Baseline metrics that may predict future myopia in young children.

PURPOSE: We used baseline data from the PICNIC longitudinal study to investigate structural, functional, behavioural and heritable metrics that may predict future myopia in young children. METHODS: Cycloplegic refractive error (M) and optical biometry were obtained in 97 young children with functional emmetropia. Children were classified as high risk (HR) or low risk (LR) for myopia based on parental myopia and M. Other metrics included axial length (AXL), axial length/corneal radius (AXL/CR) and refractive centile curves. RESULTS: Based on the PICNIC criteria, 46 children (26 female) were classified as HR (M = +0.62 ± 0.44 D, AXL = 22.80 ± 0.64 mm) and 51 (27 female) as LR (M = +1.26 ± 0.44 D, AXL = 22.77 ± 0.77 mm). Based on centiles, 49 children were HR, with moderate agreement compared with the PICNIC classification (k = 0.65, p < 0.01). ANCOVA with age as a covariate showed a significant effect for AXL (p < 0.01), with longer AXL and deeper anterior chamber depth (ACD) (p = 0.01) in those at HR (differences AXL = 0.16 mm, ACD = 0.13 mm). Linear regression models showed that central corneal thickness (CCT), ACD, posterior vitreous depth (PVD) (=AXL - CCT - ACD-lens thickness (LT)), corneal radius (CR) and age significantly predicted M (R = 0.64, p < 0.01). Each 1.00 D decrease in hyperopia was associated with a 0.97 mm elongation in PVD and 0.43 mm increase in CR. The ratio AXL/CR significantly predicted M (R = -0.45, p < 0.01), as did AXL (R = -0.25, p = 0.01), although to a lesser extent. CONCLUSIONS: Although M and AXL were highly correlated, the classification of pre-myopic children into HR or LR was significantly different when using each parameter, with AXL/CR being the most predictive metric. At the end of the longitudinal study, we will be able to assess the predictability of each metric.

Retinal Responses to Simulated Optical Blur Using a Novel Dead Leaves ERG Stimulus.

Purpose: The purpose of this study was to evaluate retinal responses to different types and magnitudes of simulated optical blur presented at specific retinal eccentricities using naturalistic images. Methods: Electroretinograms (ERGs) were recorded from 27 adults using 30-degree dead leaves naturalistic images, digitally blurred with one of three types of optical blur (defocus, astigmatism, and spherical aberrations), and one of three magnitudes (0.1, 0.3, or 0.5 µm) of blur. Digitally computed blur was applied to the entire image, or on an area outside the central 6 degrees or 12 degrees of retinal eccentricity. Results: ERGs were significantly affected by blur type, magnitude, and retinal eccentricity. ERGs were differentially affected by defocus and spherical aberrations; however, astigmatism had no effect on the ERGs. When blur was applied only beyond the central 12 degrees eccentricity, the ERGs were unaffected. However, when blur was applied outside the central 6 degrees, the ERG responses were significantly reduced and were no different from the ERGs recorded with entirely blurred images. Conclusions: Blur type, magnitude, and location all affect the retinal responses. Our data indicate that the retinal area between 6 and 12 degrees eccentricity has the largest effect on the retinal responses to blur. In addition, certain optical blur types appear to have a more detrimental effect on the ERGs than others. These results cannot be solely explained by changes to image contrast and spatial frequency content, suggesting that retinal neurons might be sensitive to spatial cues in order to differentiate between different blur types.

Blue light activates pulvinar nuclei in longstanding idiopathic photophobia: A case report.

Numerous pathologies can contribute to photophobia. When considering light transduction alone, photophobia may be triggered through melanopsin pathways (non-image forming), rod and cone pathways (image-forming), or some combination of the two. We evaluated a 39 year old female patient with longstanding idiopathic photophobia that was exacerbated by blue light, and tested her by presenting visual stimuli in an event-related fMRI experiment. Analysis showed significantly greater activation in bilateral pulvinar nuclei, associated with the melanopsin intrinsically photosensitive retinal ganglion cell (ipRGC) visual pathway, and their activation is consistent with the patient's report that blue light differentially evoked photophobia. This appears to be the first demonstration of functional activation of the ipRGC pathway during photophobia in a patient.

Age-related changes in ON and OFF responses to luminance increments and decrements.

Impulse response functions for an incremental luminous pulse (ON flash) or a decremental luminous pulse (OFF flash) were derived for twelve young (19-24 years old) and ten old (65-84 years old) observers. Thresholds were measured for two pulses separated by stimulus-onset-asynchronies from 13.3 to 186.7 ms. The pulses had a spatial Gaussian shape and were presented as increments or decrements on a 15 cd/m2 equal-energy white background, having the same chromaticity as the pulse. A spatial four-alternative forced-choice method was combined with a staircase procedure. Retinal illuminance was equated individually by heterochromatic flicker photometry and using a 2.3-mm exit pupil in a Maxwellian-view optical system to reduce the effects of age-related changes and individual variations in lens density and pupil size. Luminance ON- and OFF-impulse response functions calculated from the threshold data revealed significant age-related changes in the response amplitude of both first excitatory and first inhibitory phases. However, there were no significant changes in the time to the first peak or the second peak. These age-related changes in luminance varying ON- and OFF-impulse response functions (IRFs), reflecting putative properties of the magnocellular pathway, are discussed in relation to motion detection and the balance of ON and OFF pathways across the life span.

Senescent Changes and Topography of the Dark-Adapted Multifocal Electroretinogram.

Purpose: To investigate the topographic changes of the dark-adapted multifocal electroretinogram (mfERG) across adulthood in the central retina and compare the topography between macular versus extramacular, nasal versus temporal, and inferior versus superior retinal areas. Methods: Sixty-five subjects (18-88 years) received a comprehensive dilated eye examination to ensure the health of their retina and were tested with a dark-adapted mfERG protocol using a 61-hexagon pattern. The lens absorption of each subject was also estimated using a heterochromatic flicker photometry (HFP) paradigm. Results: The response amplitude and latency of the dark-adapted mfERG showed a significant change with age, which was best described with a linear model. All the retinal areas examined demonstrated similar aging effects. The extramacular and temporal retina showed higher response amplitude and faster response latency when compared with the macular and nasal retinae, respectively. No difference was found in response amplitude and latency between the inferior and superior retina. The HFP results also showed a significant correlation with age, consistent with senescent increases in short wavelength absorption by the crystalline lens. However, the change in lens absorption did not exceed the magnitude of the change in response amplitude and latency. Discussion: Our results indicate that there is a decline in dark-adapted retinal activity as measured with the mfERG. These aging processes affect rods and rod-bipolar cells. Their decrease in response can be attributed to both optical and neural factors.

Age-related change in fast adaptation mechanisms measured with the scotopic full-field ERG.

PURPOSE: To quantify the response dynamics of fast adaptation mechanisms of the scotopic ERG in younger and older adults using full-field m-sequence flash stimulation. METHODS: Scotopic ERGs were measured for a series of flashes separated by 65 ms over a range of 260 ms in 16 younger (20-26, 22.2 ± 2.1; range mean ±1 SD) and 16 older (65-85, 71.2 ± 7) observers without retinal pathology. A short-wavelength (λ peak = 442 nm) LED was used for scotopic stimulation, and the flashes ranged from 0.0001 to 0.01 cd s m(-2). The complete binary kernel series was derived from the responses to the m-sequence flash stimulation, and the first- and second-order kernel responses were analyzed. The first-order kernel represented the response to a single, isolated flash, while the second-order kernels reflected the adapted flash responses that followed a single flash by one or more base intervals. B-wave amplitudes of the adapted flash responses were measured and plotted as a function of interstimulus interval to describe the recovery of the scotopic ERG. A linear function was fitted to the linear portion of the recovery curve, and the slope of the line was used to estimate the rate of fast adaptation recovery. RESULTS: The amplitudes of the isolated flash responses and rates of scotopic fast adaptation recovery were compared between the younger and older participants using a two-way ANOVA. The isolated flash responses and rates of recovery were found to be significantly lower in the older adults. However, there was no difference between the two age groups in response amplitude or recovery rate after correcting for age-related changes in the density of the ocular media. CONCLUSIONS: These results demonstrated that the rate of scotopic fast adaptation recovery of normal younger and older adults is similar when stimuli are equated for retinal illuminance.

Discrimination thresholds of normal and anomalous trichromats: Model of senescent changes in ocular media density on the Cambridge Colour Test.

Age-related changes in chromatic discrimination along dichromatic confusion lines were measured with the Cambridge Colour Test (CCT). One hundred and sixty-two individuals (16 to 88 years old) with normal Rayleigh matches were the major focus of this paper. An additional 32 anomalous trichromats classified by their Rayleigh matches were also tested. All subjects were screened to rule out abnormalities of the anterior and posterior segments. Thresholds on all three chromatic vectors measured with the CCT showed age-related increases. Protan and deutan vector thresholds increased linearly with age while the tritan vector threshold was described with a bilinear model. Analysis and modeling demonstrated that the nominal vectors of the CCT are shifted by senescent changes in ocular media density, and a method for correcting the CCT vectors is demonstrated. A correction for these shifts indicates that classification among individuals of different ages is unaffected. New vector thresholds for elderly observers and for all age groups are suggested based on calculated tolerance limits.

Progress on Developing Adaptive Optics-Optical Coherence Tomography for In Vivo Retinal Imaging: Monitoring and Correction of Eye Motion Artifacts.

Recent progress in retinal image acquisition techniques, including optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO), combined with improved performance of adaptive optics (AO) instrumentation, has resulted in improvement in the quality of in vivo images of cellular structures in the human retina. Here, we present a short review of progress on developing AO-OCT instruments. Despite significant progress in imaging speed and resolution, eye movements present during acquisition of a retinal image with OCT introduce motion artifacts into the image, complicating analysis and registration. This effect is especially pronounced in high-resolution datasets acquired with AO-OCT instruments. Several retinal tracking systems have been introduced to correct retinal motion during data acquisition. We present a method for correcting motion artifacts in AO-OCT volume data after acquisition using simultaneously captured adaptive optics-scanning laser ophthalmoscope (AO-SLO) images. We extract transverse eye motion data from the AO-SLO images, assign a motion adjustment vector to each AO-OCT A-scan, and re-sample from the scattered data back onto a regular grid. The corrected volume data improve the accuracy of quantitative analyses of microscopic structures.

Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings.

PURPOSE: Because human bone marrow (BM) CD34+ stem cells home into damaged tissue and may play an important role in tissue repair, this pilot clinical trial explored the safety and feasibility of intravitreal autologous CD34+ BM cells as potential therapy for ischemic or degenerative retinal conditions. METHODS: This prospective study enrolled six subjects (six eyes) with irreversible vision loss from retinal vascular occlusion, hereditary or nonexudative age-related macular degeneration, or retinitis pigmentosa. CD34+ cells were isolated under Good Manufacturing Practice conditions from the mononuclear cellular fraction of the BM aspirate using a CliniMACs magnetic cell sorter. After intravitreal CD34+ cell injection, serial ophthalmic examinations, microperimetry/perimetry, fluorescein angiography, electroretinography (ERG), optical coherence tomography (OCT), and adaptive optics OCT were performed during the 6-month follow-up. RESULTS: A mean of 3.4 million (range, 1-7 million) CD34+ cells were isolated and injected per eye. The therapy was well tolerated with no intraocular inflammation or hyperproliferation. Best-corrected visual acuity and full-field ERG showed no worsening after 6 months. Clinical examination also showed no worsening during follow-up except among age-related macular degeneration subjects in whom mild progression of geographic atrophy was noted in both the study eye and contralateral eye at 6-month follow-up, concurrent with some possible decline on multifocal ERG and microperimetry. Cellular in vivo imaging using adaptive optics OCT showed changes suggestive of new cellular incorporation into the macula of the hereditary macular degeneration study eye. CONCLUSIONS: Intravitreal autologous BM CD34+ cell therapy appears feasible and well tolerated in eyes with ischemic or degenerative retinal conditions and merits further exploration. (ClinicalTrials.gov number, NCT01736059.).

Multimodal assessment of microscopic morphology and retinal function in patients with geographic atrophy.

PURPOSE: To correlate retinal function and visual sensitivity with retinal morphology revealed by ultrahigh-resolution imaging with adaptive optics-optical coherence tomography (AO-OCT), on patients with geographic atrophy. METHODS: Five eyes from five subjects were tested (four with geographic atrophy [66.3 ± 6.4 years, mean ± 1 SD] and one normal [61 years]). Photopic and scotopic multifocal electroretinograms (mfERGs) were recorded. Visual fields were assessed with microperimetry (mP) combined with a scanning laser ophthalmoscope for high-resolution confocal retinal fundus imaging. The eye tracker of the microperimeter identified the preferred retinal locus that was then used as a reference for precise targeting of areas for advanced retinal imaging. Images were obtained with purpose-built, in-house, ultrahigh resolution AO-OCT. Fundus autofluorescence (FAF) and color fundus (CF) photographs were also acquired. RESULTS: The AO-OCT imaging provided detailed cross-sectional structural representation of the retina. Up to 12 retinal layers were identified in the normal subject while many severe retinal abnormalities (i.e., calcified drusen, drusenoid pigment epithelium detachment, outer retinal tubulation) were identified in the retinae of the GA patients. The functional tests showed preservation of sensitivities, although somewhat compromised, at the border of the GA. CONCLUSIONS: The images provided here advance our knowledge of the morphology of retinal layers in GA patients. While there was a strong correlation between altered retinal structure and reduction in visual function, there were a number of examples in which the photoreceptor inner/outer segment (IS/OS) junctions lost reflectivity at the margins of GA, while visual function was still demonstrated. This was shown to be due to changes in photoreceptor orientation near the GA border.

Simultaneous chromatic and luminance human electroretinogram responses.

The parallel processing of information forms an important organisational principle of the primate visual system. Here we describe experiments which use a novel chromatic­achromatic temporal compound stimulus to simultaneously identify colour and luminance specific signals in the human electroretinogram (ERG). Luminance and chromatic components are separated in the stimulus; the luminance modulation has twice the temporal frequency of the chromatic modulation. ERGs were recorded from four trichromatic and two dichromatic subjects (1 deuteranope and 1 protanope). At isoluminance, the fundamental (first harmonic) response was elicited by the chromatic component in the stimulus. The trichromatic ERGs possessed low-pass temporal tuning characteristics, reflecting the activity of parvocellular post-receptoral mechanisms. There was very little first harmonic response in the dichromats' ERGs. The second harmonic response was elicited by the luminance modulation in the compound stimulus and showed, in all subjects, band-pass temporal tuning characteristic of magnocellular activity. Thus it is possible to concurrently elicit ERG responses from the human retina which reflect processing in both chromatic and luminance pathways. As well as providing a clear demonstration of the parallel nature of chromatic and luminance processing in the human retina, the differences that exist between ERGs from trichromatic and dichromatic subjects point to the existence of interactions between afferent post-receptoral pathways that are in operation from the earliest stages of visual processing.

Phases of daylight and the stability of color perception in the near peripheral human retina.

Typical daylight extends from blue (morning sky) to orangey red (evening sky) and is represented mathematically as the Daylight Locus in color space. In this study, we investigate the impact of this daylight variation on human color vision. Thirty-eight color normal human observers performed an asymmetric color match in the near peripheral visual field. Unique hues were identified using a naming paradigm. The observers' performance for matching was almost perfectly coincident with the Daylight Locus but declined markedly in other regions. Interobserver variability reached a conspicuous minimum adjacent to the Daylight Locus and was maximal in the red and yellowish-green regions. In the naming task, unique blue and yellow were virtually coincident with the Daylight Locus. The results suggest that the mechanisms of color perception mediated by the phylogenetically older (blue-yellow) color pathway have been strongly influenced by the different phases of daylight.

The relationship between peripherally matched invariant hues and unique hues: a cone-contrast approach.

A characteristic shift in hue and saturation occurs when colored targets are viewed peripherally compared with centrally. Four hues, one in each of the red, blue, green, and yellow regions of color space, remain unchanged when presented in the peripheral field. Apart from green, these peripherally invariant hues correspond almost exactly in color space with the unique hues. We explore this puzzling observation using asymmetric color-matching and color-naming experiments and computing cone contrasts for peripheral and central stimuli. We find that the difference between cone contrasts for the peripheral and central stimuli reaches a maximum at the chromatic axis corresponding to peripherally invariant green. We speculate that the effect is linked to a weakened signal from M-cones and probably associated with a reduced number of M-cones in peripheral retina.

Systematic violations of von Kries rule reveal its limitations for explaining color and lightness constancy.

Cone contrast remains constant, when the same object/background is seen under different illuminations-the von Kries rule [Shevell, Vis. Res. 18, 1649 (1978)]. Here we explore this idea using asymmetric color matching. We find that von Kries adaptation holds, regardless of whether chromatic constancy index is low or high. When illumination changes the stimulus luminance (reflectance), lightness constancy is weak and matching is dictated by object/background luminance contrast. When this contrast is masked or disrupted, lightness constancy mechanisms are more prominent. Thus von Kries adaptation is incompatible with lightness constancy, suggesting that cortical mechanisms must underlie color constancy, as expected from neurophysiological studies [Zeki, Nature 284, 412 (1980); Wild, Nature 313, 133 (1985)].

Real-world stimuli show perceived hue shifts in the peripheral visual field.

Certain hues undergo shifts in their appearance when they are viewed by the peripheral retina. This has often been shown on a 3-primary color CRT monitor. To investigate the possible role of metamerism, we replicated our peripheral color matching experiments using Munsell paper stimuli viewed under real and simulated daylight (using a 3-primary projection system). Using stimuli of constant value and chroma (7/4), observers adjusted the hue of a 3 deg target presented 18 deg nasally, until it matched a 1 deg target presented 1 deg nasally. The magnitude and pattern of measured hue shifts were similar to those measured using CRT stimuli. We conclude that the perceived hue shifts that have previously been reported in the peripheral retina are independent of the nature of the stimulus and of the illuminant.

Sex-related differences in peripheral human color vision: a color matching study.

There has been much controversy as to whether there are sex-related differences in human color vision. While previous work has concentrated on testing the central visual field, this study compares male versus female color vision in the near peripheral retina. Male (n = 19) and female (n = 19) color normal observers who exhibited no significant differences either in the midpoints or the ranges of their Rayleigh matches were tested with a color matching paradigm. They adjusted hue and saturation of a 3° test spot (18° eccentricity) until it matched a 1° probe (1° eccentricity). Both groups demonstrated measurable shifts in the appearance of the peripheral color stimuli similar to those that have been previously reported. However, females showed substantially less saturation loss than males (p < 0.003) in the green-yellow region of color space. No significant differences were found in other regions of color space. This difference in the perceived saturation of color stimuli was minimally affected either by the inclusion or exclusion in the analysis of potential heterozygous female carriers of deutan color vision deficiencies. We speculate that this advantage of female over male color vision is conferred by M-cone polymorphism.

The influence of retinal illuminance on L- and M-cone driven electroretinograms.

The electroretinographic response to L- and M-cone isolating stimuli was measured at different luminance levels to study the effect of retinal illuminance on amplitude and phase, and how this may influence estimates of L:M ratios in the retina. It was found that the amplitude of L- and M-cone driven responses increases differently with increasing retinal illuminance: L-cone responses increase more quickly than those of M-cones. The L:M ratio does not change strongly with retinal illuminance. The phase of both L- and M-cone driven responses advances with increasing retinal illuminance. There is considerable interindividual variability in the phase difference between the two, but generally M-cone driven responses are phase advanced.