A paradigm for characterizing motion misperception in people with typical vision and low vision.

PURPOSE: We aimed to develop a paradigm that can efficiently characterize motion percepts in people with low vision and compare their responses with well-known misperceptions made by people with typical vision when targets are hard to see. METHODS: We recruited a small cohort of individuals with reduced acuity and contrast sensitivity (n = 5) as well as a comparison cohort with typical vision (n = 5) to complete a psychophysical study. Study participants were asked to judge the motion direction of a tilted rhombus that was either high or low contrast. In a series of trials, the rhombus oscillated vertically, horizontally, or diagonally. Participants indicated the perceived motion direction using a number wheel with 12 possible directions, and statistical tests were used to examine response biases. RESULTS: All participants with typical vision showed systematic misperceptions well predicted by a Bayesian inference model. Specifically, their perception of vertical or horizontal motion was biased toward directions orthogonal to the long axis of the rhombus. They had larger biases for hard-to-see (low contrast) stimuli. Two participants with low vision had a similar bias, but with no difference between high- and low-contrast stimuli. The other participants with low vision were unbiased in their percepts or biased in the opposite direction. CONCLUSIONS: Our results suggest that some people with low vision may misperceive motion in a systematic way similar to people with typical vision. However, we observed large individual differences. Future work will aim to uncover reasons for such differences and identify aspects of vision that predict susceptibility.

Visual Axis and Stiles-Crawford Effect Peak Show a Positional Correlation in Normal Eyes: A Cohort Study.

Purpose: The purpose of this study was to locate the visual axis and evaluate its correlation with the Stiles-Crawford effect (SCE) peak. Methods: Ten young, healthy individuals (20 eyes) were enrolled. An optical system was developed to locate the visual axis and measure SCE. To locate the visual axis, 2 small laser spots at 450 nm and 680 nm were co-aligned and delivered to the retina. The participants were asked to move a translatable pinhole until these spots were perceived to overlap each other. The same system assessed SCE at 680 nm using a bipartite, 2-channel (reference and test) Maxwellian-view optical system. The peak positions were estimated using a two-dimensional Gaussian fitting function and correlated with the visual axis positions. Results: Both the visual axis (x = 0.24 ± 0.35 mm, y = -0.16 ± 0.34 mm) and the SCE peak (x = 0.27 ± 0.35 mm, y = -0.15 ± 0.31 mm) showed intersubject variability among the cohort. The SCE peak positions were highly correlated in both the horizontal and vertical meridians to the visual axes (R2 = 0.98 and 0.96 for the x and y coordinates, respectively). Nine of the 10 participants demonstrated mirror symmetry for the coordinates of the visual axis and the SCE peak between the eyes (R2 = 0.71 for the visual axis and 0.76 for the SCE peak). Conclusions: The visual axis and SCE peak locations varied among the participants; however, they were highly correlated with each other for each individual. These findings suggest a potential mechanism underlying the foveal cone photoreceptor alignment.

Suprathreshold Contrast Perception Is Altered by Long-term Adaptation to Habitual Optical Blur.

Purpose: To investigate whether visual experience with habitual blur alters the neural processing of suprathreshold contrast in emmetropic and highly aberrated eyes. Methods: A large stroke adaptive optics system was used to correct ocular aberrations. Contrast constancy was assessed psychophysically in emmetropic and keratoconic eyes using a contrast matching paradigm. Participants adjusted the contrasts of gratings at various spatial frequencies to match the contrast perception of a reference grating at 4 c/deg. Matching was done both with fully corrected and uncorrected ocular aberrations. Optical correction allowed keratoconus patients to perceive high spatial frequencies that they have not experienced for some time. Results: Emmetropic observers exhibited contrast constancy both with their native aberrations and when their aberrations were corrected. Keratoconus patients exhibited contrast constancy with their uncorrected, native optics but they did not exhibit constancy during adaptive optics correction. Instead. they exhibited striking underconstancy: they required more contrast at high spatial frequencies than the contrast of the 4-c/deg stimulus to make them seem to have the same contrast. Conclusions: The presence of contrast constancy in emmetropes and keratoconus patients viewing with their native optics suggests that they have learned to amplify neural signals to offset the effects of habitual optical aberrations. The fact that underconstancy was observed in keratoconus patients when their optics were corrected suggests that they were unable to learn the appropriate neural amplification because they did not have experience with fine spatial detail. These results show that even adults can learn neural amplification to counteract the effects of their own optical aberrations.

Binocular accommodative response with extended depth of focus under controlled convergences.

Vergence and accommodation can be mismatched under virtual reality viewing conditions, and this mismatch has been thought to be one of the main causes of visual discomfort. The goal of this study was to investigate how optical conditions of the eyes affect accommodative responses to different convergence. Specifically, we hypothesized that extending the depth of focus (DoF) could weaken the control of the screen on accommodation, so that accommodation could be induced by convergence. To test this hypothesis, we extended the DoF using Zernike spherical aberrations (fourth and sixth orders) induced by a binocular adaptive optics (AO) vision simulator. Nine normal subjects between the ages of 21 and 34 (26 ± 5) years were recruited. Three optical conditions were generated: AO condition (aberration-free), monovision condition, and extended depth of focus (EDoF) condition. Binocular accommodative responses, along with binocular visual acuity and stereoacuity, were measured under all three optical conditions with varied binocular vergence levels. At 3 diopters of binocular convergence, the EDoF condition was the most efficient in inducing excessive accommodative response compared with the monovision condition and the AO condition. Visual acuity was impaired with EDoF as compared with the other two conditions. The average stereoscopic thresholds (at 0 vergence) under the EDoF condition were degraded compared with the AO condition but were superior to those of the monovision condition. Therefore, despite some compromise to visual performance, extending the DoF could allow for a more natural vergence-accommodation relationship, providing the potential for alleviating the vergence-accommodation conflict and associated visual fatigue symptoms in virtual reality.

Optics and neural adaptation jointly limit human stereovision.

Stereovision is the ability to perceive fine depth variations from small differences in the two eyes' images. Using adaptive optics, we show that even minute optical aberrations that are not clinically correctable, and go unnoticed in everyday vision, can affect stereo acuity. Hence, the human binocular system is capable of using fine details that are not experienced in everyday vision. Interestingly, stereo acuity varied considerably across individuals even when they were provided identical perfect optics. We also found that individuals' stereo acuity is better when viewing with their habitual optics rather than someone else's (better) optics. Together, these findings suggest that the visual system compensates for habitual optical aberrations through neural adaptation and thereby optimizes stereovision uniquely for each individual. Thus, stereovision is limited by small optical aberrations and by neural adaptation to one's own optics.

Functional reallocation of sensory processing resources caused by long-term neural adaptation to altered optics.

The eye's optics are a major determinant of visual perception. Elucidating how long-term exposure to optical defects affects visual processing is key to understanding the capacity for, and limits of, sensory plasticity. Here, we show evidence of functional reallocation of sensory processing resources following long-term exposure to poor optical quality. Using adaptive optics to bypass all optical defects, we assessed visual processing in neurotypically-developed adults with healthy eyes and with keratoconus - a corneal disease causing severe optical aberrations. Under fully-corrected optical conditions, keratoconus patients showed altered contrast sensitivity, with impaired sensitivity for fine spatial details and better-than-typical sensitivity for coarse spatial details. Both gains and losses in sensitivity were more pronounced in patients experiencing poorer optical quality in their daily life and mediated by changes in signal enhancement mechanisms. These findings show that adult neural processing adapts to better match the changes in sensory inputs caused by long-term exposure to altered optics.

An Alternative Theory of Binocularity.

The fact that seeing with two eyes is universal among vertebrates raises a problem that has long challenged vision scientists: how do animals with overlapping visual fields combine non-identical right and left eye images to achieve fusion and the perception of depth that follows? Most theories address this problem in terms of matching corresponding images on the right and left retinas. Here we suggest an alternative theory of binocular vision based on anatomical correspondence that circumvents the correspondence problem and provides a rationale for ocular dominance.

Solving the stereo correspondence problem with false matches.

The stereo correspondence problem exists because false matches between the images from multiple sensors camouflage the true (veridical) matches. True matches are correspondences between image points that have the same generative source; false matches are correspondences between similar image points that have different sources. This problem of selecting true matches among false ones must be overcome by both biological and artificial stereo systems in order for them to be useful depth sensors. The proposed re-examination of this fundamental issue shows that false matches form a symmetrical pattern in the array of all possible matches, with true matches forming the axis of symmetry. The patterning of false matches can therefore be used to locate true matches and derive the depth profile of the surface that gave rise to them. This reverses the traditional strategy, which treats false matches as noise. The new approach is particularly well-suited to extract the 3-D locations and shapes of camouflaged surfaces and to work in scenes characterized by high degrees of clutter. We demonstrate that the symmetry of false-match signals can be exploited to identify surfaces in random-dot stereograms. This strategy permits novel depth computations for target detection, localization, and identification by machine-vision systems, accounts for physiological and psychophysical findings that are otherwise puzzling and makes possible new ways for combining stereo and motion signals.

Attentional selection in judgments of stereo depth.

Stereoscopic depth is most useful when it comes from relative rather than absolute disparities. However, the depth perceived from relative disparities can vary with stimulus parameters that have no connection with depth or are irrelevant to the task. We investigated observers' ability to judge the stereo depth of task-relevant stimuli while ignoring irrelevant stimuli. The calculation of depth from disparity differs for 1-D and 2-D stimuli and we investigated the role this difference plays in observers' ability to selectively process relevant information. We show that the presence of irrelevant disparities affects perceived depth differently depending on stimulus dimensionality. Observers could not ignore disparities of irrelevant stimuli when they judged the relative depth between a 1-D stimulus (a grating) and a 2-D stimulus (a plaid). Yet these irrelevant disparities did not affect judgments of the relative depth between 2-D stimuli. Two processes contributing to stereo depth were identified, only one of which computes depth from a horizontal disparity metric and permits attentional selection. The other uses all stimuli, relevant and irrelevant, to calculate an effective disparity direction for comparing disparity magnitudes. These processes produce inseparable effects in most data sets. Using multiple disparity directions and comparing 1-D and 2-D stimuli can distinguish them.

Perceived depth in non-transitive stereo displays.

The separation between the eyes shapes the distribution of binocular disparities and gives a special role to horizontal disparities. However, for one-dimensional stimuli, disparity direction, like motion direction, is linked to stimulus orientation. This makes the perceived depth of one-dimensional stimuli orientation dependent and generally non-veridical. It also allows perceived depth to violate transitivity. Three stimuli, A, B, and C, can be arranged such that A > B (stimulus A is seen as farther than stimulus B when they are presented together) and B > C, yet A ⩽ C. This study examines how the visual system handles the depth of A, B, and C when they are presented together, forming a pairwise inconsistent stereo display. Observers' depth judgments of displays containing a grating and two plaids resolved transitivity violations among the component stimulus pairs. However, these judgments were inconsistent with judgments of the same stimuli within depth-consistent displays containing no transitivity violations. To understand the contribution of individual disparity signals, observers were instructed in subsequent experiments to judge the depth of a subset of display stimuli. This attentional instruction was ineffective; relevant and irrelevant stimuli contributed equally to depth judgments. Thus, the perceived depth separating a pair of stimuli depended on the disparities of the other stimuli presented concurrently. This context dependence of stereo depth can be approximated by an obligatory pooling and comparison of the disparities of one- and two-dimensional stimuli along an axis defined locally by the stimuli.

Network connections that evolve to circumvent the inverse optics problem.

A fundamental problem in vision science is how useful perceptions and behaviors arise in the absence of information about the physical sources of retinal stimuli (the inverse optics problem). Psychophysical studies show that human observers contend with this problem by using the frequency of occurrence of stimulus patterns in cumulative experience to generate percepts. To begin to understand the neural mechanisms underlying this strategy, we examined the connectivity of simple neural networks evolved to respond according to the cumulative rank of stimulus luminance values. Evolved similarities with the connectivity of early level visual neurons suggests that biological visual circuitry uses the same mechanisms as a means of creating useful perceptions and behaviors without information about the real world.

Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin.

Phosphotyrosine-binding domains, typified by the SH2 (Src homology 2) and PTB domains, are critical upstream components of signal transduction pathways. The E3 ubiquitin ligase Hakai targets tyrosine-phosphorylated E-cadherin via an uncharacterized domain. In this study, the crystal structure of Hakai (amino acids 106-206) revealed that it forms an atypical, zinc-coordinated homodimer by utilizing residues from the phosphotyrosine-binding domain of two Hakai monomers. Hakai dimerization allows the formation of a phosphotyrosine-binding pocket that recognizes specific phosphorylated tyrosines and flanking acidic amino acids of Src substrates, such as E-cadherin, cortactin and DOK1. NMR and mutational analysis identified the Hakai residues required for target binding within the binding pocket, now named the HYB domain. ZNF645 also possesses a HYB domain but demonstrates different target specificities. The HYB domain is structurally different from other phosphotyrosine-binding domains and is a potential drug target due to its novel structural features.

An adjacent arginine, and the phosphorylated tyrosine in the c-Met receptor target sequence, dictates the orientation of c-Cbl binding.

Previously, we have demonstrated that the tyrosine phosphorylated hepatocyte growth factor receptor (Met) binds to the c-Cbl phosphotyrosine-recognition, tyrosine kinase binding (TKB) domain in a reverse orientation compared to other c-Cbl binding partners. A Met peptide with the DpYR motif changed to RpYD (MetRD) retains a similar TKB binding affinity as the native Met peptide. However, the TKB: MetRD complex crystal structure reveals a complete reversal of the binding orientation. Collated data indicates that both binding and orientation is dictated by the phosphorylated tyrosine and an adjacent arginine forming intra-peptide hydrogen bonds and aligning unidirectionally with complementary charges in the phosphotyrosine binding pocket of c-Cbl.

Additional serine/threonine phosphorylation reduces binding affinity but preserves interface topography of substrate proteins to the c-Cbl TKB domain.

The E3-ubiquitin ligase, c-Cbl, is a multi-functional scaffolding protein that plays a pivotal role in controlling cell phenotype. As part of the ubiquitination and downregulation process, c-Cbl recognizes targets, such as tyrosine kinases and the Sprouty proteins, by binding to a conserved (NX/R)pY(S/T)XXP motif via its uniquely embedded SH2 domain (TKB domain). We previously outlined the mode of binding between the TKB domain and various substrate peptide motifs, including epidermal growth factor receptor (EGFR) and Sprouty2 (Spry2), and demonstrated that an intrapetidyl hydrogen bond forms between the (pY-1) arginine or (pY-2) asparagine and the phosphorylated tyrosine, which is crucial for binding. Recent reports demonstrated that, under certain types of stimulation, the serine/threonine residues at the pY+1 and/or pY+2 positions within this recognition motif of EGFR and Sprouty2 may be endogenously phosphorylated. Using structural and binding studies, we sought to determine whether this additional phosphorylation could affect the binding of the TKB domain to these peptides and consequently, whether the type of stimulation can dictate the degree to which substrates bind to c-Cbl. Here, we show that additional phosphorylation significantly reduces the binding affinity between the TKB domain and its target proteins, EGFR and Sprouty2, as compared to peptides bearing a single tyrosine phosphorylation. The crystal structure indicates that this is accomplished with minimal changes to the essential intrapeptidyl bond and that the reduced strength of the interaction is due to the charge repulsion between c-Cbl and the additional phosphate group. This obvious reduction in binding affinity, however, indicates that Cbl's interactions with its TKB-centered binding partners may be more favorable in the absence of Ser/Thr phosphorylation, which is stimulation and context specific in vivo. These results demonstrate the importance of understanding the environment in which certain residues are phosphorylated, and the necessity of including this in structural investigations.

Crystal structure of a fructokinase homolog from Halothermothrix orenii.

Fructokinase (FRK; EC 2.7.1.4) catalyzes the phosphorylation of d-fructose to d-fructose 6-phosphate (F6P). This irreversible and near rate-limiting step is a central and regulatory process in plants and bacteria, which channels fructose into a metabolically active state for glycolysis. Towards understanding the mechanism of FRK, here we report the crystal structure of a FRK homolog from a thermohalophilic bacterium Halothermothrixorenii (Hore_18220 in sequence databases). The structure of the Hore_18220 protein reveals a catalytic domain with a Rossmann-like fold and a beta-sheet "lid" for dimerization. Based on comparison of Hore_18220 to structures of related proteins, we propose its mechanism of action, in which the lid serves to regulate access to the substrate binding sites. Close relationship of Hore_18220 and plant FRK enzymes allows us to propose a model for the structure and function of FRKs.

Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.

The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.