Altered grid-like coding in early blind people.

Cognitive maps in the hippocampal-entorhinal system are central for the representation of both spatial and non-spatial relationships. Although this system, especially in humans, heavily relies on vision, the role of visual experience in shaping the development of cognitive maps remains largely unknown. Here, we test sighted and early blind individuals in both imagined navigation in fMRI and real-world navigation. During imagined navigation, the Human Navigation Network, constituted by frontal, medial temporal, and parietal cortices, is reliably activated in both groups, showing resilience to visual deprivation. However, neural geometry analyses highlight crucial differences between groups. A 60° rotational symmetry, characteristic of a hexagonal grid-like coding, emerges in the entorhinal cortex of sighted but not blind people, who instead show a 90° (4-fold) symmetry, indicative of a square grid. Moreover, higher parietal cortex activity during navigation in blind people correlates with the magnitude of 4-fold symmetry. In sum, early blindness can alter the geometry of entorhinal cognitive maps, possibly as a consequence of higher reliance on parietal egocentric coding during navigation.

Visuomotor coordination and cognitive capacity in blindsight.

Classical literature on blindsight described that some patients with lesions to the primary visual cortex could respond to visual stimuli without subjective awareness. Recent studies addressed more complex arguments on the conscious state of blindsight subjects such as existence of partial awareness, namely "feeling of something happening" in the lesion-affected visual field, termed 'type II blindsight', and high-level performance in complex cognitive tasks in blindsight model monkeys. Endeavors to clarify the visual pathways for blindsight revealed the parallel thalamic routes mediating the visual inputs from the superior colliculus to extrastriate and frontoparietal cortices, which may underlie the flexible visuomotor association and cognitive control in the blindsight subjects. Furthermore, involvement of post-lesion plasticity is suggested for these neural systems to operate.

Contingent negative variation to tactile stimuli - differences in anticipatory and preparatory processes between participants with and without blindness.

People who are blind demonstrate remarkable abilities within the spared senses and compensatory enhancement of cognitive skills, underscored by substantial plastic reorganization in relevant neural areas. However, little is known about whether people with blindness form top-down models of the world on short timescales more efficiently to guide goal-oriented behavior. This electroencephalography study investigates this hypothesis at the neurophysiological level, focusing on contingent negative variation (CNV) as a marker of anticipatory and preparatory processes prior to expected events. In sum, 20 participants with blindness and 27 sighted participants completed a classic CNV task and a memory CNV task, both containing tactile stimuli to exploit the expertise of the former group. Although the reaction times in the classic CNV task did not differ between groups, participants who are blind reached higher performance rates in the memory task. This superior performance co-occurred with a distinct neurophysiological profile, relative to controls: greater late CNV amplitudes over central areas, suggesting enhanced stimulus expectancy and motor preparation prior to key events. Controls, in contrast, recruited more frontal sites, consistent with inefficient sensory-aligned control. We conclude that in more demanding cognitive contexts exploiting the spared senses, people with blindness efficiently generate task-relevant internal models to facilitate behavior.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review.

PURPOSE: Osteogenesis imperfecta (OI) is a rare inherited heterogeneous connective tissue disorder characterized by bone fragility, low bone mineral density, skeletal deformity and blue sclera. The dominantly inherited forms of OI are predominantly caused by mutations in either the COL1A1 or COL1A2 gene. Collagen type I is one of the major structural proteins of the eyes and therefore is the eye theoretically prone to alterations in OI. The aim of this systematic review was to provide an overview of the known ocular problems reported in OI. METHODS: A literature search (in PubMed, Embase and Scopus), which included articles from inception to August 2020, was performed in accordance with the PRISMA guidelines. RESULTS: The results of this current review show that almost every component of the eye could be affected in OI. Decreased thickness of the cornea and sclera is an important factor causing eye problems in patients with OI such as blue sclera. Findings that stand out are ruptures, lacerations and other eye problems that occur after minor trauma, as well as complications from standard surgical procedures. DISCUSSION: Alterations in collagen type I affect multiple structural components of the eye. It is recommended that OI patients wear protective glasses against accidental eye trauma. Furthermore, when surgery is required, it should be approached with caution. The prevalence of eye problems in different types of OI is still unknown. Additional research is required to obtain a better understanding of the ocular defects that may occur in OI patients and the underlying pathology.

X-Linked Retinoschisis: Novel Clinical Observations and Genetic Spectrum in 340 Patients.

PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.

Functional Availability of ON-Bipolar Cells in the Degenerated Retina: Timing and Longevity of an Optogenetic Gene Therapy.

Degenerative diseases of the retina are responsible for the death of photoreceptors and subsequent loss of vision in patients. Nevertheless, the inner retinal layers remain intact over an extended period of time, enabling the restoration of light sensitivity in blind retinas via the expression of optogenetic tools in the remaining retinal cells. The chimeric Opto-mGluR6 protein represents such a tool. With exclusive ON-bipolar cell expression, it combines the light-sensitive domains of melanopsin and the intracellular domains of the metabotropic glutamate receptor 6 (mGluR6), which naturally mediates light responses in these cells. Albeit vision restoration in blind mice by Opto-mGluR6 delivery was previously shown, much is left to be explored in regard to the effects of the timing of the treatment in the degenerated retina. We performed a functional evaluation of Opto-mGluR6-treated murine blind retinas using multi-electrode arrays (MEAs) and observed long-term functional preservation in the treated retinas, as well as successful therapeutical intervention in later stages of degeneration. Moreover, the treatment decreased the inherent retinal hyperactivity of the degenerated retinas to levels undistinguishable from healthy controls. Finally, we observed for the first time micro electroretinograms (mERGs) in optogenetically treated animals, corroborating the origin of Opto-mGluR6 signalling at the level of mGluR6 of ON-bipolar cells.

Neurally-constrained modeling of human gaze strategies in a change blindness task.

Despite possessing the capacity for selective attention, we often fail to notice the obvious. We investigated participants' (n = 39) failures to detect salient changes in a change blindness experiment. Surprisingly, change detection success varied by over two-fold across participants. These variations could not be readily explained by differences in scan paths or fixated visual features. Yet, two simple gaze metrics-mean duration of fixations and the variance of saccade amplitudes-systematically predicted change detection success. We explored the mechanistic underpinnings of these results with a neurally-constrained model based on the Bayesian framework of sequential probability ratio testing, with a posterior odds-ratio rule for shifting gaze. The model's gaze strategies and success rates closely mimicked human data. Moreover, the model outperformed a state-of-the-art deep neural network (DeepGaze II) with predicting human gaze patterns in this change blindness task. Our mechanistic model reveals putative rational observer search strategies for change detection during change blindness, with critical real-world implications.

Backward spatial perception can be augmented through a novel visual-to-auditory sensory substitution algorithm.

Can humans extend and augment their natural perceptions during adulthood? Here, we address this fascinating question by investigating the extent to which it is possible to successfully augment visual spatial perception to include the backward spatial field (a region where humans are naturally blind) via other sensory modalities (i.e., audition). We thus developed a sensory-substitution algorithm, the "Topo-Speech" which conveys identity of objects through language, and their exact locations via vocal-sound manipulations, namely two key features of visual spatial perception. Using two different groups of blindfolded sighted participants, we tested the efficacy of this algorithm to successfully convey location of objects in the forward or backward spatial fields following ~ 10 min of training. Results showed that blindfolded sighted adults successfully used the Topo-Speech to locate objects on a 3 × 3 grid either positioned in front of them (forward condition), or behind their back (backward condition). Crucially, performances in the two conditions were entirely comparable. This suggests that novel spatial sensory information conveyed via our existing sensory systems can be successfully encoded to extend/augment human perceptions. The implications of these results are discussed in relation to spatial perception, sensory augmentation and sensory rehabilitation.

Human click-based echolocation: Effects of blindness and age, and real-life implications in a 10-week training program.

Understanding the factors that determine if a person can successfully learn a novel sensory skill is essential for understanding how the brain adapts to change, and for providing rehabilitative support for people with sensory loss. We report a training study investigating the effects of blindness and age on the learning of a complex auditory skill: click-based echolocation. Blind and sighted participants of various ages (21-79 yrs; median blind: 45 yrs; median sighted: 26 yrs) trained in 20 sessions over the course of 10 weeks in various practical and virtual navigation tasks. Blind participants also took part in a 3-month follow up survey assessing the effects of the training on their daily life. We found that both sighted and blind people improved considerably on all measures, and in some cases performed comparatively to expert echolocators at the end of training. Somewhat surprisingly, sighted people performed better than those who were blind in some cases, although our analyses suggest that this might be better explained by the younger age (or superior binaural hearing) of the sighted group. Importantly, however, neither age nor blindness was a limiting factor in participants' rate of learning (i.e. their difference in performance from the first to the final session) or in their ability to apply their echolocation skills to novel, untrained tasks. Furthermore, in the follow up survey, all participants who were blind reported improved mobility, and 83% reported better independence and wellbeing. Overall, our results suggest that the ability to learn click-based echolocation is not strongly limited by age or level of vision. This has positive implications for the rehabilitation of people with vision loss or in the early stages of progressive vision loss.

Periocular Necrotizing Fasciitis Causing Posterior Orbitopathy and Vision Loss: How to Manage?

Necrotizing fasciitis (NF) is a rare, rapidly progressive bacterial infection. Periorbital NF may spread from the eyelid into the posterior orbit. Extent of the infection is critical in planning surgical debridement. A diabetic 70-year-old man presented with a black wound and severe pain in the left periorbital area following a mild trauma. Clinical findings were consistent with NF involving the eyelids, temporal and malar regions. In addition, he had proptosis, diffuse ophthalmoplegia, and central retinal artery occlusion, suggesting deep orbital involvement. Computed tomography showed soft tissue abnormalities in the anterior orbit. The patient was successfully treated with subcutaneous debridement, antibiotherapy, and metabolic support. Periorbital NF may be complicated with posterior orbital cellulitis-like symptoms and retinal vascular occlusions, possibly because of remote vascular thrombi induced by bacterial toxins. This clinical manifestation should be distinguished from true bacterial invasion of the posterior orbit, which may require more aggressive surgical treatments such as exenteration.

Effect of vision impairment on match-related performance and technical variation in attacking moves in Paralympic judo.

In Paralympic judo for athletes with vision impairment (VI judo) all eligible athletes (i.e. B1, B2 and B3 classes) compete against each other in the same competition. Evidence suggests that athletes with more impairment may be disadvantaged, but that more sensitive measures of performance are necessary to understand the impact of impairment on performance. The aim of this study was to investigate the relationship between Para sport class and technical variation, time-motion variables, and performance in Paralympic judo. All 175 judo matches from the Rio 2016 Paralympic Games were analysed across 129 competitors (82 male and 47 female). The main results indicated that athletes who demonstrated less technical variation also experienced less competitive success, with the functionally blind athletes (class B1) demonstrating less technical variation than partially sighted (class B2 and B3) athletes (p < 0.05). There was no difference in the time-motion variables between sport classes (p > 0.05). We conclude that measures of technical variation are sensitive to differences in impairment and are suitable for studies that investigate the impairment-performance relationship in VI judo. Results further confirm that some athletes with impairment are disadvantaged under the current rules of VI judo.

The effect of congenital blindness on resting-state functional connectivity revisited.

Lower resting-state functional connectivity (RSFC) between 'visual' and non-'visual' neural circuits has been reported as a hallmark of congenital blindness. In sighted individuals, RSFC between visual and non-visual brain regions has been shown to increase during rest with eyes closed relative to rest with eyes open. To determine the role of visual experience on the modulation of RSFC by resting state condition-as well as to evaluate the effect of resting state condition on group differences in RSFC-, we compared RSFC between visual and somatosensory/auditory regions in congenitally blind individuals (n = 9) and sighted participants (n = 9) during eyes open and eyes closed conditions. In the sighted group, we replicated the increase of RSFC between visual and non-visual areas during rest with eyes closed relative to rest with eyes open. This was not the case in the congenitally blind group, resulting in a lower RSFC between 'visual' and non-'visual' circuits relative to sighted controls only in the eyes closed condition. These results indicate that visual experience is necessary for the modulation of RSFC by resting state condition and highlight the importance of considering whether sighted controls should be tested with eyes open or closed in studies of functional brain reorganization as a consequence of blindness.

Partial recovery of visual function in a blind patient after optogenetic therapy.

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.

'Visual' cortices of congenitally blind adults are sensitive to response selection demands in a go/no-go task.

Studies of occipital cortex plasticity in blindness provide insight into how intrinsic constraints interact with experience to determine cortical specialization. We tested the cognitive nature and anatomical origins of occipital responses during non-verbal, non-spatial auditory tasks. In a go/no-go task, congenitally blind (N=23) and sighted (N=24) individuals heard rapidly occurring (<1/s) non-verbal sounds and made one of two button presses (frequent-go 50%, infrequent-go 25%) or withheld a response (no-go, 25%). Rapid and frequent button presses heighten response selection/inhibition demands on the no-go trials: In sighted and blind adults a right-lateralized prefrontal (PFC) network responded most to no-go trials, followed by infrequent-go and finally frequent-go trials. In the blind group only, a right-lateralized occipital network showed the same response profile and the laterality of occipital and PFC responses was correlated across blind individuals. A second experiment with spoken sentences and equations (N=16) found that no-go responses in occipital cortex are distinct from previously identified occipital responses to spoken language. Finally, in resting-state data (N=30 blind, N=31 blindfolded sighted), no-go responsive 'visual' cortex of blind relative to sighted participants was more synchronized with PFC and less synchronized with primary auditory and sensory-motor cortices. No-go responsive occipital cortex showed higher resting-state correlations with no-go responsive PFC than language responsive inferior frontal cortex. We conclude that in blindness, a right-lateralized occipital network responds to non-verbal executive processes, including response selection. These results suggest that connectivity with fronto-parietal executive networks is a key mechanism for plasticity in blindness.

Graphomotor memory in Exner's area enhances word learning in the blind.

Handwriting is thought to impede vocabulary learning in sighted adults because the motor execution of writing interferes with efficient audiovisual processing during encoding. However, the motor memory of writing may facilitate adult word learning when visual sensory inputs are severely restricted. Using functional MRI, we show that late-blind participants, but not sighted participants, learned novel words by recruiting the left dorsal premotor cortex known as Exner's writing area and its functional coupling with the left hippocampus. During later recall, the phonological and semantic contents of these words are represented in the activation patterns of the left hippocampus as well as in those of left frontotemporal language areas. These findings suggest that motor codes of handwriting help blind participants maintain word-form representations during learning and retrieval. We propose that such reliance on the motor system reflects a broad architecture of the cerebral language network which encompasses the limb motor system as a hardwired component.

Topographic maps and neural tuning for sensory substitution dimensions learned in adulthood in a congenital blind subject.

Topographic maps, a key principle of brain organization, emerge during development. It remains unclear, however, whether topographic maps can represent a new sensory experience learned in adulthood. MaMe, a congenitally blind individual, has been extensively trained in adulthood for perception of a 2D auditory-space (soundscape) where the y- and x-axes are represented by pitch and time, respectively. Using population receptive field mapping we found neural populations tuned topographically to pitch, not only in the auditory cortices but also in the parietal and occipito-temporal cortices. Topographic neural tuning to time was revealed in the parietal and occipito-temporal cortices. Some of these maps were found to represent both axes concurrently, enabling MaMe to represent unique locations in the soundscape space. This case study provides proof of concept for the existence of topographic maps tuned to the newly learned soundscape dimensions. These results suggest that topographic maps can be adapted or recycled in adulthood to represent novel sensory experiences.

The acts of opening and closing the eyes are of importance for congenital blindness: Evidence from resting-state fMRI.

Volitional eye closure is observed only in conscious and awake humans, and is rare in animals. It is believed that eye closure can focus one's attention inward and facilitate activities such as meditation and mental imagery. Congenital blind individuals are also required to close their eyes for these activities. Resting-state functional magnetic resonance imaging (RS-fMRI) studies have found robust differences between the eyes-closed (EC) and eyes-open (EO) conditions in some brain regions in the sighted. This study analyzed data from 21 congenital blind individuals and 21 sighted controls by using amplitude of low-frequency fluctuation (ALFF) of RS-fMRI. The blind group and the sighted group shared similar pattern of differences between the EC and EO condition: ALFF was higher in the EC condition than the EO condition in the bilateral primary sensorimotor cortex, bilateral supplementary motor area, and inferior occipital cortex, while ALFF was lower in the EC condition than the EO condition in the medial prefrontal cortex, highlighting the "nature" effect on the difference between the EC and EO conditions. The results of other matrices such as fractional ALFF (fALFF) and regional homogeneity (ReHo) showed similar patterns to that of ALFF. Moreover, no significant difference was observed between the EC-EO pattern of the two subgroups of congenital blind (i.e., with and without light perception), suggesting that the EC-EO difference is irrespective of residual light perception which reinforced the "nature" effect. We also found between-group differences, i.e., more probably "nurture effect", in the posterior insula and fusiform. Our results suggest that the acts of closing and opening the eyes are of importance for the congenital blind, and that these actions and their differences might be inherent in the nature of humans.