Congenital Blindness Research Articles

Crossmodal reorganization of face-voice interactions in Cochlear implanted deaf patients

A recent trend in functional magnetic resonance imaging is to test for association of clinical disorders with every possible connection between selected brain parcels. We investigated the impact of the resolution of functional brain parcels, ranging from large-scale networks to local regions, on a mass univariate general linear model (GLM) of connectomes. For each resolution taken independently, the Benjamini–Hochberg procedure controlled the false-discovery rate (FDR) at nominal level on realistic simulations. However, the FDR for tests pooled across all resolutions could be inflated compared to the FDR within resolution. This inflation was severe in the presence of no or weak effects, but became negligible for strong effects. We thus developed an omnibus test to establish the overall presence of true discoveries across all resolutions. Although not a guarantee to control the FDR across resolutions, the omnibus test may be used for descriptive analysis of the impact of resolution on a GLM analysis, in complement to a primary analysis at a predefined single resolution. On three real datasets with significant omnibus test (schizophrenia, congenital blindness, motor practice), markedly higher rate of discovery were obtained at low resolutions, below 50, in line with simulations showing increase in sensitivity at such resolutions. This increase in discovery rate came at the cost of a lower ability to localize effects, as low resolution parcels merged many different brain regions together. However, with 30 or more parcels, the statistical effect maps were biologically plausible and very consistent across resolutions. These results show that resolution is a key parameter for GLM-connectome analysis with FDR control, and that a functional brain parcellation with 30 to 50 parcels may lead to an accurate summary of full connectome effects with good sensitivity in many situations.

Psychophysical measures of visual function and everyday perceptual experience in a case of congenital stationary night blindness.

An appreciation of the relation between laboratory measures of visual deficit and everyday perceptual experience is fundamental to understanding the impact of a visual condition on patients and so to a fuller characterization of the disorder. This study aims to understand better the interpretative processes by which modified sensory information is perceived by a patient with congenital stationary night blindness and the adaptive strategies that are devised to deal with their measurable visual loss. Psychophysical measurements of temporal resolution, spectral sensitivity, and color discrimination were conducted on a 78-year-old male patient with the condition, who was also interviewed at length about the ways in which his diagnosis affected his daily life. Narrative analysis was employed to identify the relation between his subjective perceptual experiences and functional deficits in identifiable components of the visual system. Psychophysical measurements indicated a complete lack of rod perception and substantially reduced cone sensitivity. Two particular effects of this visual loss emerged during interviews: 1) the development of navigational techniques that relied on light reflections and point sources of light and 2) a reluctance to disclose the extent of visual loss and resulting lifelong psychosocial consequences. This study demonstrates the valuable complementary role that rich descriptive patient testimony can play, in conjunction with laboratory and clinical measurements, in more fully characterizing a disorder and in reaching a more complete understanding of the experience of vision loss. It also evidences the particular suitability of filmmaking techniques as a means of accessing and communicating subjective patient experience.

Structural role of the T94I rhodopsin mutation in congenital stationary night blindness

Congenital stationary night blindness (CSNB) is an inherited and non-progressive retinal dysfunction. Here, we present the crystal structure of CSNB-causing T94I2.61 rhodopsin in the active conformation at 2.3 Å resolution. The introduced hydrophobic side chain prolongs the lifetime of the G protein activating metarhodopsin-II state by establishing a direct van der Waals contact with K2967.43, the site of retinal attachment. This is in stark contrast to the light-activated state of the CSNB-causing G90D2.57 mutation, where the charged mutation forms a salt bridge with K2967.43 To find the common denominator between these two functional modifications, we combined our structural data with a kinetic biochemical analysis and molecular dynamics simulations. Our results indicate that both the charged G90D2.57 and the hydrophobic T94I2.61 mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E1133.28 We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients.

Editorial: Color Vision Sensation and Perception.

Color vision is one of the most intriguing phenomena of the visual experience and has been the object of study from vision scientists to philosophers of perception. The wavelengths, their intensity and purity are experienced as hue, brightness and saturation based on complex information processing of the light entering the eyes. This special research topic is devoted to covering from basic aspects based on light and retinal processes to perceptual and cognitive mechanisms and their respective applications in clinical settings. The reader will find a series of papers organized in two chapters, one devoted to the more basic phenomena and processing, the other focused on the more cognitive and cultural aspects. The integrative aspect of luminance in color vision starts our journey. Reduction in number of levels of luminance in pseudoisochromatic stimulations affects the chromaticity thresholds measured psychophysically, suggesting interactions between luminance and color in those stimuli with luminance steps lower than seven (Souza et al.). Color sensation was also investigated under low-light levels. Mesopic and scotopic conditions could be considered an interference zone for color vision since rods activities generate physiological interferences in cone-driven retinal chromatic pathways. This review paper keeps us up to date regarding the range and impact of rod–cone interactions on human visual function and performance (Zele and Cao). Clinical applications centered on congenital color blindness end the first chapter. Sensory psychophysical thresholds on the tritanopic color confusion axis were investigated in protanomalous and deuteranomalous subjects (Costa et al.). Reduction in discrimination was found for both types of congenital color blindness, protanomalous and deuteranomalous, but subjects in the latter group showed worse results. Electrophysiological assessments regarding luminance and compound stimuli (luminance plus red-green stimulus) were also evaluated in congenital color blindness subjects. Since compound stimuli elicited small or no response in red-green congenital color blinds, this finding could indicate that the cortical response for compound stimuli in the present experiment was dominated by chromatic contribution (Risuenho et al.). A search for discrimination thresholds addressed using the pseudoisochromatic plates configures a new psychophysical application for the traditional and widely used color test (Jurasevska et al.). Basic perceptual phenomena of Gestalt theories regarding color vision were addressed using figure-ground perception on saturation and contrast polarity modulations. The study conducted by Dresp-Langley and Reeves investigated the lightness dependency of the achromatic loci in color space. The results pointed toward a hitherto undocumented functional role of color saturation in the genesis of form, and in particular figure-ground percepts. Two experiments conducted by Kuriki showed that first, a color-appearance space normalized to daylight may be defined for the human visual system and second, that color space could reduce the discrepancy between the achromatic loci and the lightness axis of the color appearance models. The last study of the perceptual mechanism section relates retinal image quality for the display red and blue pixel radiation with the chromostereopsis retinal disparity achieved (zolinsh and Muizniece). Color is also important from an anthropological view in which a long debate regarding the existence of natural categories of hue and their universality has been addressed by ethological, electrophysiological, behavioral and psychophysical perspectives. The color naming and gender section presents contributions regarding the variations in color naming occurring in congenital color blindness subjects and the gender and cultural aspects related to color preferences. The study of Nagy et al. shows that dichromatic subjects involve the brightness properties of the different spectral stimuli when judging their chromatic content and that at the shorter wavelengths the signal of the intact tritos photoreceptor dominates the decision making in color naming tasks, even for the anopes. Al-Rasheed provides evidence that both sex differences and cultural differences are relevant in hue preference in terms of how stimulus-background cone-contrast was weighted summarizing color preference quantitatively rather than using subjective color names. The question of how we see colors and how we can discuss their impact in many dimensions of our life is an actual and multidiscipline inquiry to which we hope to contribute with this special research topic. Enjoy this special topic on color vision.

Brain Plasticity in Blind Subjects Centralizes Beyond the Modal Cortices.

It is well established that the human brain reorganizes following sensory deprivations. In blind individuals, visual processing regions including the lateral occipital cortex (LOC) are activated by auditory and tactile stimuli as demonstrated by neurophysiological and neuroimaging investigations. The mechanisms for such plasticity remain unclear, but shifts in connectivity across existing neural networks appear to play a critical role. The majority of research efforts to date have focused on neuroplastic changes within visual unimodal regions, however we hypothesized that neuroplastic alterations may also occur in brain networks beyond the visual cortices including involvement of multimodal integration regions and heteromodal cortices. In this study, two recently developed graph-theory based functional connectivity analyses, interconnector analyses and local and distant connectivity, were applied to investigate functional reorganization in regional and distributed neural-systems in late-onset blind (LB) and congenitally blind (CB) cohorts each compared to their own group of sighted controls. While functional network alterations as measured by the degree of differential links (DDL) occurred in sensory cortices, neuroplastic changes were most prominent within multimodal and association cortices. Subjects with LB showed enhanced multimodal integration connections in the parieto-opercular, temporoparietal junction (TPJ) and ventral premotor (vPM) regions, while CB individuals exhibited increased superior parietal cortex (SPC) connections. This study reveals the critical role of recipient multi-sensory integration areas in network reorganization and cross-modal plasticity in blind individuals. These findings suggest that aspects of cross-modal neuroplasticity and adaptive sensory-motor and auditory functions may potentially occur through reorganization in multimodal integration regions.

Redundant contribution of a Transient Receptor Potential cation channel Member 1 exon 11 single nucleotide polymorphism to equine congenital stationary night blindness.

BackgroundCongenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts.ResultsRetinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression.ConclusionsThese finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.

Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics.

BackgroundAmyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO).ResultsUsing histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, APLP2-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the APP-KO photoreceptor ribbon synapses and bipolar cells were intact. The APLP2-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the APLP2-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including CACNA1F, GRM6, TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, VSX1 and OTX2.ConclusionsThese findings demonstrate that APLP2 couples retina development and synaptic genes and present the first evidence that APLP2 expression may be linked to synaptic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0245-z) contains supplementary material, which is available to authorized users.

Pain hypersensitivity in congenital blindness is associated with faster central processing of C-fibre input.

We have recently shown that visual deprivation from birth exacerbates responses to painful thermal stimuli. However, the mechanisms underlying pain hypersensitivity in congenital blindness are unclear. To study the contribution of Aδ- and C-fibres in pain perception, we measured thresholds and response times to selective C- and Aδ-fibre activation in congenitally blind, late blind and normally sighted participants. Ultrafast constant-temperature heat pulses were delivered to the hand with a CO2 laser using an interleaved adaptive double staircase procedure. Participants were instructed to respond asquickly as possible when detecting a laser-induced sensation. We useda650ms cut-off criterion to distinguish fast Aδ- from slow C-fibre-mediated sensations. Congenitally blind participants showed significantly faster reaction times to C- but not to Aδ-fibre-mediated sensations. In contrast, thresholds for Aδ- and C-fibre stimulation did not differ between groups. Late blind individuals did not differ from sighted controls in any aspect. A follow-up experiment using only suprathreshold stimuli for Aδ- and C-fibre activation confirmed these findings and further showed that congenitally blind individuals detected significantly more C-fibre-mediated stimuli than sighted controls. A decomposition analysis of the reaction times indicated that the faster response times in the congenitally blind are due to more efficient central processing of C-fibre-mediated sensations. The increased sensitivity to painful thermal stimulation in congenital blindness may be due to more efficient central processing of C-fibre-mediated input, which may help to avoid impending dangerous encounters with stimuli that threaten the bodily integrity. WHAT DOES THIS STUDY ADD?: Hypersensitivity to heat pain in congenital blindness is associated with faster responses to C-fibre activation, likely caused by more efficient central processing of C-fibre-mediated input.

From auditory focus, to auditory influence, to multimodal experience in psychomusicological research.

Psychomusicology: Music, Mind and Brain Volume 26 is pleased to add to its growing collection of special issues the following special issue on Music as a Multimodal Experience coedited by Renee Timmers and Roni Granot. When research in music psychology began to escalate in the 1980s, its focus was primarily the auditory domain, building bridges between psychoacoustics and music perception, between music theory and music cognition, and between verbal and music memory. Perhaps this was all that researchers could do to encourage recognition of music as a legitimate stimulus deserving of attention in the psychology laboratory. In 1994, Volume 13 of Psychomusicology made a radical departure from this sound-only focus with its special issue on the Psychology of Film Music. For the first time, a collection of empirical articles explored a link between music and a nonauditory domain. That set of papers examined in a variety of contexts how music influenced the interpretation of motion images, be it closure in a film (Thompson, Russo, & Sinclair, 1994), meaning of a Hollywood blockbuster (Lipscomb & Kendall, 1994), the social interactions of wolves (Bolivar, Cohen, & Fentress, 1994), a short feature film (Bullerjahn & Guldenring, 1994), a music video (Iwamiya, 1994), or an abstract animation (Sirius & Clarke, 1994). A growing interest in music and film or media interactions since then has been captured in a book entitled the Psychology of Music in Multimedia (Tan, Cohen, Lipscomb, & Kendall, 2013). But here again, the focus has been typically on interpretation: how music changes the interpretation of visual media, and occasionally, how visual information changes the interpretation of the music (Boltz, 2013).In recent years the notion of musical embodiment has engaged the attention of many researchers (Leman, 2008, reviewed by Repp, 2009), although hints of this certainly came earlier, for example with Clarke's (2001, 2005) focus on affordances and motion, and long before in the little known work of Alexandar Truslit (cf. Haverkamp, 2013a; Repp, 1993). Research on synesthesia is also only now coming into its own (Ward, 2015; Ward & Mattingley, 2006). Ideas of musical embodiment on the one hand and synesthesia on the other go beyond interactions of music and the visual, and suggest that the experience of music extends outside the auditory realm from the outset, and that it is inherently multimodal. From this perspective, music is then even larger than was once thought, by virtue of multiple mediators. So I was delighted to learn from the journal's Associate Editor Renee Timmers of an International Conference on the Multimodal Experience of Music at Sheffield University in March, 2015 that she initiated under the auspices of the British Academy, through a collaboration of the University of Sheffield, Tel Aviv University, and The Hebrew University of Jerusalem. I was even more delighted when Renee suggested the possibility of a special issue for Psychomusicology based on the conference. Renee had just completed coediting an insightful book on expressiveness in human performance (Fabian, Timmers, & Schubert, 2014; for review see Ginsborg, 2015) and had guest coedited a special issue of Psychomusicology on the Emotion and Cognition of Music (Coutinho & Timmers, 2014). She had previously published in the area of crossmodal associations (Eitan & Timmers, 2010), and was about to begin a fellowship at the MARCS Institute of the University of Western Sydney examining the role of cross-modal information in interperformer synchronization. Clearly, the proposed special issue would be in good hands, especially when Roni Granot accepted Renee's invitation to serve as Guest Coeditor. Roni Granot had published research on several new aspects of the multimodal experience of music including cross-domain mappings of music in persons with congenital or early blindness (Eitan, Ornoy, & Granot, 2012), and on the ways listeners associate changes in musical variables with physical space and bodily motion (Eitan & Granot, 2006). …

620. Use of Transgenic Mice to Quantify Transduction Efficiency and Specificity of Novel AAV Vectors in Retina

Modifications to surface-exposed residues of recombinant Adeno-associated virus (AAV), incorporation of novel regulatory elements into the vector cassette, alternative injection routes, and combinations thereof are being explored as strategies to enhance gene delivery to retina. We previously showed that intravitreal injection of a novel AAV capsid was capable of transducing all neuronal layers of the retina, including photoreceptors (PRs). We also demonstrated that this capsid, when combined with a novel promoter (“Ple155”) was capable of driving therapeutic nyctalopin (Nyx) expression exclusively in ON bipolar cells (ON BCs) and partially restoring retinal function to a mouse model of complete Congenital Stationary Night Blindness (CSNB1) following early (postnatal day 2) treatment. In order to achieve more efficient transduction of PRs and ON BCs, further modifications will be required. Methods with which to quantify relative transduction efficiencies of novel variants in vivo are warranted. The purpose of this study was to develop robust methods for quantifying transduction efficiency or transgene expression in PRs and ON BCs, respectively by rAAVs in vivo. Specifically, we sought to develop methods that don't require time consuming subjective analysis. To do so, we employed two transgenic mouse models: Nrl-GFP and Grm6-GFP mice which have constitutively fluorescent rod PRs and ON BCs, respectively. Adult mice (~postnatal day 30) were injected either subretinally (SR) or intravitreally (Ivt) with rAAVs containing the mCherry transgene. Fundoscopy was performed at 1 month post injection. Immediately thereafter, retinas were dissociated and evaluated by FACS for GFP and mCherry fluorescence, the overlap of which indicated targeted transduction of either ON BCs or rods, depending on mouse model. A subset of retinas was also evaluated with immunohistochemistry. In agreement with previous experiments, Ivt and SR delivered AAV2(quadY-F+T-V) and AAV2(4pMut) transduced a relatively large percentage of retina, including PRs. However, ON BC transduction was minimal, with ~6% transduced by Ivt AAV2(quadY-F+T-V)-CBA-mCherry delivery. AAV2 weakly transduced retina via both delivery routes. AAV2(4pMut)ΔHS, which lacks canonical HSPG binding residues, failed to transduce retina by Ivt injection, but efficiently transduced rods (75%) following SR delivery, indicative of significant ‘lateral spread’ from the injection bleb. Incorporation of the ON BC-specific promoter (“Ple155”) used in the CSNB1 gene replacement study abolished non-ON BC retinal expression. Experiments are ongoing to assess the extent to which rAAVs containing Ple155 can increase expression efficiency in ON BCs relative to CBA, and to determine whether the addition of other transcriptional and post transcriptional regulatory elements can further increase rAAV-mediated expression in these cells. In summary, we have developed a method for quantifying transduction of PRs and ON BCs by novel rAAVs in vivo. As the AAV vector toolkit expands, such a method will be highly useful for scoring relative performance of novel vectors. We also conclude that while the ubiquitous CBA promoter effectively drives transgene expression in PRs, it drives relatively poor transgene expression in ON BCs and caution that CBA should not be considered as a default universal promoter for retinal expression.

Neurological Nature of vision and thought and Mechanisms of Perception Experiences

Understanding of the phenomena of vision and thought require clarification of the general mechanism of perception. So far, philosophical inquiries and scientific investigations have not been able to address clearly the mysteries surrounding them. The present work is an attempt to unravel the essences of these phenomenal based on the presumption of computational brain. Within this context, the natures of thought is clarified, and the basis of the experience of perception is established. And by drawing from the successes of the developed tactile vision substitution systems (TVSS), which render some measure of vision,in vision handicapped persons, early or congenital blinds, the true nature of vision as cutaneous sensations is also divulged. The mechanism of perception involves sensing of the stimuli, and autonomous engagement of brain neuronal complexity resolution patterns; that is the brain implicit embedded computational instructions. Upon commencement of the triggers, brain computations, which aso involve engaging body's biophysical feedback system, are performed; and the results are outputted as motor signals that render the realization of perception. However, this requires deployment of a perception medium; an interface. Given the nature of efferent signals, there must be a (known) bio-mechanical system interface, other than the body muscle and skeletal system, which performs the needed function: Considering the fact that the vocal system performs such task for verbalization of brain's synthesis of language, the possibility of its further role in the experience of thought and vision, in the form of mostly quiet (inaudible) recital of the related motor signals, is suggested.

Congenital stationary night blindness with hypoplastic discs, negative electroretinogram and thinning of the inner nuclear layer.

To describe congenital stationary night blindness (CSNB) with negative electroretinogram, hypoplastic discs, nystagmus and thinning of the inner nuclear layer (INL). Retinal structure was analyzed qualitatively with spectral domain optical coherence tomography and wide field imaging. Retinal function was evaluated with full-field electroretinography (ffERG). Molecular genetic testing included next-generation sequencing (NGS) of the known genes involved in CSNB. Patients presented with CSNB presented with nystagmus, high myopia, hypoplastic discs and negative ffERG with no measurable rod response. The retinas appeared normal and automated segmentation of retinal layers demonstrated a relative reduction of thickness of the INL. There was no significant change in the ffERG after prolonged 2hour dark adaptation compared to standard 30minute dark adaptation. Affected family members harboured the homozygous 1-bp deletion c.2394delC in exon 18 of the TRPM1 gene, whereas their unaffected parents were heterozygous carriers. This data expands the genotype and phenotype spectrum of CSNB. The lack of improvement of rod responses after prolonged dark adaptation, together with thinning of the INL, is compatible with postreceptoral transmission dysfunction in the bipolar cells. Such knowledge may prove useful in future development of treatment for outer retinal dystrophies, using opsin genes to restore light responses in survivor neurons in the inner retina.

Sight restoration after congenital blindness does not reinstate alpha oscillatory activity in humans

Functional brain development is characterized by sensitive periods during which experience must be available to allow for the full development of neural circuits and associated behavior. Yet, only few neural markers of sensitive period plasticity in humans are known. Here we employed electroencephalographic recordings in a unique sample of twelve humans who had been blind from birth and regained sight through cataract surgery between four months and 16 years of age. Two additional control groups were tested: a group of visually impaired individuals without a history of total congenital blindness and a group of typically sighted individuals. The EEG was recorded while participants performed a visual discrimination task involving intact and scrambled biological motion stimuli. Posterior alpha and theta oscillations were evaluated. The three groups showed indistinguishable behavioral performance and in all groups evoked theta activity varied with biological motion processing. By contrast, alpha oscillatory activity was significantly reduced only in individuals with a history of congenital cataracts. These data document on the one hand brain mechanisms of functional recovery (related to theta oscillations) and on the other hand, for the first time, a sensitive period for the development of alpha oscillatory activity in humans.

Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.

Reduced Discrimination in the Tritanopic Confusion Line for Congenital Color Deficiency Adults.

In congenital color blindness the red–green discrimination is impaired resulting in an increased confusion between those colors with yellow. Our post-receptoral physiological mechanisms are organized in two pathways for color perception, a red–green (protanopic and deuteranopic) and a blue–yellow (tritanopic). We argue that the discrimination losses in the yellow area in congenital color vision deficiency subjects could generate a subtle loss of discriminability in the tritanopic channel considering discrepancies with yellow perception. We measured color discrimination thresholds for blue and yellow of tritanopic channel in congenital color deficiency subjects. Chromaticity thresholds were measured around a white background (0.1977 u′, 0.4689 v′ in the CIE 1976) consisting of a blue–white and white–yellow thresholds in a tritanopic color confusion line of 21 congenital colorblindness subjects (mean age = 27.7; SD = 5.6 years; 14 deuteranomalous and 7 protanomalous) and of 82 (mean age = 25.1; SD = 3.7 years) normal color vision subjects. Significant increase in the whole tritanopic axis was found for both deuteranomalous and protanomalous subjects compared to controls for the blue–white (F2,100 = 18.80; p < 0.0001) and white–yellow (F2,100 = 22.10; p < 0.0001) thresholds. A Principal Component Analysis (PCA) found a weighting toward to the yellow thresholds induced by deuteranomalous subjects. In conclusion, the discrimination in the tritanopic color confusion axis is significantly reduced in congenital color vision deficiency compared to normal subjects. Since yellow discrimination was impaired the balance of the blue–yellow channels is impaired justifying the increased thresholds found for blue–white discrimination. The weighting toward the yellow region of the color space with the deuteranomalous contributing to that perceptual distortion is discussed in terms of physiological mechanisms.

Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

Severe hemophilia A (HA) is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII) clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1–2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

Differentiation of murine models of "negative ERG" by single and repetitive light stimuli.

Marked attenuation of the single-flash electroretinographic (ERG) b-wave in the presence of a normal-amplitude or less-attenuated a-wave is commonly referred to as the "negative ERG." The purpose of this study was to investigate whether the disparate origins of the negative ERG in three murine models can be discriminated using flickering stimuli. Three models were selected: (1) the Nyx (nob) mouse model of complete congenital stationary night blindness, (2) the oxygen-induced retinopathy (OIR) rat model of retinopathy of prematurity (ROP), and (3) the Rs1 knockout (KO) mouse model of X-linked juvenile retinoschisis. Directly after a dark-adapted, single-flash ERG luminance series, a flicker ERG frequency series (0.5-30 Hz) was performed at a fixed luminance of 0.5 log cd s/m(2). This series includes frequency ranges that are dominated by activity in (A) the rod pathways (below 5 Hz), (B) the cone ON-pathway (5-15 Hz), and (C) the cone OFF-pathway (above 15 Hz). All three models produced markedly attenuated single-flash ERG b-waves. In the Nyx (nob) mouse, which features postsynaptic deficits in the ON-pathways, the a-wave was normal and flicker responses were attenuated in ranges A and B, but not C. The ROP rat is characterized by inner-retinal ischemia which putatively affects both ON- and OFF-bipolar cell activity; flicker responses were reduced in all ranges (A-C). Notably, the choroid supplies the photoreceptors and is thought to be relatively intact in OIR, an idea supported by the nearly normal a-wave. Finally, in the Rs1 KO mouse, which has documented abnormality of the photoreceptor-bipolar synapse affecting both ON- and OFF-pathways, the flicker responses were attenuated in all ranges (A-C). The a-wave was also attenuated, likely as a consequence to schisms in the photoreceptor layer. Consideration of both single-flash and flickering ERG responses can discriminate the functional pathology of the negative ERG in these animal models of human disease.

Psychosis in a blindness patient: A case report

IntroductionUsing a clinical case as illustration, the present work engages the different psychopathologic alterations that blindness patients could present.MethodsThe presentation and discussion of a clinical case of psychosis in a blind patient are addressed. The scientific documentation used as support was obtained from PubMed/Medline search engines using as keywords blindness and psychosis.ResultsA 43-years-old male patient, with a medical history of arterial hypertension, heroine dependence (presently with methadone schema) and bilateral blindness caused by a bilateral retinal detachment 20 years ago, was admitted in the psychiatric ward. The patient's historical record includes a previous personality with paranoid characteristics, as well as a hospitalization due to persecutory and auto-reference ideas and kinaesthetic hallucinations with 1 month of evolution, coincident with address changes. Lab tests revealed the following results: haemoglobin 13.8; Leucocytosis 13,400; CRP: 6.2; ALT &gt; AST. Positive results were obtained in the drug tests for cannabinoids, as well as for the anti-HCV antibody (IgG). Finally, the patient was medicated with an antipsychotic and humour stabilizer, achieving a significant improvement after 10 days of hospitalization.ConclusionsAlthough studies reveal that mental and behavioural disorders, especially those with symptoms of psychosis and mental retardation, are common among people with congenital blindness, more knowledge of the prevalence and aetiology of mental and behavioural disorders among people suffering from blindness is needed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Superior verbal abilities in congenital blindness

Superior verbal abilities in congenital blindness

The Effect of Early Visual Deprivation on the Neural Bases of Auditory Processing

Transient congenital visual deprivation affects visual and multisensory processing. In contrast, the extent to which it affects auditory processing has not been investigated systematically. Research in permanently blind individuals has revealed brain reorganization during auditory processing, involving both intramodal and crossmodal plasticity. The present study investigated the effect of transient congenital visual deprivation on the neural bases of auditory processing in humans. Cataract-reversal individuals and normally sighted controls performed a speech-in-noise task while undergoing functional magnetic resonance imaging. Although there were no behavioral group differences, groups differed in auditory cortical responses: in the normally sighted group, auditory cortex activation increased with increasing noise level, whereas in the cataract-reversal group, no activation difference was observed across noise levels. An auditory activation of visual cortex was not observed at the group level in cataract-reversal individuals. The present data suggest prevailing auditory processing advantages after transient congenital visual deprivation, even many years after sight restoration. The present study demonstrates that people whose sight was restored after a transient period of congenital blindness show more efficient cortical processing of auditory stimuli (here speech), similarly to what has been observed in congenitally permanently blind individuals. These results underscore the importance of early sensory experience in permanently shaping brain function.