Effect of Dioptric Blur on Pattern-Reversal and Motion-Onset VEPs as Used in Clinical Research.

Purpose: To describe the effect of dioptric blur on visual evoked potentials (VEPs) induced by motion onset (MO-VEPs). Methods: The effect of dioptric blur up to 4 D on MO-VEPs was tested on 12 subjects using central, peripheral, and full-field stimulation with a low-contrast structure of concentric circles with spatial frequency <1 c/°. The results were compared to VEPs evoked by 15' and 60' checkerboard pattern-reversal (PR-VEPs). The relationship between peak time and interpeak amplitude of the dominant components was related to the level of dioptric blur using linear regression. Results: The MO-VEPs did not show a significant peak prolongation (P > 0.28) or amplitude attenuation (P > 0.14) with the blur, whereas for the PR-VEPs we observed a significant decrease in amplitude (P < 0.001) and increase in peak time (P < 0.001) for both checkerboard sizes. Conclusions: For MO-VEPs induced by radial motion of low contrast and low spatial frequency pattern, the change in retinal blur does not affect the peak time or the interpeak amplitude of the dominant N2 component. Translational Relevance: The resistance to retinal blur that we demonstrated for MO-VEP provides a diagnostic opportunity to test the integrity of the visual system and reveal a retrobulbar impairment even in uncorrected refractive errors.

Emulated retinal image capture (ERICA) to test, train and validate processing of retinal images.

High resolution retinal imaging systems, such as adaptive optics scanning laser ophthalmoscopes (AOSLO), are increasingly being used for clinical research and fundamental studies in neuroscience. These systems offer unprecedented spatial and temporal resolution of retinal structures in vivo. However, a major challenge is the development of robust and automated methods for processing and analysing these images. We present ERICA (Emulated Retinal Image CApture), a simulation tool that generates realistic synthetic images of the human cone mosaic, mimicking images that would be captured by an AOSLO, with specified image quality and with corresponding ground-truth data. The simulation includes a self-organising mosaic of photoreceptors, the eye movements an observer might make during image capture, and data capture through a real system incorporating diffraction, residual optical aberrations and noise. The retinal photoreceptor mosaics generated by ERICA have a similar packing geometry to human retina, as determined by expert labelling of AOSLO images of real eyes. In the current implementation ERICA outputs convincingly realistic en face images of the cone photoreceptor mosaic but extensions to other imaging modalities and structures are also discussed. These images and associated ground-truth data can be used to develop, test and validate image processing and analysis algorithms or to train and validate machine learning approaches. The use of synthetic images has the advantage that neither access to an imaging system, nor to human participants is necessary for development.

Feature issue introduction: applications of adaptive optics.

This feature issue of Optics Express follows the 2020 Imaging and Applied Optics Congress and comprises of articles on the development and use of adaptive optics across the broad range of domains in which the technique has been applied - including atmospheric correction, ophthalmology, vision science, microscopy, optical communications and beam control. This review provides a basic introduction to adaptive optics and a summary of the multidisciplinary articles included in this issue.

Predicting Middle School Profiles of Algebra Performance Using Fraction Knowledge.

Fraction knowledge and algebraic skill are closely linked. Algebra is a gatekeeper for advanced courses (Booth & Newton, 2012; Brown & Quinn, 2007). This study uses the person-centered approach of latent profile analysis to examine individual differences in middle schoolers' (N = 350) algebra performance at the end of the year (EOY). The relative importance of a range of fraction skills is considered in predicting the likelihood of displaying a particular profile of EOY algebra knowledge, measured by feature knowledge, equation encoding, equation solving, and word-problem skills. Notably, fraction number line estimation did not predict algebra performance on any of the four measures. Fraction arithmetic at the beginning of the year is most predictive of displaying the highest performing EOY algebra profile.

Comparison between optical and digital blur using near visual acuity.

In a low-cost laboratory setup, we compared visual acuity (VA) for stimuli rendered with Zernike aberrations to an equivalent optical dioptric defocus in emmetropic individuals using a relatively short observing distance of 60 cm. The equivalent spherical refractive error of + 1, + 2 or + 4 D, was applied in the rendering of Landolt Rings. Separately, the refractive error was introduced dioptrically in: (1) unchanged Landolt Rings with an added external lens (+ 1, + 2 or + 4 D) at the subject's eye; (2) same as (1) but with an added accommodation and a vertex distance adjustment. To compare all three approaches, we examined VA in 10 healthy men. Stimuli were observed on a PC CRT screen. For all three levels of refractive error, the pairwise comparison did not show a statistically significant difference between digital blur and accommodation-plus-vertex-distance-adjusted dioptric blur (p < 0.204). The best agreement, determined by Bland-Altman analysis, was measured for + 4 D and was in line with test-retest limits for examination in the clinical population. Our results show that even for a near observing distance, it is possible to use digitally rendered defocus to replicate dioptric blur without a significant change in VA in emmetropic subjects.

What makes a microsaccade? A review of 70 years of research prompts a new detection method.

A new method for detecting microsaccades in eye-movement data is presented, following a review of reported microsaccade properties between the 1940s and today. The review focuses on the parameter ranges within which certain physical markers of microsaccades are thought to occur, as well as any features of microsaccades that have been stably reported over time. One feature of microsaccades, their binocularity, drives the new microsaccade detection method. The binocular correlation method for microsaccade detection is validated on two datasets of binocular eye-movements recorded using video-based systems: one collected as part of this study, and one from Nyström et al, 2017. Comparisons between detection methods are made using precision-recall statistics. This confirms that the binocular correlation method performs well when compared to manual coders and performs favourably compared to the commonly used Engbert & Kliegl (2003) method with subsequent modifications (Engbert & Mergenthaler, 2006). The binocular correlation microsaccade detection method is easy to implement and MATLAB code is made available to download.

Absence of potential gadolinium toxicity symptoms following 22,897 gadoteric acid (Dotarem®) examinations, including 3,209 performed on renally insufficient individuals.

OBJECTIVES: Recent safety concerns regarding gadolinium-based contrast agents (GdCAs) concluded with the suspension of some agents from the European market, yet a clinical consequence remains unknown. We used electronic health records to investigate the incidence of potential toxicity to gadoteric acid (Dotarem®) within our local population, including those with renal insufficiency (RI). METHODS: Data for patients who underwent contrast-enhanced MRI were identified, stratified by renal function at time of scan and retrospectively followed using routinely collected health data. Searches performed were: records of hypersensitivity reactions; diagnoses of nephrogenic systemic fibrosis (NSF); onset of chronic pain, a symptom that has been associated with NSF and the theorised gadolinium deposition disease (GDD); and post-contrast acute kidney injury (PC-AKI). Comparisons were made between patients and controls (those who underwent non-contrast scans) via chi-square and ANOVA statistical tests. RESULTS: Of the 22,897 contrast-enhanced MRI scans performed locally from 2004-2016 (adult, n = 22,325 and paediatric, n = 572), 14% were performed on patients with RI (30 ≤ eGFR < 60, n = 2,622; 15 ≤ eGFR < 30, n = 464; eGFR < 15, n = 123). Two adult patients (0.01%) suffered hypersensitivity reactions. Zero cases of NSF were reported, with an average follow-up time of 6.0 ± 2.5 years (range, 8 months-15 years). Analysis failed to highlight statistically higher rates of chronic pain onset post-MRI (adult: p = 0.777, paediatric: p = 0.578), or PC-AKI (adult: p = 0.566, paediatric: p = 0.841), in the patient groups compared to controls. CONCLUSIONS: These data indicate that administration of gadoteric acid to RI patients does not result in a higher rate of signs or symptoms that may be associated with gadolinium toxicity when compared to controls. KEY POINTS: • Following 22,897 administrations of gadoteric acid to a local population, there was no association with symptoms that may be associated with gadolinium toxicity. • Zero cases of nephrogenic systemic fibrosis were reported following 3,209 gadoteric acid administrations to a cohort of renally insufficient patients. • A low number of hypersensitivity reactions were observed (0.01%) and no higher rate of chronic pain or post-contrast acute kidney injury were noted when compared with a control cohort of non-contrast-enhanced examinations.

The Impact of Different Magnetic Resonance Imaging Equipment and Scanning Parameters on Signal Intensity Ratio Measurements in Phantoms and Healthy Volunteers: Implications for Interpreting Gadolinium Signal Changes Within the Brain.

OBJECTIVES: The aim of this study was to examine the variation in signal intensity ratio (SIR) values in Eurospin gel phantoms and healthy volunteer (HV) brain images in response to different magnetic resonance imaging hardware and software settings. MATERIALS AND METHODS: Gel phantoms with T1 relaxation times similar to the dentate nucleus (DN), pons (P), globus palladus (GP), and thalamus (Th) were scanned using a T1-weighted 2-dimensional spin-echo sequence on 2 magnetic resonance imaging scanners (3 T and 1.5 T). Imaging was performed by sequentially altering selected magnetic resonance (MR) parameters relative to a default pulse sequence, and the protocol was implemented repeatedly over 3 months. The experiment was also repeated on a cohort of 15 young HVs. Calculations of DN/P and GP/Th SIR values were derived for the images of the gels (GelDN/P and GelGP/Th) and the HVs (HVDN/P and HVGP/Th). RESULTS: For the default sequence, the mean SIR values of GelDN/P and GelGP/Th varied by ±2.20% and ±0.75%, respectively, when measured over multiple imaging sessions (3 T). Within a single imaging session, these variations were smaller (±0.17% for GelDN/P and ±0.15% for GelGP/Th). At 1.5 T, the equivalent SIR variations for GelDN/P were ±1.41% (multiple sessions) and ±0.41% (single session), and that for GelGP/Th were ±0.47% (multiple sessions) and ±0.33% (single session).Sequential changes to the MR sequence parameters resulted in gel SIR variations as follows: 14.07% ± 2.43% (with/without normalization filters), -7.80% ± 0.28% (different echo times, TE), and -5.06% ± 0.59% (selective activation of RF coil elements). The largest variations were noted when the gels were positioned below the scanner isocenter, where SIR measurements were different by 22%.For the HVs, the SIR values were found to be consistently within 0.64% (single session) for the default sequence. Sequential changes to the MR sequence parameters resulted in SIR variations of -24.47% ± 2.47% (with/without normalization filters), -15.32% ± 7.71% (different echo times, TE), and -2.90% ± 0.78% (selective activation of RF coil elements). CONCLUSIONS: This study has demonstrated that SIR percentage changes from baseline of a similar magnitude to brain gadolinium contrast agent signal hyperintensities can be replicated in phantom models and HVs by altering common MR acquisition parameters and hardware.

Non-invasive in vivo quantification of the developing optical properties and graded index of the embryonic eye lens using SPIM.

Graded refractive index lenses are inherent to advanced visual systems in animals. By understanding their formation and local optical properties, significant potential for improved ocular healthcare may be realized. We report a novel technique measuring the developing optical power of the eye lens, in a living animal, by exploiting the orthogonal imaging modality of a selective plane illumination microscope (SPIM). We have quantified the maturation of the lenticular refractive index at three different visible wavelengths using a combined imaging and ray tracing approach. We demonstrate that the method can be used with transgenic and vital dye labeling as well as with both fixed and living animals. Using a key eye lens morphogen and its inhibitor, we have measured their effects both on lens size and on refractive index. Our technique provides insights into the mechanisms involved in the development of this natural graded index micro-lens and its associated optical properties.

Compact, modular and in-plane AOSLO for high-resolution retinal imaging.

The adaptive optics scanning laser ophthalmoscope (AOSLO) was first developed in 2002 and since then the technology has been adopted in several laboratories around the world, for both clinical and psychophysical research. There have been a few major design implementations of the AOSLO. The first used on-axis tilted spherical mirrors in a planar arrangement, and the second minimized the build up of astigmatism present in the first design by using a non-planar arrangement. Other designs have avoided astigmatism by using custom-made toroidal mirrors or by using lenses on-axis, rather than mirrors. We present a new design implementation for an AOSLO that maintains a planar optical alignment without the build up astigmatism using compact, reconfigurable modules based on an Offner relay system. We additionally use an off-the-shelf digital oscilloscope for data capture and custom-written Python code for generating and analyzing the retinal images. This design results in a compact system that is simple to align and, being composed of modular relays, has the potential for additional components to be added. We show that this system maintains diffraction-limited image quality across the field of view and that cones are clearly resolved in the central retina. The modular relay design is generally applicable to any system requiring one or more components in the pupil conjugate plane. This is likely to be useful for any point-scanned system, such as a standard scanning laser ophthalmoscope or non-ophthalmic confocal imaging system.

Vision science and adaptive optics, the state of the field.

Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system.

Critical band masking reveals the effects of optical distortions on the channel mediating letter identification.

There is evidence that letter identification is mediated by only a narrow band of spatial frequencies and that the center frequency of the neural channel thought to underlie this selectivity is related to the size of the letters. When letters are spatially filtered (at a fixed size) the channel tuning characteristics change according to the properties of the spatial filter (Majaj et al., 2002). Optical aberrations in the eye act to spatially filter the image formed on the retina-their effect is generally to attenuate high frequencies more than low frequencies but often in a non-monotonic way. We might expect the change in the spatial frequency spectrum caused by the aberration to predict the shift in channel tuning observed for aberrated letters. We show that this is not the case. We used critical-band masking to estimate channel-tuning in the presence of three types of aberration-defocus, coma and secondary astigmatism. We found that the maximum masking was shifted to lower frequencies in the presence of an aberration and that this result was not simply predicted by the spatial-frequency-dependent degradation in image quality, assessed via metrics that have previously been shown to correlate well with performance loss in the presence of an aberration. We show that if image quality effects are taken into account (using visual Strehl metrics), the neural channel required to model the data is shifted to lower frequencies compared to the control (no-aberration) condition. Additionally, we show that when spurious resolution (caused by π phase shifts in the optical transfer function) in the image is masked, the channel tuning properties for aberrated letters are affected, suggesting that there may be interference between visual channels. Even in the presence of simulated aberrations, whose properties change from trial-to-trial, observers exhibit flexibility in selecting the spatial frequencies that support letter identification.

Accounting for the phase, spatial frequency and orientation demands of the task improves metrics based on the visual Strehl ratio.

Advances in ophthalmic instrumentation have allowed high order aberrations to be measured in vivo. These measurements describe the distortions to a plane wavefront entering the eye, but not the effect they have on visual performance. One metric for predicting visual performance from a wavefront measurement uses the visual Strehl ratio, calculated in the optical transfer function (OTF) domain (VSOTF) (Thibos et al., 2004). We considered how well such a metric captures empirical measurements of the effects of defocus, coma and secondary astigmatism on letter identification and on reading. We show that predictions using the visual Strehl ratio can be significantly improved by weighting the OTF by the spatial frequency band that mediates letter identification and further improved by considering the orientation of phase and contrast changes imposed by the aberration. We additionally showed that these altered metrics compare well to a cross-correlation-based metric. We suggest a version of the visual Strehl ratio, VScombined, that incorporates primarily those phase disruptions and contrast changes that have been shown independently to affect object recognition processes. This metric compared well to VSOTF for letter identification and was the best predictor of reading performance, having a higher correlation with the data than either the VSOTF or cross-correlation-based metric.

Different aberrations raise contrast thresholds for single-letter identification in line with their effect on cross-correlation-based confusability.

We previously showed that different types of aberration defocus, coma, and secondary astigmatism affect reading performance via different mechanisms. In this paper, we show the contrary result that, for identification of isolated letters, the effects of rendering different types of aberration can be described by a single cross-correlation-based metric. Aberrations reduce the effective resolution of an optical system, quantified by the high-frequency fall-off of the modulation transfer function. They additionally cause spatial-frequency-dependent phase and contrast changes, which have a size-dependent effect on letter forms. We used contrast threshold as our performance measure, instead of distance acuity, to separate the effects of form alterations from those of resolution limits. This measure is additionally appropriate in comparing single-letter-based performance to reading at a fixed distance. The relationship between a cross-correlation-based measure of letter confusability and performance was the same for all three types of aberration. For reading, we had found a different relationship for coma than for defocus and secondary astigmatism. We conclude that even when two tasks--letter identification and reading--use the same component stimulus set, the combination of multiple letters in a reading task produces functional differences between the effects of these aberrations that are not present for isolated letters.

Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor.

Protein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05-3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.

Not all aberrations are equal: reading impairment depends on aberration type and magnitude.

The eye's optical components are imperfect and cause distortions in the retinal image that cannot be corrected completely by conventional spectacles. It is important to understand how these uncorrected aberrations (those excluding defocus and primary astigmatism) affect visual performance. We assessed reading performance using text with a simulated monochromatic aberration (defocus, coma, or secondary astigmatism), all of which typically occur in the normal population. We found that the rate of decline in reading performance with increasing aberration amplitude was smaller for coma than for secondary astigmatism or defocus. Defocus and secondary astigmatism clearly had an impact on word identification, as revealed by an analysis of a lexical frequency effect. The spatial form changes caused by these aberrations are particularly disruptive to letter identification, which in turn impacts word recognition and has consequences for further linguistic processing. Coma did not have a significant effect on word identification. We attribute reading impairment caused by coma to effects on saccade targeting, possibly due to changes in the spacings between letters. Effects on performance were not accompanied by a loss of comprehension confirming that even if an aberration is not severe enough to make text illegible it may still have a significant impact on reading.