Catarina Mateus

Retinal and cortical patterns of spatial anisotropy in contrast sensitivity tasks

It has often been postulated that asymmetries in performance within the visual field (VF) are not characteristic of early visual processing. Here, human retinal (naso/temporal), cortical (left/right) and superior/inferior patterns of asymmetry were explored with achromatic contrast sensitivity (CS) tasks, that probed distinct spatiotemporal frequency channels. Low spatial, high temporal frequency stimuli (illusory frequency-doubling (FD)) yielded superior and temporal field disadvantage. Independent right and nasal visual hemifield patterns of disadvantage were found when probing an intermediate spatial frequency (ISF) channel, with stationary sinusoidal gratings. These findings show that asymmetries in spatial vision are explained by independent retinal and cortical mechanisms.

Asymmetry of visual sensory mechanisms: Electrophysiological, structural, and psychophysical evidences

Psychophysical visual field asymmetries are widely documented and have been attributed to anatomical anisotropies both at the retinal and cortical levels. This debate on whether such differences originate within the retina itself or are due to higher visual processing may be illuminated if concomitant anatomical, physiological, and psychophysical measures are taken in the same individuals. In the current study, we have focused on the study of objective functional and structural asymmetries at the retinal level and examined their putative correlation with visual performance asymmetries. Forty healthy participants (80 eyes; 13 male and 27 female subjects) were included in this study. Objective functional/structural asymmetries were probed using the multifocal electroretinogram (mfERG) technique and optical coherence tomography (OCT), respectively. A nasal/temporal pattern of asymmetry (nasal visual hemifield disadvantage) was found for all methods (retinal thickness, contrast sensitivity, and mfERG P1 amplitude). Furthermore, superior/inferior asymmetries could be documented only with psychophysics and structural measures. These patterns likely arise at different levels of the retina as inferred by partly independent correlation patterns. We conclude that patterns of structural/functional asymmetries arise at different levels of visual processing with a strong retinal contribution.

Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome

Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21) genes and affects almost all body organs. Children with DS have defects in visual processing that may have a negative impact on their daily life and cognitive development. However, there is little known about the genes and pathogenesis underlying these defects. Here, we show morphometric in vivo data indicating that the neural retina is thicker in DS individuals than in the normal population. A similar thickening specifically affecting the inner part of the retina was also observed in a trisomic model of DS, the Ts65Dn mouse. Increased retinal size and cellularity in this model correlated with abnormal retinal function and resulted from an impaired caspase-9-mediated apoptosis during development. Moreover, we show that mice bearing only one additional copy of Dyrk1a have the same retinal phenotype as Ts65Dn mice and normalization of Dyrk1a gene copy number in Ts65Dn mice completely rescues both, morphological and functional phenotypes. Thus, triplication of Dyrk1a is necessary and sufficient to cause the retinal phenotype described in the trisomic model. Our data demonstrate for the first time the implication of DYRK1A overexpression in a developmental alteration of the central nervous system associated with DS, thereby providing insights into the aetiology of neurosensorial dysfunction in a complex disease.

Neuroretinal Dysfunction With Intact Blood-Retinal Barrier and Absent Vasculopathy in Type 1 Diabetes

It is unknown whether independent neural damage may occur in the pre-/absent vascular diabetic retinopathy (DR). To exclude vasculopathy, it is important to measure the integrity of the blood-retinal barrier (BRB). This cross-sectional study addressed this problem in type 1 diabetic patients with normal ocular fundus and absent breakdown of the BRB (confirmed with vitreous fluorometry). These were compared with a group with disrupted BRB (with normal fundus or initial DR) and normal controls. Multifocal electroretinography and chromatic/achromatic contrast sensitivity were measured in these 42 patients with preserved visual acuity. Amplitudes of neurophysiological responses (multifocal electroretinogram) were decreased in all eccentricity rings in both clinical groups, when compared with controls, with sensitivity >78% for a specificity level of 90%. Implicit time changes were also found in the absence of initial DR. Impaired contrast sensitivity along chromatic axes was also observed, and achromatic thresholds were also different between controls and both clinical groups. The pattern of changes in the group without baseline BRB permeability alterations, as probed by psychophysical and electrophysiological measurements, does thereby confirm independent damage mechanisms. We conclude that retinal neuronal changes can be diagnosed in type 1 diabetes, independently of the breakdown of the BRB and onset of vasculopathy.

Aging of Low and High Level Vision: From Chromatic and Achromatic Contrast Sensitivity to Local and 3D Object Motion Perception

The influence of normal aging in early, intermediate and high-level visual processing is still poorly understood. We have addressed this important issue in a large cohort of 653 subjects divided into five distinct age groups, [20;30[, [30;40[, [40;50[, [50;60[and [60;[. We applied a broad range of psychophysical tests, testing distinct levels of the visual hierarchy, from local processing to global integration, using simple gratings (spatial contrast sensitivity -CS- using high temporal/low spatial frequency or intermediate spatial frequency static gratings), color CS using Landolt patches, moving dot stimuli (Local Speed Discrimination) and dot patterns defining 3D objects (3D Structure from Motion, 3D SFM). Aging data were fitted with linear or quadratic regression models, using the adjusted coefficient of determination (R2 a) to quantify the effect of aging. A significant effect of age was found on all visual channels tested, except for the red-green chromatic channel. The high temporal low spatial frequency contrast sensitivity channel showed a mean sensitivity loss of 0.75 dB per decade (R2 a = 0.17, p<0.001), while the lower intermediate spatial frequency channel showed a more pronounced decrease, around 2.35 dB (R2 a = 0.55, p<0.001). Concerning low-level motion perception, speed discrimination decreased 2.71°/s (R2 a = 0.18, p<0.001) and 3.15°/s (R2 a = 0.13, p<0.001) only for short presentations for horizontal and oblique meridians, respectively. The 3D SFM task, requiring high-level integration across dorsal and ventral streams, showed the strongest (quadratic) decrease of motion coherence perception with age, especially when the task was temporally constrained (R2 a = 0.54, p<0.001). These findings show that visual channels are influenced by aging into different extent, with time presenting a critical role, and high-level dorso-ventral dominance of deterioration, which accelerates with aging, in contrast to the other channels that show a linear pattern of deterioration.

Independent patterns of damage to retinocortical pathways in multiple sclerosis without a previous episode of optic neuritis

Asymptomatic visual loss is a feature of multiple sclerosis (MS) but its relative impact on distinct retinocortical pathways is still unclear. The goal of this work was to investigate patterns of subclinical visual impairment in patients with MS with and without clinically associated previous optic neuritis (ON). We have used functional methods that assess parvo-, konio- and magnocellular pathways in order to compare pathophysiological mechanisms of damage in a population of 44 subjects with MS (87 eyes), with and without a previous episode of ON. These methods included chromatic contrast sensitivity across multiple chromatic axes (Cambridge Colour Test–parvo/konio pathways), perimetric achromatic contrast sensitivity for the magno pathway [frequency doubling technique (FDT)] and pattern visual evoked potentials (VEP). These measures were correlated with field sensitivity measures obtained using conventional automated static perimetry (ASP) and were also compared with conventional clinical chromatic/achromatic contrast sensitivity chart-based measures. We have found evidence for uncorrelated damage of all retinocortical pathways only in patients with MS without ON. VEP evidence for axonal damage was found in this group supporting the emerging notion of axonal damage even in sub-clinical stages of ON/MS pathophysiology. Only in this group was significant correlation of functional measures with disease stage observed, suggesting that distinct pathophysiological milestones are present before and after ON has occurred.

Long term cortical plasticity in visual retinotopic areas in humans with silent retinal ganglion cell loss.

Visual cortical plasticity induced by overt retinal lesions (scotomas) has remained a controversial phenomenon. Here we studied cortical plasticity in a silent model of retinal ganglion cell loss, documented by in vivo optical biopsy using coherence tomography. The cortical impact of non-scotomatous subtle retinal ganglion cell functional and structural loss was investigated in carriers of the mitochondrial DNA 11778G>A mutation causing Lebers hereditary optic neuropathy. We used magnetic resonance imaging (MRI) to measure cortical thickness and fMRI to define retinotopic cortical visual areas V1, V2 and V3 in silent carriers and matched control groups. Repeated Measures analysis of variance revealed a surprising increase in cortical thickness in the younger carrier group (below 21 years of age). This effect dominated in extrastriate cortex, and notably V2. This form of structural plasticity suggests enhanced plastic developmental mechanisms in extrastriate retinotopic regions close to V1 and not receiving direct retinocortical input.

Physiological evidence for impairment in autosomal dominant optic atrophy at the pre-ganglion level.

BackgroundFunctional studies in patients with autosomal dominant optic atrophy (ADOA) are usually confined to analysis of physiological and clinical impact at the ganglion cell (GG) and post GC levels. Here we aimed to investigate the impact of the disease at a pre-GC level and its correlation with GC/post-GC related measures.MethodsVisual function was assessed in a population of 22 subjects (44 eyes) from 13 families with ADOA submitted to OPA1 mutation analysis. Quantitative psychophysical methods were used to assess konio and parvocellular chromatic pathways (Cambridge Colour Test) and distinct achromatic spatial frequency channels (Metropsis Contrast Sensitivity Test). Preganglionic and GC measures were assessed with the Multifocal Electroretinogram (mfERG) and Pattern Electroretinogram (PERG) respectively. Global Pattern and Multifocal VEP (visual evoked potentials) were used to assess retinocortical processing, in order to characterize impaired processing at the post GC level. Perimetric sensitivity, retinal and ganglion cell nerve fibre layer (RNFL) thickness measurements were also obtained.ResultsChromatic thresholds were significantly increased for protan, deutan and tritan axes (p < <0.001 for all comparisons) and achromatic contrast sensitivity (CS) was reduced for all studied six spatial frequency channels (p < <0.001). We observed significant decreases in peripapillary (p ≤ 0.0008), macular (ring2: p = 0.02; ring 3: p < 0.0001) RNFL, as well as in overall retinal thickness (p < 0.0001 in all regions, except the central one). Interestingly, we found significant decreases in pre-ganglionic multifocal ERG response amplitudes (P1-wave: p ≤ 0.005) that were correlated with retinal thickness (ring 2: r = 0.512; p = 0.026/ring 3: r = 0.583; p = 0.011) and visual acuity (r = 0.458; p = 0.03, central ring 1).Reductions in GC and optic nerve responses amplitude (PERG: p < 0.0001, P50 and N95 components; Pattern VEP: p < 0.0001, P100) were accompanied by abnormalities of the MfVEP, primarily in central locations (ring 1: p = 0.0007; ring 2: p = 0.012).ConclusionsIn the ADOA model of ganglion cell damage, parvo-, konio- and magnocellular pathways are concomitantly affected. Structural changes and physiological impairment also occurs at a preganglionic level, suggesting a retrograde damage mechanism with a significant clinical impact on visual function, as shown by correlation analysis. Cortical impairment is only moderately explained by the retinal phenotype, suggesting additional damage mechanisms at the cortical level.

Genetically induced impairment of retinal ganglion cells at the axonal level is linked to extrastriate cortical plasticity.

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder, which leads to initially silent visual loss due to retinal ganglion cell (RGC) degeneration. We aimed to establish a link between features of retinal progressive impairment and putative cortical changes in a cohort of 15 asymptomatic patients harboring the 11778G>A mutation with preserved visual acuity and normal ocular examination. To study plasticity evoked by clinically silent degeneration of RGC we only studied mutation carriers. We phenotyped pre-clinical silent degeneration from the psychophysical, neurophysiological and structural points of view to understand whether retinal measures could be related to cortical reorganization, using pattern electrophysiology, chromatic contrast sensitivity and high-resolution optical coherence tomography to measure macular, RGC nerve fiber layer as well as inner/outer retinal layer thickness. We then performed correlation analysis of these measures with cortical thickness estimates in functionally mapped retinotopic visual cortex. We found that compensatory cortical plasticity occurring in V2/V3 is predicted by the swelling (indicating deficits of axonal transport and intracellular edema) of the macular RGC axonal layer. Increased cortical thickness (CT) in V2 and V3 was observed in peripheral regions, like visual field loss, in these mutation carriers. CT was a very discriminative measure between carriers and controls, as revealed by ROC analysis. Importantly, the substantial cortical reorganization that occurs in the carrier state can be used to provide statistical discrimination between carriers and controls to a level that is similar to measures of retinal dysfunction. We conclude that peripheral cortical compensatory plasticity in early visual areas V2/V3 may be triggered by pathology in peripheral RGC axons in combination with potential developmental changes.

Development and aging of visual hemifield asymmetries in contrast sensitivity.

The relation of development and aging with models of visual anisotropies and their influence on low-level visual processing remain to be established. Our main goal was to explore visual performance asymmetries in development and normal aging using low-level contrast sensitivity behavioral tasks [probing two distinct spatiotemporal frequency channels, (a) intermediate spatial and null temporal frequency (3.5 cycles per degree (cpd) and 0 Hz); and (b) low spatial and high temporal frequency (0.25 cpd undergoing 25 Hz counterphase flicker)]. Different patterns of functional asymmetries were investigated within four (two neurodevelopmental and two adult) age groups (N = 258 participants; 8-65 years). We found a left visual hemifield/right hemisphere advantage for only the intermediate spatial frequency channel that was present early in life and remained stable throughout adulthood. In contrast, inferior/superior visual hemifield asymmetries, with a direct ecological meaning, were found for both spatiotemporal frequency channels. This inferior visual hemifield advantage emerged early in life and persisted throughout aging. These findings show that both right hemispheric and dorsal retinotopic patterns of dominance in low-level vision emerge early in childhood, maintaining during aging.