Decreased activity of piriform cortex and orbitofrontal hyperactivation in Usher Syndrome, a human disorder of ciliary dysfunction.

Usher syndrome (USH) is a condition characterized by ciliary dysfunction leading to retinal degeneration and hearing/vestibular loss. Putative olfactory deficits in humans have been documented at the psychophysical level and remain to be proven at the neurophysiological level. Thus, we aimed to study USH olfactory impairment using functional magnetic resonance imaging. We analyzed differences in whole-brain responses between 27 USH patients and 26 healthy participants during an olfactory detection task with a bimodal odorant (n-butanol). The main research question was whether between-group differences could be identified using a conservative whole-brain approach and in a ROI-based approach in key olfactory brain regions. Results indicated higher olfactory thresholds in USH patients, thereby confirming the hypothesis of reduced olfactory acuity. Importantly, we found decreased BOLD activity for USH patients in response to odorant stimulation in the right piriform cortex, while right orbitofrontal cortex showed increased activity. We also found decreased activity in other higher-level regions in a whole brain approach. We suggest that the hyper activation in the orbitofrontal cortex possibly occurs as a compensatory mechanism after the under-recruitment of the piriform cortex. This study suggests that olfactory deficits in USH can be objectively assessed using functional neuroimaging which reveals differential patterns of activity both in low- and high-level regions of the olfactory network.

Enhanced Visual Attentional Modulation in Patients with Inherited Peripheral Retinal Degeneration in the Absence of Cortical Degeneration.

The role of attentional mechanisms in peripheral vision loss remains an outstanding question. Our study was aimed at determining the effect of genetically determined peripheral retinal dystrophy caused by Retinitis Pigmentosa (RP) on visual cortical function and tested the recruitment of attentional mechanisms using functional magnetic resonance imaging (fMRI). We included thirteen patients and twenty-two age- and gender-matched controls. We analyzed cortical responses under attentional demands and passive viewing conditions while presenting a visual stimulus covering the central and paracentral visual field. Brain activity was studied in visual areas V1, V2, and V3 as well as in cortical regions of interest corresponding to the preserved and the damaged visual field. The influence of visual field extent and age of disease onset were also investigated. Cortical thickness of visual areas was also measured. We found that cortical visual responses under attentional demands were increased in patients with larger degeneration of visual field, as demonstrated by significant interaction effects between group and task conditions. Moreover, activation during the task condition was increased for patients in two cortical regions of interest corresponding to the preserved and damaged visual field, specifically in patients with severe visual field loss. These findings were observed in the presence of preserved visual cortical structure. We conclude that RP patients have enhanced visual attention recruitment despite their retinal degeneration, while cortical structure and overall response levels remain intact. The unmasking of feedback signals from higher level visual regions involved in attentional processes may explain the increased cortical responses. These findings are relevant for the design of strategies for treating retinal diseases, based on attentional cuing.

Visual and ocular motor function in the atypical form of neurodegeneration with brain iron accumulation type I.

BACKGROUND/AIMS: Neurodegeneration with brain iron accumulation (NBIA) type I is a rare disease that can be divided into a classical or atypical variant, according to age of onset and clinical pattern. Neuro-ophthalmological involvement has been documented in the classical variant but only anecdotically in the atypical variant. We sought to describe the visual and ocular motor function in patients with atypical form of NBIA type I. METHODS: Cross-sectional study, including patients with genetically confirmed NBIA type I and classified as atypical variant, who underwent ophthalmological examination with best corrected visual acuity (BCVA), optical coherence tomography (OCT), fundus autofluorescence (FAF), electroretinography (ERG), visual evoked potentials (VEP) and video-oculography. RESULTS: Seven patients with a mean BCVA of 0.12±0.14 logMAR were included. Only two patients showed structural evidence of advanced retinopathy in OCT and FAF, and there were no cases of optic atrophy. ERG data, however, showed abnormal scotopic and/or photopic responses in all patients. VEP were normal in all three patients. Ocular fixation was markedly unstable (eg, increased rate of saccadic pulses) in the majority of patients (5). Additional mild ocular motor disturbances included low gain pursuit (2), hypermetric saccades (1), low gain optokinetic (2) and caloric and rotatory responses (3). CONCLUSION: Functional retinal changes associated with marked instability of ocular fixation should be included in the clinical spectrum of NBIA, particularly in the atypical form.

Early visual cortical structural changes in diabetic patients without diabetic retinopathy.

BACKGROUND: It is known that diabetic patients have changes in cortical morphometry as compared to controls, but it remains to be clarified whether the visual cortex is a disease target, even when diabetes complications such as retinopathy are absent. Therefore, we compared type 2 diabetes patients without diabetic retinopathy with control subjects using magnetic resonance imaging to assess visual cortical changes when retinal damage is not yet present. METHODS: We performed T1-weighted imaging in 24 type 2 diabetes patients without diabetic retinopathy and 27 age- and gender-matched controls to compare gray matter changes in the occipital cortex between groups using voxel based morphometry. RESULTS: Patients without diabetic retinopathy showed reduced gray matter volume in the occipital lobe when compared with controls. CONCLUSIONS: Reduced gray matter volume in the occipital cortex was found in diabetic patients without retinal damage. We conclude that cortical early visual processing regions may be affected in diabetic patients even before retinal damage occurs.

Primary visual cortical remapping in patients with inherited peripheral retinal degeneration.

Human studies addressing the long-term effects of peripheral retinal degeneration on visual cortical function and structure are scarce. Here we investigated this question in patients with Retinitis Pigmentosa (RP), a genetic condition leading to peripheral visual degeneration. We acquired functional and anatomical magnetic resonance data from thirteen patients with different levels of visual loss and twenty-two healthy participants to study primary (V1) visual cortical retinotopic remapping and cortical thickness. We identified systematic visual field remapping in the absence of structural changes in the primary visual cortex of RP patients. Remapping consisted in a retinotopic eccentricity shift of central retinal inputs to more peripheral locations in V1. Importantly, this was associated with changes in visual experience, as assessed by the extent of the visual loss, with more constricted visual fields resulting in larger remapping. This pattern of remapping is consistent with expansion or shifting of neuronal receptive fields into the cortical regions with reduced retinal input. These data provide evidence for functional changes in V1 that are dependent on the magnitude of peripheral visual loss in RP, which may be explained by rapid cortical adaptation mechanisms or long-term cortical reorganization. This study highlights the importance of analyzing the retinal determinants of brain functional and structural alterations for future visual restoration approaches.

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.

A New Approach to Assess Early Progressive Loss Across Multiple Visual Channels In the Natural History of Glaucoma.

PURPOSE: We aimed to evaluate the ability of new psychophysical discrimination tests, based on readily available hardware, to probe motion, achromatic, and chromatic contrast sensitivity, across the natural history of glaucoma. We assessed the sensitivity of these tests to detect functional damage at ocular hypertension stage, using receiver operating characteristic analysis. We also explored whether eccentricity-related patterns of damage change with disease progression. PATIENTS AND METHODS: We studied a cohort of 43 participants, who were divided between different groups: ocular hypertension (n=16 eyes), glaucoma suspects (n=15), and primary open-angle glaucoma (n=12). These patients were compared with an age-matched control group (n=15 eyes). We tested distinct subsets of retinal ganglion cell populations using 3 novel 2-alternative forced choice psychophysical discrimination tests (independent variables: motion, achromatic, and chromatic L, M, and S-cone contrasts) between 2 separated peripheral, small moving single dots at 4 distinct meridians. Notably these tests were implemented in relatively standard hardware. RESULTS: All tests showed significant correlation with disease progression (mean ρ±SD=0.708±0.075; P<0.0001) and had sufficient power to discriminate glaucoma subgroups. Most tests using this design had large sensitivity (above 90% for 80% specificity) to detect functional damage at the ocular hypertensive stage. Disease-related eccentricity patterns of damage were also found, matching the expected pattern of progression. CONCLUSIONS: Our new psychophysical discrimination tests are capable of probing disease progression and to detect functional damage at ocular hypertension stage. It is therefore possible to customize psychophysical test software to detect early changes and monitor disease progression, including progressive loss of functional reserve, using relatively simple hardware.

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.

Developmental dissociation of visual dorsal stream parvo and magnocellular representations and the functional impact of negative retinotopic BOLD responses.

Localized neurodevelopmental defects provide an opportunity to study structure-function correlations in the human nervous system. This unique multimodal case report of epileptogenic dysplasia in the visual cortex allowed exploring visual function across distinct pathways in retinotopic regions and the dorsal stream, in relation to fMRI retinotopic mapping and spike triggered BOLD responses. Pre-surgical EEG/video monitoring, MRI/DTI, EEG/fMRI, PET and SPECT were performed to characterize structure/function correlations in this patient with a very early lesion onset. In addition, we included psychophysical methods (assessing parvo/konio and magnocellular pathways) and retinotopic mapping. We could identify dorsal stream impairment (with extended contrast sensitivity deficits within the input magno system contrasting with more confined parvocellular deficits) with disrupted active visual field input representations in regions neighboring the lesion. Simultaneous EEG/fMRI identified perilesional and retinotopic bilaterally symmetric BOLD deactivation triggered by interictal spikes, which matched the contralateral spread of magnocellular dysfunction revealed in the psychophysical tests. Topographic changes in retinotopic organization further suggested long term functional effects of abnormal electrical discharges during brain development. We conclude that fMRI based visual field cortical mapping shows evidence for retinotopic dissociation between magno and parvocellular function well beyond striate cortex, identifiable in high level dorsal visual representations around visual area V3A which is consistent with the effects of epileptic spike triggered negative BOLD.

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 Leber's 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.

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.

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

BACKGROUND: Functional 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. METHODS: Visual 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. RESULTS: Chromatic 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). CONCLUSIONS: In 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.

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.

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.

Retinal function in best macular dystrophy: relationship between electrophysiological, psychophysical, and structural measures of damage.

PURPOSE: To establish structure-function correlations across the visual field, to investigate disease progression in Best macular dystrophy (BMD), by correlating structural damage with retinal function as assessed by the combination of psychophysics and multifocal electrophysiology. METHODS: Spatial achromatic and chromatic contrast sensitivities (probing red-green and blue-yellow pathways) were assessed using custom-made psychophysical software to evaluate retinal damage in BMD and age-matched control eyes (n = 19 and n = 22, respectively). Neurosensory retinal dysfunction was also evaluated by means of multifocal electroretinography (mfERG). Correlation analysis was performed between functional parameters in BMD, clinical measures, and morphologic data obtained by optical coherence tomography (OCT). RESULTS: Significant peripheral impairment of retinal function, as measured by mfERG and spatial achromatic contrast sensitivity (CS) methods, was found in BMD. Furthermore, changes in thickness of the neurosensory retina, as measured by OCT, and reduced mfERG responses were also indicators of early loss in BMD and often occurred even with preserved visual acuity. Disease duration was significantly correlated with psychophysical deterioration in chromatic and achromatic tasks but not with mfERG measures. Interestingly, partial correlation analysis revealed a significant independent correlation with our CS measures. CONCLUSIONS: Novel topographic achromatic and chromatic CS methods can detect and quantify functional impairment in early stages of BMD, including the involvement of the peripheral retina and the central chromatic pathway, and can provide new pathophysiological information with added value in relation to electrophysiological and structural measures of damage.

Evidence of widespread retinal dysfunction in patients with stargardt disease and morphologically unaffected carrier relatives.

PURPOSE: To characterize contrast sensitivity (CS) across the visual field for two achromatic spatial-temporal frequencies in 21 families with Stargardt disease (STGD) and to correlate psychophysical impairment with patterns of change in multifocal electroretinography (mfERG). METHODS: Twenty-seven eyes from patients with STGD, 16 eyes from asymptomatic relatives, and 44 age-matched control eyes were included. Chromatic CS function was assessed by comparing protan, deutan, and tritan (Cambridge Color Test; Cambridge Research Systems Ltd., Rochester, UK) and anomaloscope measures (IF-2; Roland Consult, Wiesbaden, Germany). Achromatic CS measures were obtained with custom-made software in nine locations by using randomly interleaved staircases. The first task-low spatial frequency (LSF)-matched the known frequency-doubling method that is believed to activate the magnocellular pathway preferentially. The second included an intermediate spatial frequency (ISF, 3.5 cyc/deg). mfERGs (RETIscan; Roland Consult) were also obtained. Relatives were screened for ABCA4 mutations by ABCR400 microarray and direct sequencing. RESULTS: Central impairment of achromatic and chromatic CS (along the three isolation axes) was observed in STGD. LSF and ISF tasks revealed significant and widespread dysfunction in patients and their morphologically unaffected relatives, 80% of whom were found to be ABCA4 mutation carriers. Significant reduction of P1 amplitudes was also observed in both groups. CONCLUSIONS: CS function is impaired in patients with STGD at distinct spatial-temporal frequencies, which, in addition to the color vision deficits, suggests dual impairment of the magno- parvocellular pathways. STGD morphologically unaffected carriers may show patterns of psychophysical dysfunction that are mirrored by abnormal mfERG responses.

Visual phenotype in Williams-Beuren syndrome challenges magnocellular theories explaining human neurodevelopmental visual cortical disorders.

Williams-Beuren syndrome (WBS), a neurodevelopmental genetic disorder whose manifestations include visuospatial impairment, provides a unique model to link genetically determined loss of neural cell populations at different levels of the nervous system with neural circuits and visual behavior. Given that several of the genes deleted in WBS are also involved in eye development and the differentiation of retinal layers, we examined the retinal phenotype in WBS patients and its functional relation to global motion perception. We discovered a low-level visual phenotype characterized by decreased retinal thickness, abnormal optic disk concavity, and impaired visual responses in WBS patients compared with age-matched controls by using electrophysiology, confocal and coherence in vivo imaging with cellular resolution, and psychophysics. These mechanisms of impairment are related to the magnocellular pathway, which is involved in the detection of temporal changes in the visual scene. Low-level magnocellular performance did not predict high-level deficits in the integration of motion and 3D information at higher levels, thereby demonstrating independent mechanisms of dysfunction in WBS that will require remediation strategies different from those used in other visuospatial disorders. These findings challenge neurodevelopmental theories that explain cortical deficits based on low-level magnocellular impairment, such as regarding dyslexia.