Pupillometric analysis for assessment of gene therapy in Leber Congenital Amaurosis patients

Background: Objective techniques to assess the amelioration of vision in patients with impaired visual function are needed to standardize efficacy assessment in gene therapy trials for ocular diseases. Pupillometry has been investigated in several diseases in order to provide objective information about the visual reflex pathway and has been adopted to quantify visual impairment in patients with Leber Congenital Amaurosis (LCA). In this paper, we describe detailed methods of pupillometric analysis and a case study on three Italian patients affected by Leber Congenital Amaurosis (LCA) involved in a gene therapy clinical trial at two follow-up time-points: 1 year and 3 years after therapy administration. Methods: Pupillary light reflexes (PLR) were measured in patients who had received a unilateral subretinal injection in a clinical gene therapy trial. Pupil images were recorded simultaneously in both eyes with a commercial pupillometer and related software. A program was generated with MATLAB software in order to enable enhanced pupil detection with revision of the acquired images (correcting aberrations due to the inability of these severely visually impaired patients to fixate), and computation of the pupillometric parameters for each stimulus. Pupil detection was performed through Hough Transform and a non-parametric paired statistical test was adopted for comparison. Results: The developed program provided correct pupil detection also for frames in which the pupil is not totally visible. Moreover, it provided an automatic computation of the pupillometric parameters for each stimulus and enabled semi-automatic revision of computerized detection, eliminating the need for the user to manually check frame by frame. With reference to the case study, the amplitude of pupillary constriction and the constriction velocity were increased in the right (treated eye) compared to the left (untreated) eye at both follow-up time-points, showing stability of the improved PLR in the treated eye. Conclusions: Our method streamlined the pupillometric analyses and allowed rapid statistical analysis of a range of parameters associated with PLR. The results confirm that pupillometry is a useful objective measure for the assessment of therapeutic effect of gene therapy in patients with LCA

High Speed Pupillometry

Measuring the parameters of the pupil in the human eye has become increasingly important in customised refractive surgery and other eye care applications. High-speed and high resolution CMOS cameras can be used to study the dynamics of eyelids and their interaction with the pupil at different illumination levels. We consider the problem of measuring the pupil size from a high-speed video. In particular, we develop a novel algorithm for setting intra-lid sectors for the detection and estimation of the pupil and iris outlines from a sequence of digital images. An application of the proposed methodology to the estimation of the pupil parameters during an eye blink is given

Using Pupil Diameter to Measure Cognitive Load

In this paper, we will present a method for measuring cognitive load and online real-time feedback using the Tobii Pro 2 eye-tracking glasses. The system is envisaged to be capable of estimating high cognitive load states and situations, and adjust human-machine interfaces to the user's needs. The system is using well-known metrics such as average pupillary size over time. Our system can provide cognitive load feedback at 17-18 Hz. We will elaborate on our results of a HRI study using this tool to show it's functionality.Comment: Presented at AI-HRI AAAI-FSS, 2018 (arXiv:1809.06606

Decision-Making in a Social Multi-Armed Bandit Task: Behavior, Electrophysiology and Pupillometry

Understanding, predicting, and learning from other people's actions are fundamental human social-cognitive skills. Little is known about how and when we consider other's actions and outcomes when making our own decisions. We developed a novel task to study social influence in decision-making: the social multi-armed bandit task. This task assesses how people learn policies for optimal choices based on their own outcomes and another player's (observed) outcomes. The majority of participants integrated information gained through observation of their partner similarly as information gained through their own actions. This lead to a suboptimal decision-making strategy. Interestingly, event-related potentials time-locked to stimulus onset qualitatively similar but the amplitudes are attenuated in the solo compared to the dyadic version. This might indicate that arousal and attention after receiving a reward are sustained when a second agent is present but not when playing alone.Comment: Accepted for publication in The 41st Annual Meeting of the Cognitive Science Society (CogSci 2019

A physiological marker of recognition memory in adults with autism spectrum disorder? The Pupil Old/New Effect

This study investigated the pupil Old/New effect in individuals with Autism Spectrum Disorder (ASD) and typical development (TD). Participants studied verbal and visual meaningful and meaningless materials in black and white on a computer screen. Pupil sizes were measured while participants performed a Remember (episodic memory with context) /Know (semantic memory, no context) recognition memory test. ASD compared to TD individuals showed significantly reduced recognition rates for all materials. Both groups showed better memory for visual compared to verbal (picture superiority effect) and meaningful compared to meaningless materials. A pupil size ratio (pupil size for test item divided by baseline) for old (studied) and new (unstudied) materials indicated larger pupils for old compared to new materials only for the TD but not the ASD group. Pupil size in response to old versus new items was positively related to recognition accuracy, confirming that the pupil Old/New effect reflects a memory phenomenon in the ASD group. In addition, this study suggests an involvement of the noradrenergic neurotransmitter system in the abnormal hippocampal functioning in ASD. Implications of these findings as well as their underlying neurophysiology will be discussed in relation to current theories of memory in ASD

Comparison of pupillometry measurements in myopic, emmetropic and hyperopic children

To compare spherical and cylindrical equivalent, and pupillometry measurements between non-amblyopic myopic, emmetropic, and hyperopic children. The study was conducted prospectively and cross-sectionally in a single-centered eye clinic. Three non-amblyopic groups were included in the study: myopic (Myopia Group), emmetropic (Emmetropia Group), and hyperopic (Hyperopia Group) children. The groups were compared in terms of best-corrected visual acuity (BCVA), intraocular pressure (IOP), spherical equivalent (SE), and pupillometry measurements, including minimum dynamic pupillometry, maximum dynamic pupillometry, mesopic pupillometry, and photopic pupillometry. The correlation analysis was also performed between the measurements. We noted significant differences in mean SE values between the three groups and between the paired groups (p0.05 for all). The hyperopia group had the lowest mean minimum dynamic pupillometry, maximum dynamic pupillometry, mesopic pupillometry, and photopic pupillometry values (1.97±0.57, 5.23±051, 4.96±0.41, and 3.30±0.54, respectively). We found significant differences in all pupillometry measurements between the three groups (p0.05 for all). We also did not observe any correlation between the pupil diameter and age or gender (p>0.05 for both). Our study might be unique regarding the comparison of pupillometry measurements in non-amblyopic children with refractive errors. Myopia in the pediatric population may have potential pupillometric effects when compared to emmetropia and hyperopia. This should be considered in terms of the clinical relevance of pediatric refractive examination under different illumination conditions

Pupillometric measurement of operator workload

Pupillometry as a method of measuring workload is described. Pupillometric measures provide an indication of momentary fluctuations in central nervous system excitability that occur as cognitive operations are performed; the magnitude of these changes may serve as a sensitive indicator of the workload imposed by cognitive tasks

Pupillometry, a bioengineering overview

The pupillary control system is examined using a microprocessor based integrative pupillometer. The real time software functions of the microprocessor include: data collection, stimulus generation and area to diameter conversion. Results of an analysis of linear and nonlinear phenomena are presented

Use of the Neurological Pupil Index to Predict Postoperative Visual Function After Resection of a Tuberculum Sellae Meningioma: A Case Report.

The Neurological Pupil index (NPi) is a standardized method for evaluating pupil reactivity that removes inter-examiner variability. Changes in the NPi can predict clinical deterioration in patients with traumatic brain injury (TBI); however, its use to predict visual impairment after the resection of parasellar meningiomas has not been described. A 71-year-old female underwent a modified expanded bifrontal craniotomy for resection of a 3.1 cm tuberculum sella meningioma that caused compression of the optic chiasm and resulted in left temporal and right superior temporal visual field deficits. Postoperatively, she lost vision in the right eye. Pupillometer measurements demonstrated an asymmetrically low NPi at that time, which improved to normal prior to partial vision recovery. The average NPi in the right pupil was 1.67 during the time of vision loss compared to 3.47 in the left pupil (p=1.7x10-10). Statistical analysis was performed with the Student's t-test and the significance level was set at p-value < 0.01. Resection of parasellar meningiomas is challenging because of the proximity of the optic apparatus. We report a case of unilateral vision loss after resection of a tuberculum sella meningioma in which the impaired eye's NPi value correlated closely with visual function. NPi values that decrease below 3 predict spikes in intracranial pressure in TBI patients; similarly, increases in the NPi value above 2.5-3 predict improvement in vision in the case reported here. By monitoring the proximal portion of the oculomotor reflex, the NPi can be a marker of visual impairment after surgery

Listening to limericks: a pupillometry investigation of perceivers’ expectancy

What features of a poem make it captivating, and which cognitive mechanisms are sensitive to these features? We addressed these questions experimentally by measuring pupillary responses of 40 participants who listened to a series of Limericks. The Limericks ended with either a semantic, syntactic, rhyme or metric violation. Compared to a control condition without violations, only the rhyme violation condition induced a reliable pupillary response. An anomaly-rating study on the same stimuli showed that all violations were reliably detectable relative to the control condition, but the anomaly induced by rhyme violations was perceived as most severe. Together, our data suggest that rhyme violations in Limericks may induce an emotional response beyond mere anomaly detection