA, even discontinuation of pilocarpine in Patient 2. CONCLUSION: In younger patients with good central vision, topical pilocarpine might ameliorate accommodation loss and pupillary dilation after mTLT.

Effects of caffeine intake on pupillary parameters in humans: a systematic review and meta-analysis.

Caffeine is a widely used drug that broadly affects human cognition and brain function. Caffeine acts as an antagonist to the adenosine receptors in the brain. Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. We only included original research articles written in English reporting studies with human participants, in which caffeine was administered, and pupil diameter was measured using objective methods. Using broad search strategies, we consulted various databases (PsycINFO, Medline, Embase, Cochrane Library, bioRxiv and medRxiv) and used the Covidence platform to screen, review and extract data from studies. After importing studies identified through database search (n = 517 imported, n = 46 duplicates), we screened the title and abstracts (n = 471), finding 14 studies meeting our eligibility criteria. After full-text review, we excluded seven studies, leaving only a very modest number of included studies (n = 7). Extraction of information revealed that the existing literature on the effect of caffeine on pupil parameters is very heterogeneous, differing in pupil assessment methods, time of day of caffeine administration, dose, and protocol timing and design. The evidence available in the literature does not provide consistent results but studies rated as valid by quality assessment suggest a small effect of caffeine on pupil parameters. We summarize the numeric results as both differences in absolute pupil diameter and in terms of effect sizes. More studies are needed using modern pupil assessment methods, robust study design, and caffeine dose-response methodology.

Pupil contagion variation with gaze, arousal, and autistic traits.

Pupillary contagion occurs when one's pupil size unconsciously adapts to the pupil size of an observed individual and is presumed to reflect the transfer of arousal. Importantly, when estimating pupil contagion, low level stimuli properties need to be controlled for, to ensure that observations of pupillary changes are due to internal change in arousal rather than the external differences between stimuli. Here, naturalistic images of children's faces depicting either small or large pupils were presented to a group of children and adolescents with a wide range of autistic traits, a third of whom had been diagnosed with autism. We examined the extent to which pupillary contagion reflects autonomic nervous system reaction through pupil size change, heart rate and skin conductance response. Our second aim was to determine the association between arousal reaction to stimuli and degree of autistic traits. Results show that pupil contagion and concomitant heart rate change, but not skin conductance change, was evident when gaze was restricted to the eye region of face stimuli. A positive association was also observed between pupillary contagion and autistic traits when participants' gaze was constrained to the eye region. Findings add to a broader understanding of the mechanisms underlying pupillary contagion and its association with autism.

Empathy in autistic children: Emotional overarousal in response to others' physical pain.

Different empathic responses are often reported in autism but remain controversial. To investigate which component of empathy is most affected by autism, we examined the affective, cognitive, and motivational components of empathy in 25 5- to 8-year-old autistic and 27 neurotypical children. Participants were presented with visual stimuli depicting people's limbs in painful or nonpainful situations while their eye movements, pupillary responses, and verbal ratings of pain intensity and empathic concern were recorded. The results indicate an emotional overarousal and reduced empathic concern to others' pain in autism. Compared with neurotypical children, autistic children displayed larger pupil dilation accompanied by attentional avoidance to others' pain. Moreover, even though autistic children rated others in painful situations as painful, they felt less sorry than neurotypical children. Interestingly, autistic children felt more sorry in nonpainful situations compared with neurotypical children. These findings demonstrated an emotional overarousal in response to others' pain in autistic children, and provide important implications for clinical practice aiming to promote socio-emotional understanding in autistic children.