In primary visual cortex fMRI responses to chromatic and achromatic stimuli are interdependent and predict contrast detection thresholds.

Chromatic and achromatic signals in primary visual cortex have historically been considered independent of each other but have since shown evidence of interdependence. Here, we investigated the combination of two components of a stimulus; an achromatic dynamically changing check background and a chromatic (L-M or S cone) target grating. We found that combinations of chromatic and achromatic signals in primary visual cortex were interdependent, with the dynamic range of responses to chromatic contrast decreasing as achromatic contrast increased. A contrast detection threshold study also revealed interdependence of background and target, with increasing chromatic contrast detection thresholds as achromatic background contrast increased. A model that incorporated a normalising effect of achromatic contrast on chromatic responses, but not vice versa, best predicted our V1 data as well as behavioural thresholds. Further along the visual hierarchy, the dynamic range of chromatic responses was maintained when compared to achromatic responses, which became increasingly compressive.

Improved Structure and Function in Early-Detected Second-Eye Neovascular Age-Related Macular Degeneration: FASBAT/Early Detection of Neovascular Age-Related Macular Degeneration Report 1.

PURPOSE: Visual acuity (VA) and structural biomarker assessment before and 24-months after early detection and routine treatment of second-eye involvement with neovascular age-related macular degeneration (nAMD) and additional comparison with the first eye affected. DESIGN: Prospective, 22-center observational study of participants with unilateral nAMD in the Early Detection of Neovascular AMD (EDNA) study, coenrolled into the Observing Fibrosis, Macular Atrophy and Subretinal Highly Reflective Material, Before and After Intervention with anti-VEGF Treatment (FASBAT) study for an additional 2-year follow-up. PARTICIPANTS: Older adults (> 50 years) with new onset nAMD in the first eye. METHODS: Assessment of both eyes with OCT, color fundus photography (CFP), clinic-measured VA, and quality of life (QoL). MAIN OUTCOME MEASURES: Prevalence of atrophy, subretinal hyperreflective material (SHRM), intraretinal fluid (IRF), subretinal fluid (SRF), and changes in VA over the study duration in both the first and second eyes affected with nAMD. Composite QoL scores over time. RESULTS: Of 431 participants recruited to the FASBAT study, the second eye converted to nAMD in 100 participants at a mean of 18.9 months. Visual acuity was 18 letters better at the time of early diagnosis in the second eye compared with conventional diagnosis in the first eye (72.9 vs. 55.6 letters). Visual acuity remained better in the second eye 24.9 months postconversion, at 69.5 letters compared with 59.7 letters at a similar matched time point in the first eye (18.9 months). A greater proportion of participants had vision > 70 letters in the second eye versus the first eye, 24.9 months postconversion (61 vs. 35). Prevalence of SHRM and IRF was lower in the second eye compared with the first eye 24.9 months postconversion. However, SRF prevalence was greater in the second eye 24.9 months postconversion. The development and progression of total area of atrophy appears similar in both eyes. Mean composite QoL scores increased over time, with a significant correlation between VA for the second eye only 24.9 months postconversion. CONCLUSION: This study has shown that early detection of exudative AMD in the second eye is associated with reduced prevalence of SHRM and IRF and greater VA, which is significantly correlated with maintained QoL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

The Emergence of Tuning to Global Shape Properties of Radial Frequency Patterns in the Ventral Visual Pathway.

Radial frequency (RF) patterns, created by sinusoidal modulations of a circle's radius, are processed globally when RF is low. These closed shapes therefore offer a useful way to interrogate the human visual system for global processing of curvature. RF patterns elicit greater responses than those to radial gratings in V4 and more anterior face-selective regions of the ventral visual pathway. This is largely consistent with work on nonhuman primates showing curvature processing emerges in V4, but is evident also higher up the ventral visual stream. Rather than contrasting RF patterns with other stimuli, we presented them at varied frequencies in a regimen that allowed tunings to RF to be derived from 8 human participants (3 female). We found tuning to low RF in lateral occipital areas and to some extent in V4. In a control experiment, we added a high-frequency ripple to the stimuli disrupting the local contour. Low-frequency tuning to these stimuli remained in the ventral visual stream, underscoring its role in global processing of shape curvature. We then used representational similarity analysis to show that, in lateral occipital areas, the neural representation was related to stimulus similarity, when it was computed with a model that captured how stimuli are perceived. We therefore show that global processing of shape curvature emerges in the ventral visual stream as early as V4, but is found more strongly in lateral occipital regions, which exhibit responses and representations that relate well to perception.SIGNIFICANCE STATEMENT We show that tuning to low radial frequencies, known to engage global shape processing mechanisms, was localized to lateral occipital regions. When low-level stimulus properties were accounted for such tuning emerged in V4 and LO2 in addition to the object-selective region LO. We also documented representations of global shape properties in lateral occipital regions, and these representations were predicted well by a proxy of the perceptual difference between the stimuli.

Increasing spatial frequency of S-cone defined gratings reduces their visibility and brain response more than for gratings defined by L-M cone contrast.

Chromatic sensitivity reduces as spatial frequency increases. Here, we explore the behavioural and neuronal responses to chromatic stimuli at two spatial frequencies for which the difference in sensitivity will be greater for S-cone than L-M stimuli. Luminance artefacts were removed using the Random Luminance Modulation (RLM) technique. As expected, doubling the spatial frequency increased the detection threshold more for S-cone than for isoluminant L-M gratings. We then used fMRI to measure the cortical BOLD responses to the same two chromatic stimuli (S and L-M) at the same two spatial frequencies. Responses were measured in six visual areas (V1, V2, V3, V3a, hV4, TO1/2). We found a significant interaction between spatial frequency in V1, V2 and V4 suggesting that the behaviourally observed increase in contrast threshold for high spatial frequency S-cone stimuli is reflected in these retinotopic areas. Our measurements show that neural responses consistent with psychophysical behaviour in a colour detection task can be observed as early as primary visual cortex.

Assessing the structure of the posterior visual pathway in bilateral macular degeneration.

Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

In a case of longstanding low vision regions of visual cortex that respond to tactile stimulation of the finger with Braille characters are not causally involved in the discrimination of those same Braille characters.

Braille reading and other tactile discrimination tasks recruit the visual cortex of both blind and normally sighted individuals undergoing short-term visual deprivation. Prior functional magnetic resonance imaging (fMRI) work in patient 'S', a visually impaired adult with the rare ability to read both highly magnified print visually and Braille by touch, found that foveal representations of S's visual cortex were recruited during tactile perception, whereas peripheral regions were recruited during visual perception. Here, we test the causal nature of tactile responses in the visual cortex of S by combining tactile and visual psychophysics with repetitive transcranial magnetic stimulation. First, we replicate the previous fMRI findings in S. Second, we demonstrate that transient disruption of S's foveal visual cortex has no measurable impact on S's tactile processing performance compared to that of healthy controls - a pattern not predicted by the fMRI results. Third, stimulation of foveal visual cortex maximally disrupted visual processing performance in both S and controls, suggesting the possibility of preserved visual processing within S's foveal representation. Finally, stimulation of somatosensory cortex induced the expected disruption to tactile processing performance in both S and controls. These data suggest that tactile responses in S's foveal representation reflect unmasking of latent connections between visual and somatosensory cortices and not behaviourally relevant cross-modal plasticity. Unlike studies in congenitally blind individuals, it is possible that the absence of complete visual loss in S has limited the degree of causally impactful cross-modal reorganisation.

Cortical Atrophy Predicts Visual Performance in Long-Term Central Retinal Disease; GCL, pRNFL and Cortical Thickness Are Key Biomarkers.

Purpose: The aim of this study was to assess both retinal and cortical structure in a cohort of patients with long-term acquired central retinal disease in order to identify potential disease biomarkers and to explore the relationship between the anterior and posterior visual pathways. Methods: Fourteen participants diagnosed with long-term central retinal disease underwent structural assessments of the retina using spectral-domain optical coherence tomography, including macular ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (pRNFL) thickness. Structural magnetic resonance imaging was used to measure visual cortex, including cortical volume of the entire occipital lobe and cortical thickness of the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively. Results: Mean thickness was significantly reduced in both the macular GCL and the inferior temporal pRNFL across patients. Cortical thickness was significantly reduced in both the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively. Disease duration significantly correlated with GCL thickness with a large effect size, whereas a medium effect size suggests the possibility that cortical thickness in the occipital pole may correlate with visual acuity. Conclusions: Long-term central retinal disease is associated with significant structural changes to both the retina and the brain. Exploratory analysis suggests that monitoring GCL thickness may be a sensitive biomarker of disease progression and reductions in visual cortical thickness may be associated with reduced visual acuity. Although this study is limited by its heterogeneous population, larger cohort studies would be needed to better establish some of the relationships detected between disease dependent structural properties of the anterior and posterior visual pathway given the effect sizes reported in our exploratory analysis.

Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia.

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.

CHIASM, the human brain albinism and achiasma MRI dataset.

We describe a collection of T1-, diffusion- and functional T2*-weighted magnetic resonance imaging data from human individuals with albinism and achiasma. This repository can be used as a test-bed to develop and validate tractography methods like diffusion-signal modeling and fiber tracking as well as to investigate the properties of the human visual system in individuals with congenital abnormalities. The MRI data is provided together with tools and files allowing for its preprocessing and analysis, along with the data derivatives such as manually curated masks and regions of interest for performing tractography.

Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia.

Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.

Assessing functional reorganization in visual cortex with simulated retinal lesions.

Macular degeneration (MD) causes central vision loss, removing input to corresponding representations in the primary visual cortex. There is disagreement concerning whether the cortical regions deprived of input can remain responsive, and the source of reported cortical responses is still debated. To simulate MD in controls, normally sighted participants viewed a bright central disk to adapt the retina, creating a transient 'retinal lesion' during a functional MRI experiment. Participants viewed blocks of faces, scrambled faces and uniform grey stimuli, either passively or whilst performing a one-back task. To assess the impact of the simulated lesion, participants repeated the paradigm using a more conventional mean luminance simulated scotoma without adaptation. Our results suggest our attempt to create a more realistic simulation of a lesion did not impact on responses in the representation of the simulated lesion. While most participants showed no evidence of stimulus-driven activation within the lesion representation, a few individuals (22%) exhibited responses similar to a participant with juvenile MD who completed the same paradigm (without adaptation). Reliability analysis showed that responses in the representation of the lesion were generally consistent irrespective of whether positive or negative. We provide some evidence that peripheral visual stimulation can also produce responses in central representations in controls while performing a task. This suggests that the 'signature of reorganization of visual processing', is not found solely in patients with retinal lesions, consistent with the idea that activity may be driven by unmasked top-down feedback.

Electronic retinal prosthesis for severe loss of vision in geographic atrophy in age-related macular degeneration: First-in-human use.

BACKGROUND: To date there are yet no available approved therapies for Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD). METHODS: Single site, non-randomized safety and efficacy study presenting the preliminary results in a cohort of five late stage AMD (GA) patients successfully implanted with the Argus II Retinal Prosthesis System (Second Sight Medical Products Inc., Sylmar, CA, USA). Extensive fundus imaging including retinal photographs from which the GA area was measured. A combination of custom and traditional tests designed for very low vision subjects assessed visual function in study subjects. A Functional Low-Vision Observer Rated Assessment was carried out to evaluate the impact of the system on the subject's daily life. In addition, a study to evaluate structural characteristics of the visual cortex of the brain was performed in one subject using magnetic resonance imaging. RESULTS: Seven device-related adverse events were reported, four of which were classed as serious adverse events. Retinal detachment was reported in three patients and was successfully treated within 12 months of onset. Testing showed an improvement in visual function in three of five patients with the system turned on. Magnetic resonance imaging assessed in one patient after implantation indicates a selective increase in cortical myelin and thickness in visual brain regions 1 year post implantation. CONCLUSIONS: Epiretinal prostheses can successfully be implanted in those affected by GA secondary to late-stage AMD and can elicit visual percepts by electrical stimulation of residual neuroretinal elements and improve basic visual function in those affected.

Neural markers of suppression in impaired binocular vision.

Even after conventional patching treatment, individuals with a history of amblyopia typically lack good stereo vision. This is often attributed to atypical suppression between the eyes, yet the specific mechanism is still unclear. Guided by computational models of binocular vision, we tested explicit predictions about how neural responses to contrast might differ in individuals with impaired binocular vision. Participants with a history of amblyopia (N = 25), and control participants with typical visual development (N = 19) took part in the study. Neural responses to different combinations of contrast in the left and right eyes, were measured using both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Stimuli were sinusoidal gratings with a spatial frequency of 3c/deg, flickering at 4 Hz. In the fMRI experiment, we also ran population receptive field and retinotopic mapping sequences, and a phase-encoded localiser stimulus, to identify voxels in primary visual cortex (V1) sensitive to the main stimulus. Neural responses in both modalities increased monotonically with stimulus contrast. When measured with EEG, responses were attenuated in the weaker eye, consistent with a fixed tonic suppression of that eye. When measured with fMRI, a low contrast stimulus in the weaker eye substantially reduced the response to a high contrast stimulus in the stronger eye. This effect was stronger than when the stimulus-eye pairings were reversed, consistent with unbalanced dynamic suppression between the eyes. Measuring neural responses using different methods leads to different conclusions about visual differences in individuals with impaired binocular vision. Both of the atypical suppression effects may relate to binocular perceptual deficits, e.g. in stereopsis, and we anticipate that these measures could be informative for monitoring the progress of treatments aimed at recovering binocular vision.

Cortical Reorganization: Reallocated Responses without Rewiring.

Is the brain able to reorganise following loss of sensory input? New work on individuals with sight loss shows that, while brain areas normally allocated to vision respond to other sensory stimuli, those responses are unlikely to mean the brain has rewired.

Triple visual hemifield maps in a case of optic chiasm hypoplasia.

In humans, each hemisphere comprises an overlay of two visuotopic maps of the contralateral visual field, one from each eye. Is the capacity of the visual cortex limited to these two maps or are plastic mechanisms available to host more maps? We determined the cortical organization of the visual field maps in a rare individual with chiasma hypoplasia, where visual cortex plasticity is challenged to accommodate three hemifield maps. Using high-resolution fMRI at 7T and diffusion-weighted MRI at 3T, we found three hemiretinal inputs, instead of the normal two, to converge onto the left hemisphere. fMRI-based population receptive field mapping of the left V1-V3 at 3T revealed three superimposed hemifield representations in the left visual cortex, i.e. two representations of opposing visual hemifields from the left eye and one right hemifield representation from the right eye. We conclude that developmental plasticity including the re-wiring of local intra- and cortico-cortical connections is pivotal to support the coexistence and functioning of three hemifield maps within one hemisphere.

Following the Status of Visual Cortex Over Time in Patients With Macular Degeneration Reveals Atrophy of Visually Deprived Brain Regions.

Purpose: Previous research has shown atrophy of visual cortex can occur in retinotopic representations of retinal lesions resulting from eye disease. However, the time course of atrophy cannot be established from these cross-sectional studies, which included patients with longstanding disease of varying severity. Our aim, therefore, was to measure visual cortical structure over time in participants after onset of unilateral visual loss resulting from AMD. Methods: Inclusion criteria were onset of acute unilateral neovascular AMD with bilateral dry AMD based on clinical examination. Therefore, substantial loss of unilateral visual input to cortex was relatively well-defined in time. Changes in cortical anatomy were assessed in the occipital lobe as a whole, and in cortical representations of the lesion and intact retina, the lesion and intact projection zones, respectively. Whole brain, T1-weighted magnetic resonance imaging was taken at diagnosis (before antiangiogenic treatment to stabilize the retina), during the 3- to 4-month initial treatment period, with a long-term follow-up approximately 5 (range 3.8-6.1 years) years later. Results: Significant cortical atrophy was detected at long-term follow-up only, with a reduction in mean cortical volume across the whole occipital lobe. Importantly, this reduction was explained by cortical thinning of the lesion projection zone, which suggests additional changes to those associated with normal aging. Over the period of study, antiangiogenic treatment stabilized visual acuity and central retinal thickness, suggesting that the atrophy detected was most likely governed by long-term decreased visual input. Conclusions: Our results indicate that consequences of eye disease on visual cortex are atrophic and retinotopic. Our work also raises the potential to follow the status of visual cortex in individuals over time to inform on how best to treat patients, particularly with restorative techniques.

Quantifying nerve decussation abnormalities in the optic chiasm.

OBJECTIVE: The human optic chiasm comprises partially crossing optic nerve fibers. Here we used diffusion MRI (dMRI) for the in-vivo identification of the abnormally high proportion of crossing fibers found in the optic chiasm of people with albinism. METHODS: In 9 individuals with albinism and 8 controls high-resolution 3T dMRI data was acquired and analyzed with a set of methods for signal modeling [Diffusion Tensor (DT) and Constrained Spherical Deconvolution (CSD)], tractography, and streamline filtering (LiFE, COMMIT, and SIFT2). The number of crossing and non-crossing streamlines and their weights after filtering entered ROC-analyses to compare the discriminative power of the methods based on the area under the curve (AUC). The dMRI results were cross-validated with fMRI estimates of misrouting in a subset of 6 albinotic individuals. RESULTS: We detected significant group differences in chiasmal crossing for both unfiltered DT (p = 0.014) and CSD tractograms (p = 0.0009) also reflected by AUC measures (for DT and CSD: 0.61 and 0.75, respectively), underlining the discriminative power of the approach. Estimates of crossing strengths obtained with dMRI and fMRI were significantly correlated for CSD (R2 = 0.83, p = 0.012). The results show that streamline filtering methods in combination with probabilistic tracking, both optimized for the data at hand, can improve the detection of crossing in the human optic chiasm. CONCLUSIONS: Especially CSD-based tractography provides an efficient approach to detect structural abnormalities in the optic chiasm. The most realistic results were obtained with filtering methods with parameters optimized for the data at hand. SIGNIFICANCE: Our findings demonstrate a novel anatomy-driven approach for the individualized diagnostics of optic chiasm abnormalities.

Asymmetries between achromatic and chromatic extraction of 3D motion signals.

Motion in depth (MID) can be cued by high-resolution changes in binocular disparity over time (CD), and low-resolution interocular velocity differences (IOVD). Computational differences between these two mechanisms suggest that they may be implemented in visual pathways with different spatial and temporal resolutions. Here, we used fMRI to examine how achromatic and S-cone signals contribute to human MID perception. Both CD and IOVD stimuli evoked responses in a widespread network that included early visual areas, parts of the dorsal and ventral streams, and motion-selective area hMT+. Crucially, however, we measured an interaction between MID type and chromaticity. fMRI CD responses were largely driven by achromatic stimuli, but IOVD responses were better driven by isoluminant S-cone inputs. In our psychophysical experiments, when S-cone and achromatic stimuli were matched for perceived contrast, participants were equally sensitive to the MID in achromatic and S-cone IOVD stimuli. In comparison, they were relatively insensitive to S-cone CD. These findings provide evidence that MID mechanisms asymmetrically draw on information in precortical pathways. An early opponent motion signal optimally conveyed by the S-cone pathway may provide a substantial contribution to the IOVD mechanism.