Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

Background: Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective: This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods: NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results: Greater subjective craving, as measured by the Tobacco Craving Questionnaire-Short Form, following active versus neutral scenes was observed (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=5.99; P=.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions: This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.

Efficacy of estimations of Hartmann-Shack sensors in small pupil sizes.

PURPOSE: The purpose of this study was to evaluate the in vivo efficacy of the estimations of wavefront analyzers using Hartmann-Shack technology to measure optical aberrations when the pupil size is smaller than the evaluated pupil area. METHODS: Patients implanted with the monofocal ZCB00 intraocular lens (Johnson and Johnson) were examined with the KR-1W Wavefront Analyzer (Topcon) without pharmacological mydriasis and with it afterward. Optical aberrations were analyzed considering a 4-mm pupil and a 6-mm pupil for both examinations. RESULTS: Sixty-six eyes of 33 patients with a mean axial length of 23.35 ± 0.91 mm were assessed. The mean pupil diameter at the baseline examination was 5.05 ± 0.88 mm and under pharmacological mydriasis, it was 6.29 ± 0.84 mm. Outcomes were similar with and without dilation in the 4-mm comparison. However, there was a great disparity in the 6-mm comparison. Most of the values obtained under mydriasis were statistically lower than at baseline (P < 0.05). CONCLUSION: The iris interferes with measurements of wavefront aberrations, and therefore, real pupil size should always be checked before evaluating optical aberrations with Hartman-Shack sensors. When pupil size is smaller than the analyzed diameter, ocular, and internal, and sometimes, corneal aberrations are estimated far more positive than real values.

The Usefulness of Reduced Anion Gap and the Possibility of Pupillary Findings in the Treatment of Acute Bromvalerylurea Intoxication.

Bromvalerylurea is found as an over-the-counter analgesic and hypnotic drug in Japan and can be purchased at drugstores or over the Internet. Therefore, both acute poisoning due to large doses taken in suicide attempts and chronic poisoning due to continuous use for chronic pain have been observed. We report a case of acute BVU poisoning due to the use of an over-the-counter hypnotic sedative for a suicide attempt. A 34-year-old woman was referred to our ICU with unexplained disturbance of consciousness, respiratory failure, and shock. During ICU management, when her pupil diameter was measured with an automatic pupillometer to confirm her conscious state, the right pupil diameter was larger than the left, but one hour later, the left pupil diameter was larger than the right. The difference between right and left fluctuated with the time of day. After awakening, it was found that the patient had taken 108 tablets of Utt, an over-the-counter hypnotic sedative, and the possibility of acute poisoning by its component, BVU, was raised. Because a blood gas analysis at the time of admission showed metabolic acidosis with anion gap ≤1, a diagnosis of acute BVU poisoning was made. The patient's general condition stabilized, and she was transferred to the psychiatric ward. Symptoms of acute BVU poisoning include impaired consciousness and respiratory and circulatory depression, which may make it impossible to obtain a medical interview. When treating a patient with suspected drug intoxication who is unable to communicate, the clinician needs to include BVU poisoning in the differential when a reduced anion gap is observed. The clinician should also know that BVU poisoning can cause ocular manifestations such as anisocoria. This may lead to early diagnosis and therapeutic intervention.

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions.

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Violation of identity-specific action-effect prediction increases pupil size and attenuates auditory event-related potentials at P2 latencies when action-effects are behaviorally relevant.

Self-initiated sensory action effects are widely assumed to lead to less intense perception and reduced neural responses compared to externally triggered stimuli (sensory attenuation). However, it is unclear if sensory attenuation occurs in all cases of action-effect prediction. Specifically, when predicted action-effects are relevant to determine follow-up actions attenuation could be detrimental. We quantified auditory event-related potentials (ERP) in electroencephalography (EEG) when human participants created two-sound sequences by pressing two keys on a keyboard associated with different pitch, giving rise to identity-specific action-effect prediction after the first keypress. The first sound corresponded to (congruent) or violated (incongruent) the predicted pitch and was either relevant for the selection of the second keypress to correctly complete the sequence (Relevance) or irrelevant (Control Movement), or there was only one keypress and sound (Baseline). We found a diminished P2-timed ERP component in incongruent compared to congruent trials when the sound was relevant for the subsequent action. This effect of action-effect prediction was due to an ERP reduction for incongruent relevant sounds compared to incongruent irrelevant sounds at P2 latencies and correlated negatively with modulations of pupil dilation. Contrary to our expectation, we did not observe an N1 modulation by congruency in any condition. Attenuation of the N1 component seems absent for predicted identity-specific auditory action effects, while P2-timed ERPs as well as pupil size are sensitive to predictability, at least when action effects are relevant for the selection of the next action. Incongruent relevant stimuli thereby take a special place and seem to be subject to attentional modulations and error processing.

Population study of pupillary unrest in ambient light.

INTRODUCTION: Pupillary unrest in ambient light (PUAL) describes the fluctuation of pupil diameter observed in normal, awake subjects under typical levels of indoor light. PUAL becomes low to absent in young healthy subjects during opioid intoxication. We sought to determine the age-related distribution of PUAL values in a random sample of ambulatory participants. METHODS: Subjects ≥18 years of age were recruited. All were identified by age range (18-29, 30-49, 50-69, and ≥70), and surveyed for diabetes, beta-blocker use, and prior 24-hour opioid use. Relationship between mean PUAL, age group, comorbidity and opioid use were examined by Kruskal Wallis test, and PUAL and was modeled using stepwise multilevel linear regression, including diabetes, beta blocker use, prior 24-hour opioid use, autonomic dysfunction, and pupil diameter as fixed effects and subject as random effect. RESULTS: Among 150 subjects, 17 reported diabetes, 12 reported beta-blocker use, 14 reported prior 24-hour opioid use, and 120 reported no comorbid conditions. PUAL declined in higher age categories (by 0.0307, P < 0.001), with diabetes (by 0.0481, P = 0.025), and with beta-blocker use (by 0.0616, P = 0.005). Opioid related PUAL decline was observed, but statistical significance varied by model. Among healthy subjects, no PUAL value fell within range indicating high likelihood of opioid toxicity based on previous data from healthy subjects undergoing opioid infusion. CONCLUSION: PUAL declined in higher age groups, diabetes and beta-blocker use, conditions associated with impaired autonomic function, and with opioid use but significance varied depending on the chosen model.

Adie's tonic pupil after COVID-19: a case report and literature review.

Objective: Various neurological complications have been reported after COVID-19. The study aimed to document an unusual case of Adie's tonic pupil following COVID-19. Methods: The study was a case report. Results: A 28-year-old female had suffered a flu-like disease about 2 months before and the SARSCoV-2 polymerase chain reaction test at that time was positive. Two weeks after infection she noticed an asymmetry between the pupils. The only pathological finding on examination was anisocoria with a larger left pupil in ambient light. Light reflexes were observed in the right eye, while in the left eye, they were absent. Also, there was no near response in the left pupil. A 0.1% pilocarpine test results validated Adie's pupil diagnosis. After one year of follow-up, the anisocoria decreased but did not completely recover. Discussion: COVID-19 may cause damage to neural structures due to autoimmune ways by activating immune pathways or because of vascular complications that may affect the vasa nervorum. Adie's tonic pupil is often idiopathic, but it may develop following viral infection. Conclusions: Ocular complications that involve pupil abnormalities may manifest following COVID-19. In the cases of Adie's tonic pupil, infectious diseases, including COVID-19, should be questioned. Abbreviations: RT PCR = reverse transcription polymerase chain reaction.

Description of a new method to calculate the equator of the crystalline lens using AS-OCT images: Accuracy in non-dilated measurements.

OBJECTIVE: To establish a methodology for objectively estimating the Lens Equatorial Plane (LEP) from clinical images, comparing LEP with dilated versus non-dilated pupils. METHODS: A cohort of 91 eyes from 60 patients undergoing preoperative assessments for cataract surgery was evaluated. Anterior Segment Optical Coherence Tomography (AS-OCT) images were analysed under conditions of pharmacologically induced pupil dilation versus a non-dilated pupil. Geometrical parameters, including LEP, intersection diameter (ID), lens thickness (LT), anterior and posterior lens thickness were automatically calculated by applying standard image processing techniques to clinical AS-OCT images. RESULTS: Significant differences in lens parameters, including LEP, were observed between dilated and non-dilated conditions (all p < 0.001). A strong linear correlation was found across all geometrical variables under both conditions (r[LEP] = 0.64, r[ID] = 0.78, r[LT] = 0.99, all p < 0.001); enabling reliable correction of these differences. CONCLUSION: The study introduces an objective methodology for LEP calculation, emphasising the need to consider the eye's physiological state during preoperative measurements. Incorporating LEP into future intraocular lens (IOL) power calculation formulas and replacing the habitual effective lens position may potentially improve the accuracy of IOL power estimation and thus postoperative visual outcomes.

Deep Learning-Based Nystagmus Detection for BPPV Diagnosis.

In this study, we propose a deep learning-based nystagmus detection algorithm using video oculography (VOG) data to diagnose benign paroxysmal positional vertigo (BPPV). Various deep learning architectures were utilized to develop and evaluate nystagmus detection models. Among the four deep learning architectures used in this study, the CNN1D model proposed as a nystagmus detection model demonstrated the best performance, exhibiting a sensitivity of 94.06 ± 0.78%, specificity of 86.39 ± 1.31%, precision of 91.34 ± 0.84%, accuracy of 91.02 ± 0.66%, and an F1-score of 92.68 ± 0.55%. These results indicate the high accuracy and generalizability of the proposed nystagmus diagnosis algorithm. In conclusion, this study validates the practicality of deep learning in diagnosing BPPV and offers avenues for numerous potential applications of deep learning in the medical diagnostic sector. The findings of this research underscore its importance in enhancing diagnostic accuracy and efficiency in healthcare.

The forgotten wave of early pupillometry research.

Changes in pupil size offer a rich, continuous, and integrated neurophysiological readout of attention and cognition. I here briefly reintroduce examples of a vast, forgotten literature, full of inspiring ideas, which described attentional modulations of pupil size decades earlier than often assumed. I outline parallels between these early studies and recent developments in pupillometry.

Altered pupil light and darkness reflex and eye-blink responses in late-life depression.

BACKGROUND: Late-life depression (LLD) is a prevalent neuropsychiatric disorder in the older population. While LLD exhibits high mortality rates, depressive symptoms in older adults are often masked by physical health conditions. In younger adults, depression is associated with deficits in pupil light reflex and eye blink rate, suggesting the potential use of these responses as biomarkers for LLD. METHODS: We conducted a study using video-based eye-tracking to investigate pupil and blink responses in LLD patients (n = 25), older (OLD) healthy controls (n = 29), and younger (YOUNG) healthy controls (n = 25). The aim was to determine whether there were alterations in pupil and blink responses in LLD compared to both OLD and YOUNG groups. RESULTS: LLD patients displayed significantly higher blink rates and dampened pupil constriction responses compared to OLD and YOUNG controls. While tonic pupil size in YOUNG differed from that of OLD, LLD patients did not exhibit a significant difference compared to OLD and YOUNG controls. GDS-15 scores in older adults correlated with light and darkness reflex response variability and blink rates. PHQ-15 scores showed a correlation with blink rates, while MoCA scores correlated with tonic pupil sizes. CONCLUSIONS: The findings demonstrate that LLD patients display altered pupil and blink behavior compared to OLD and YOUNG controls. These altered responses correlated differently with the severity of depressive, somatic, and cognitive symptoms, indicating their potential as objective biomarkers for LLD.

Eyes on Memory: Pupillometry in Encoding and Retrieval.

This review critically examines the contributions of pupillometry to memory research, primarily focusing on its enhancement of our understanding of memory encoding and retrieval mechanisms mainly investigated with the recognition memory paradigm. The evidence supports a close link between pupil response and memory formation, notably influenced by the type of novelty detected. This proposal reconciles inconsistencies in the literature regarding pupil response patterns that may predict successful memory formation, and highlights important implications for encoding mechanisms. The review also discusses the pupil old/new effect and its significance in the context of recollection and in reflecting brain signals related to familiarity or novelty detection. Additionally, the capacity of pupil response to serve as a true memory signal and to distinguish between true and false memories is evaluated. The evidence provides insights into the nature of false memories and offers a novel understanding of the cognitive mechanisms involved in memory distortions. When integrated with rigorous experimental design, pupillometry can significantly refine theoretical models of memory encoding and retrieval. Furthermore, combining pupillometry with neuroimaging and pharmacological interventions is identified as a promising direction for future research.

Correlation between pupillary size and depth of focus after the implantation of extended depth of focus intraocular lenses.

PURPOSE: To evaluate whether depth of focus after the implantation of extended depth of focus (EDoF) intraocular lenses (IOLs) correlates with pupillary size. METHODS: This retrospective case series study evaluated eyes undergoing cataract surgery with implantation of EDoF IOLs. At least one month postoperatively, the depth of focus (DoF) was measured to determine the correlation with pupillary size, age, anterior chamber depth (ACD), axial length (AXL), and corneal spherical aberrations (SA). RESULTS: The study evaluated 64 eyes of 49 patients. The mean depth of focus was 2.67 diopters (D). The mean preoperative photopic pupil size was 3.36 mm. A significant negative association was found between preoperative photopic pupil size and depth of focus (r = 0.30, Pearson's correlation coefficient) and between preoperative mesopic pupil size and depth of focus (r = 0.274, Pearson's correlation coefficient).

Modulation transfer function of implantable phakic intraocular contact lens (IPCL) for myopia and presbyopia.

PURPOSE: This study aimed to assess the optical quality of myopic and presbyopic IPCLs with different additional powers, and to investigate the effects of pupil size on the optical quality of these IPCLs using an in-vitro modulation transfer function (MTF) measurement system. METHODS: Linear scatter functions (LSFs) were recorded using the OPAL Vector system and an eye phantom consisting of wet cells filled with a balanced salt solution. A myopic IPCL or a presbyopic IPCL was placed in the posterior chamber of this model. The MTF was calculated from the LSF using the fast Fourier transform techniques. The effective apertures were set at 2.0 to 5.0 mm in 1.0 mm steps. RESULTS: The in-focus MTF values of the myopic IPCL and presbyopic IPCL with additional powers of + 2.0 and + 4.0 diopters at 100 cycles/mm for an effective aperture of 3.0 mm were 43%, 27%, and 24%, respectively. The in-focus MTF value of both myopic and presbyopic IPCLs was the highest when the effective aperture was set at 3.0 mm, and it gradually worsened when the effective aperture became larger than 3.0 mm at 20, 60, and 100 cycles/mm. CONCLUSIONS: Both myopic and presbyopic IPCLs provided excellent MTF values, but the additional power profile can deteriorate optical performance in presbyopic IPCL-implanted eyes, even with a low additional power. Pupil size can influence visual quality in IPCL-implanted eyes for both myopia and presbyopia.

Association Between Myopia and Pupil Diameter in Preschoolers: Evidence from a Machine Learning Approach Based on a Real-World Large-Scale Dataset.

INTRODUCTION: Previous studies have explored the connections between various ocular biological parameters with myopia. Our previous study also found that pupil data can predict the myopic progression during the interventions for myopia. However, studies exploring the association between pupil diameter and myopia in preschoolers with myopia were lacking. Hence this study was aimed to investigate the association between pupil diameter and myopia in preschoolers with myopia based on a real-world, large-scale dataset. METHODS: Data containing 650,671 preschoolers were collected from a total of 1943 kindergartens in Shenzhen, China. Refraction and pupil parameters were collected. After data filtering, the occurrence of myopia and its association with age, gender, pupil diameter, and other variables, were analyzed. Random forest (RF) and eXtreme gradient boosting (XGBoost) were selected from seven machine learning algorithms to build the model. The mean decrease accuracy (MDA), mean decrease Gini (MDG), and gain feature importance (GFI) techniques were employed to quantify the importance of pupil diameter and other features. RESULTS: After the assessments, 51,325 valid records with complete pupil data were included, and 3468 (6.76%) were identified as myopia based on the calculated cycloplegic refraction. Preschoolers with myopia presented reduced pupil diameter and greater variation (5.00 ± 0.99 mm) compared to non-myopic preschoolers (6.22 ± 0.67 mm). A nonlinear relationship was found according to the scatterplots between pupil diameter and refraction (R2 = 0.14). Especially preschoolers with myopia had reduced pupil diameter compared to emmetropic preschoolers, but hyperope did not experience additional pupil enlargement. After adjusting for other covariates, this relationship is still consistent (P < 0.001). XGBoost and RF algorithms presented the highest performance and validated the importance of pupil diameter in myopia. CONCLUSIONS: Based on a real-world large-scale dataset, the current study illuminated that preschoolers with myopia had a reduced pupil diameter compared to emmetropic preschoolers with a nonlinear pattern. Machine learning algorithms visualized and validated the pivotal role of pupil diameter in myopia. TRIAL REGISTRATION: chictr.org Identifier: ChiCTR2200057391.

The bigger your pupils, the better my comprehension: an ERP study of how pupil size and gaze of the speaker affect syntactic processing.

Gaze direction and pupil dilation play a critical role in communication and social interaction due to their ability to redirect and capture our attention and their relevance for emotional information. The present study aimed to explore whether the pupil size and gaze direction of the speaker affect language comprehension. Participants listened to sentences that could be correct or contain a syntactic anomaly, while the static face of a speaker was manipulated in terms of gaze direction (direct, averted) and pupil size (mydriasis, miosis). Left anterior negativity (LAN) and P600 linguistic event-related potential components were observed in response to syntactic anomalies across all conditions. The speaker's gaze did not impact syntactic comprehension. However, the amplitude of the LAN component for mydriasis (dilated pupil) was larger than for miosis (constricted pupil) condition. Larger pupils are generally associated with care, trust, interest, and attention, which might facilitate syntactic processing at early automatic stages. The result also supports the permeable and context-dependent nature of syntax. Previous studies also support an automatic nature of syntax (fast and efficient), which combined with the permeability to relevant sources of communicative information, such as pupil size and emotions, is highly adaptive for language comprehension and social interaction.

Beauty is in the iris: Constricted pupils (enlarged irises) enhance attractiveness.

Physical attractiveness profoundly affects a broad array of life experiences and outcomes, and the eyes are an important determinant of physical attractiveness. We investigated whether a particular feature of the eyes - pupil size - affects perceived attractiveness. We present competing theoretical predictions of whether dilated (larger) or constricted (smaller) pupils should appear more physically attractiveness. Youthful features tend to be attractive (i.e., neoteny), and pupil size decreases across the lifespan, so dilated (enlarged) pupils may be more attractive as a signal of youth. Alternatively, constricted (small) pupils may be more attractive because, by revealing more of the iris, they increase both color and brightness of the eyes. The present experiments demonstrate that people appear more attractive when their pupils are constricted (Experiments 1-3). This effect is equally large with black-and-white images, indicating that color per se is not necessary for the effect (Experiment 4). Rather, constricted pupils make eyes appear brighter, which in turn renders the face more attractive (Experiment 5), even when controlling for how colorful the eyes appear (Experiment 6). These results identify constricted pupils as a novel facial feature that enhances attractiveness.

Neurobehavioral meaning of pupil size.

Pupil size is a widely used metric of brain state. It is one of the few signals originating from the brain that can be readily monitored with low-cost devices in basic science, clinical, and home settings. It is, therefore, important to investigate and generate well-defined theories related to specific interpretations of this metric. What exactly does it tell us about the brain? Pupils constrict in response to light and dilate during darkness, but the brain also controls pupil size irrespective of luminosity. Pupil size fluctuations resulting from ongoing "brain states" are used as a metric of arousal, but what is pupil-linked arousal and how should it be interpreted in neural, cognitive, and computational terms? Here, we discuss some recent findings related to these issues. We identify open questions and propose how to answer them through a combination of well-defined tasks, neurocomputational models, and neurophysiological probing of the interconnected loops of causes and consequences of pupil size.