Development Of Visual Pathways Research Articles

Retinal structure and visual pathway function at school age in children born extremely preterm: a population-based study

BackgroundChildren born extremely preterm (gestational age < 28 weeks) show reduced visual function even without any cerebral or ophthalmological neonatal diagnosis. In this study, we aimed to assess the retinal structure with optical coherence tomography (OCT) and visual function with pattern-reversal visual evoked potentials (PR-VEPs) in a geographically defined population-based cohort of school-aged children born extremely preterm. Moreover, we aimed to explore the association between measures of retinal structure and visual pathway function in this cohort.MethodsAll children born extremely preterm from 2006–2011 (n = 65) in Central Norway were invited to participate. Thirty-six children (55%) with a median age of 13 years (range = 10–16) were examined with OCT, OCT-angiography (OCT-A), and PR-VEPs. The foveal avascular zone (FAZ) and circularity, central macular vascular density, and flow were measured on OCT-A images. Central retinal thickness, circumpapillary retinal nerve fibre layer (RNFL) and inner plexiform ganglion cell layer (IPGCL) thickness were measured on OCT images. The N70-P100 peak-to-peak amplitude and N70 and P100 latencies were assessed from PR-VEPs.ResultsParticipants displayed abnormal retinal structure and P100 latencies (≥ 2 SD) compared to reference populations. Moreover, there was a negative correlation between P100 latency in large checks and RNFL (r = -.54, p = .003) and IPGCL (r = -.41, p = .003) thickness. The FAZ was smaller (p = .003), macular vascular density (p = .006) and flow were higher (p = .004), and RNFL (p = .006) and IPGCL (p = .014) were thinner in participants with ROP (n = 7).ConclusionChildren born extremely preterm without preterm brain injury sequelae have signs of persistent immaturity of retinal vasculature and neuroretinal layers. Thinner neuroretinal layers are associated with delayed P100 latency, prompting further exploration of the visual pathway development in preterms.

Role of glutamate in the development of visual pathways.

Glutamate is an important amino acid, metabolite and excitatory neurotransmitter, which is found in its free form in the extracellular spaces of the central nervous system (CNS). More than half of all synapses in CNS release glutamate. It is the main neurotransmitter driving the light responses in the retina. All types of photoreceptors, bipolar, ganglion and one type of glycinergic amacrine cells express specific subtypes of vesicular glutamate transporters and are the main source of endogenous glutamate in retina, besides Müller glia that are responsible for glutamate homeostasis, release and reuptake. Reduced or excessive extracellular glutamate was detected in the synaptic clefts of several naturally occurring or transgenic eye disease models, in which network rewiring and altered functions were observed. These led to the hypothesis that glutamate is one of the extrinsic signals for visual pathway development. This minireview examines experimental evidences supporting, or refuting, the influence of glutamate on prenatal and postnatal retinal development.

Erratum: Chang et al., "Novel Regulatory Mechanisms for the SoxC Transcriptional Network Required for Visual Pathway Development".

Erratum: Chang et al., "Novel Regulatory Mechanisms for the SoxC Transcriptional Network Required for Visual Pathway Development".

Reduced mTORC1-signalling in retinal progenitor cells leads to visual pathway dysfunction.

ABSTRACTDevelopment of the vertebrate central nervous system involves the co-ordinated differentiation of progenitor cells and the establishment of functional neural networks. This neurogenic process is driven by both intracellular and extracellular cues that converge on the mammalian target of rapamycin complex 1 (mTORC1). Here we demonstrate that mTORC1-signalling mediates multi-faceted roles during central nervous system development using the mouse retina as a model system. Downregulation of mTORC1-signalling in retinal progenitor cells by conditional ablation of Rptor leads to proliferation deficits and an over-production of retinal ganglion cells during embryonic development. In contrast, reduced mTORC1-signalling in postnatal animals leads to temporal deviations in programmed cell death and the consequent production of asymmetric retinal ganglion cell mosaics and associated loss of axonal termination topographies in the dorsal lateral geniculate nucleus of adult mice. In combination these developmental defects induce visually mediated behavioural deficits. These collective observations demonstrate that mTORC1-signalling mediates critical roles during visual pathway development and function.

Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring

SummaryLocal translation is rapidly regulated by extrinsic signals during neural wiring, but its control mechanisms remain elusive. Here we show that the extracellular cue Sema3A induces an initial burst in local translation that precisely controls phosphorylation of the translation initiation factor eIF2α via the unfolded protein response (UPR) kinase PERK. Strikingly, in contrast to canonical UPR signaling, Sema3A-induced eIF2α phosphorylation bypasses global translational repression and underlies an increase in local translation through differential activity of eIF2B mediated by protein phosphatase 1. Ultrasensitive proteomics analysis of axons reveals 75 proteins translationally controlled via the Sema3A-p-eIF2α pathway. These include proteostasis- and actin cytoskeleton-related proteins but not canonical stress markers. Finally, we show that PERK signaling is needed for directional axon migration and visual pathway development in vivo. Thus, our findings reveal a noncanonical eIF2 signaling pathway that controls selective changes in axon translation and is required for neural wiring.

Aberrant visual pathway development in albinism: From retina to cortex.

Albinism refers to a group of genetic abnormalities in melanogenesis that are associated neuronal misrouting through the optic chiasm. We perform quantitative assessment of visual pathway structure and function in 23 persons with albinism (PWA) and 20 matched controls using optical coherence tomography (OCT), volumetric magnetic resonance imaging (MRI), diffusion tensor imaging and visual evoked potentials (VEP). PWA had a higher streamline decussation index (percentage of total tractography streamlines decussating at the chiasm) compared with controls (Z = -2.24, p = .025), and streamline decussation index correlated weakly with inter-hemispheric asymmetry measured using VEP (r = .484, p = .042). For PWA, a significant correlation was found between foveal development index and total number of streamlines (r = .662, p < .001). Significant positive correlations were found between peri-papillary retinal nerve fibre layer thickness and optic nerve (r = .642, p < .001) and tract (r = .663, p < .001) width. Occipital pole cortical thickness was 6.88% higher (Z = -4.10, p < .001) in PWA and was related to anterior visual pathway structures including foveal retinal pigment epithelium complex thickness (r = -.579, p = .005), optic disc (r = .478, p = .021) and rim areas (r = .597, p = .003). We were unable to demonstrate a significant relationship between OCT-derived foveal or optic nerve measures and MRI-derived chiasm size or streamline decussation index. Our novel tractographic demonstration of altered chiasmatic decussation in PWA corresponds to VEP measured cortical asymmetry and is consistent with chiasmatic misrouting in albinism. We also demonstrate a significant relationship between retinal pigment epithelium and visual cortex thickness indicating that retinal pigmentation defects in albinism lead to downstream structural reorganisation of the visual cortex.

Visual evoked potentials are similar in polysomnographically defined quiet and active sleep in healthy newborns

Morphology and late components of evoked potentials change depending on wake-sleep stages in adults. Visual Evoked potentials (VEPs) have been frequently studied in newborns to identify abnormal development of visual pathways; however, large variability has been reported and there is uncertainty as to the effect of sleep stages on VEPs in neonates. ObjectiveTo describe the characteristics of VEPs in one month old, healthy full-term newborns during active sleep (AS) and quiet sleep (QS), defined by simultaneous polysomnography (PSG). MethodsVEPs were obtained by monocular LEDs stimulation of each eye during AS and QS, in 20 healthy full-term newborns (gestational age 37–40 weeks) with normal birth weights and normal prenatal Doppler ultrasound indices. Latencies and amplitudes of N2, P2 and N3 components in AS and QS were compared, and their association with absolute power of EEG frequency bands, assessed. ResultsThere were no significant differences in VEP morphology, latencies and amplitudes between sleep states. Typical wave forms were obtained in all newborns in AS; however, no VEPs could be identified clearly in 3 newborns in QS; QS VEPs were less reliable than in AS: more averaging was required; correlation was significantly lower between the VEP averages; and a larger number of babies needed more than two averages to obtain replicable responses needed for clinical purposes. ConclusionsThese results indicate that changes in amplitude and latency of some VEP components observed in NREM and REM sleep in adults are not yet present in one month old newborns probably due to immaturity of cortical and sleep mechanisms. VEPs are more reliable during AS than QS in newborns. Systematic VEP recording during AS, and polysomnographic control to identify this stage, are highly recommended as methods that can increase there liability of neonatal VEPs.

Paediatric applications

SummaryThe International Society for Clinical Visual Electrophysiology of Vision, [ISCEV], publishes standards for performing five clinical visual electrophysiology tests; ffERG, mfERG, PERG, VEP and EOG, (www.ISCEV.org/standards). Older and co‐operative children tolerate these adult standard protocols well. Less compliant, younger infants, children with systemic as well as ocular disease or those with learning difficulties can benefit from adaptations that account of visual system maturation, make the test time shorter and the test experience less stressful. This talk will describe the key maturational changes and their impact on ERGs and VEP waveforms. Ways of combining and modifying tests for alert infants will be described that account for visual pathway development and limited tolerance. These will include the effects of anaesthesia, choice of electrodes and stimulation techniques. Case examples will be presented to show how visual electrophysiology maybe used to diagnose retinal dysfunction and to monitor visual pathway dysfunction in children.

The Impact of Ecological Niche on Adaptive Flexibility of Sensory Circuitry.

Evolution and development are interdependent, particularly with regard to the construction of the nervous system and its position as the machine that produces behavior. On the one hand, the processes directing development and plasticity of the brain provide avenues through which natural selection can sculpt neural cell fate and connectivity, and on the other hand, they are themselves subject to selection pressure. For example, mutations that produce heritable perturbations in neuronal birth and death rates, transcription factor expression, or availability of axon guidance factors within sensory pathways can markedly affect the development of form and thus the function of stimulus decoding circuitry. This evolvability of flexible circuits makes them more adaptable to environmental variation. Although there is general agreement on this point, whether the sensitivity of circuits to environmental influence and the mechanisms underlying development and plasticity of sensory pathways are similar across species from different ecological niches has received almost no attention. Neural circuits are generally more sensitive to environmental influences during an early critical period, but not all niches afford the same access to stimuli in early life. Furthermore, depending on predictability of the habitat and ecological niche, sensory coding circuits might be more susceptible to sensory experience in some species than in others. Despite decades of work on understanding the mechanisms underlying critical period plasticity, the importance of ecological niche in visual pathway development has received little attention. Here, I will explore the relationship between critical period plasticity and ecological niche in mammalian sensory pathways.

Novel Regulatory Mechanisms for the SoxC Transcriptional Network Required for Visual Pathway Development.

What pathways specify retinal ganglion cell (RGC) fate in the developing retina? Here we report on mechanisms by which a molecular pathway involving Sox4/Sox11 is required for RGC differentiation and for optic nerve formation in mice in vivo, and is sufficient to differentiate human induced pluripotent stem cells into electrophysiologically active RGCs. These data place Sox4 downstream of RE1 silencing transcription factor in regulating RGC fate, and further describe a newly identified, Sox4-regulated site for post-translational modification with small ubiquitin-related modifier (SUMOylation) in Sox11, which suppresses Sox11's nuclear localization and its ability to promote RGC differentiation, providing a mechanism for the SoxC familial compensation observed here and elsewhere in the nervous system. These data define novel regulatory mechanisms for this SoxC molecular network, and suggest pro-RGC molecular approaches for cell replacement-based therapies for glaucoma and other optic neuropathies.SIGNIFICANCE STATEMENT Glaucoma is the most common cause of blindness worldwide and, along with other optic neuropathies, is characterized by loss of retinal ganglion cells (RGCs). Unfortunately, vision and RGC loss are irreversible, and lead to bilateral blindness in ∼14% of all diagnosed patients. Differentiated and transplanted RGC-like cells derived from stem cells have the potential to replace neurons that have already been lost and thereby to restore visual function. These data uncover new mechanisms of retinal progenitor cell (RPC)-to-RGC and human stem cell-to-RGC fate specification, and take a significant step toward understanding neuronal and retinal development and ultimately cell-transplant therapy.

Early-Life Organophosphate Insecticide Exposure And Visual Acuity In Infants

Introduction: Organophosphate insecticides (OPs) are neurotoxic at high doses, however effects of low dose exposure are not well understood. Laboratory studies have shown that OPs at low doses may inhibit neuronal myelination, a process critical to visual pathway development early in life. Grating visual acuity (VA) rapidly improves in infancy, reflecting visual pathway myelination. VA might thus be sensitive to OP exposure. The aim here was to investigate the effect of prenatal OP exposure on infant VA. Methods: 24 OPs and 6 OP metabolites were measured using GC-tandem MS in umbilical cord blood plasma from infants in Fuyang County, China. VA was measured using Teller Acuity Cards at 6 wk (N=300), 9 mo (N=291), and 18 mo (N=288). Composite variables were created for total OP detects and total OP metabolite detects. Individual OPs and metabolites were analyzed as dichotomous (non-detect [ND]/detect), 3-level ordinal (ND/medium/high), or continuous, depending on detection rates. Multivariate linear regression was used to evaluate relationships between OP variables and VA. Results: 16 OPs and 6 metabolites were detected in at least one sample. Analyses of composite and dichotomous OP variables did not yield significant associations with VA. Chlorpyrifos, methamidophos, and trichlorfon were detected in 40, 66, and 56% of samples, respectively, and analyses as 3-level ordinal variables revealed suggestive, but not statistically significant, inverse associations between chlorpyrifos and trichlorfon and VA at 9 and 18 mo. Naled was detected in 94% of samples and continuous analyses found inverse associations with VA at 6 wk (β=-0.01; 95%CI:-0.02--0.001; p=0.03). Conclusions: VA in infancy may be adversely affected by certain OPs, though our results are largely inconclusive. Visual system development in infancy is critical to later learning processes and altered timing of visual pathway maturation may potentially contribute to poorer developmental outcomes later on.

A novel mouse model of tuberous sclerosis complex (TSC): eye-specific Tsc1-ablation disrupts visual-pathway development.

ABSTRACTTuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

Delayed early primary visual pathway development in premature infants: high density electrophysiological evidence.

In the past decades, multiple studies have been interested in developmental patterns of the visual system in healthy infants. During the first year of life, differential maturational changes have been observed between the Magnocellular (P) and the Parvocellular (P) visual pathways. However, few studies investigated P and M system development in infants born prematurely. The aim of the present study was to characterize P and M system maturational differences between healthy preterm and fullterm infants through a critical period of visual maturation: the first year of life. Using a cross-sectional design, high-density electroencephalogram (EEG) was recorded in 31 healthy preterms and 41 fullterm infants of 3, 6, or 12 months (corrected age for premature babies). Three visual stimulations varying in contrast and spatial frequency were presented to stimulate preferentially the M pathway, the P pathway, or both systems simultaneously during EEG recordings. Results from early visual evoked potentials in response to the stimulation that activates simultaneously both systems revealed longer N1 latencies and smaller P1 amplitudes in preterm infants compared to fullterms. Moreover, preterms showed longer N1 and P1 latencies in response to stimuli assessing the M pathway at 3 months. No differences between preterms and fullterms were found when using the preferential P system stimulation. In order to identify the cerebral generator of each visual response, distributed source analyses were computed in 12-month-old infants using LORETA. Source analysis demonstrated an activation of the parietal dorsal region in fullterm infants, in response to the preferential M pathway, which was not seen in the preterms. Overall, these findings suggest that the Magnocellular pathway development is affected in premature infants. Although our VEP results suggest that premature children overcome, at least partially, the visual developmental delay with time, source analyses reveal abnormal brain activation of the Magnocellular pathway at 12 months of age.

Exploratory study of the relationship of fat-free mass to speed of brain processing in preterm infants

Preterm infants are at risk for long-term neurodevelopmental impairment as a function of postnatal nutritional status. Despite adequate neonatal weight gain, preterm infants have altered body composition, with lower fat-free mass (FFM) and higher adiposity at term corrected gestational age (CGA) than their term counterparts. The relationship between postnatal body composition and speed of brain processing in preterm infants is unknown. Anthropometric measurements and body composition testing via air displacement plethysmography were performed on 16 appropriate-for-gestational age (GA) preterm (mean GA: 30.4 ± 2.8 wk) infants at term and 4 mo CGA. Infant visual pathway development was assessed at 4 mo CGA using pattern-reversal visual evoked potential (VEP); P100 (positive peak) latency was used to index neuronal speed of processing. Increased FFM at discharge (P = 0.02) and 4 mo CGA (P = 0.006) was associated with shorter latencies to the P100 peak. P100 latency was not related to total body weight, fat mass, or body fat percentage. FFM reflects protein accretion and indexes growth of organs, including the brain. The association of shorter VEP latency (i.e., faster neuronal processing) with higher FFM (i.e., better protein status) may be attributed to the positive effects of protein status on neuronal growth and differentiation.

Delayed early primary visual pathway development in premature infants: high density electrophysiological evidence

Delayed early primary visual pathway development in premature infants: high density electrophysiological evidence

The development of visual pathways for reading

The development of visual pathways for reading

Divergent Phenotypes of Vision and Accessory Visual Function in Mice with Visual Cycle Dysfunction (Rpe65rd12) or Retinal Degeneration (rd/rd)

Tests of vision for mice remain limited and the visual phenotype of some retinal disorders in mice remain poorly understood. A novel assay of vision was used to determine how the form and extent of retinal disease affects visual phenotype in mice. Retinal histology, the suppression of locomotion by light and visual guidance of locomotion, were assessed in mice with progressive photoreceptor degeneration (rd/rd) or visual cycle dysfunction (Rpe65 rd12). In wild-type mice, there was visual guidance of locomotor activity in dim light and suppression of activity (negative masking) in bright light. In rd/rd mice, vision was sufficient to guide locomotion at postnatal day (P)34 but was lost from P46 onward. In bright light rd/rd mice had enhanced negative masking. Although Rpe65 rd12 mice had no dim light response, with high illumination, vision was sufficient to guide locomotion at all ages tested. A major concern for gene and cell replacement therapies is the development of visual pathways through which restored retinal function can connect to visual centers of the brain. The residual retinal response to high illumination in Rpe65 rd12 mice translates into useful vision, and visual pathways remain functional--a prerequisite for restoring vision in disorders of the retina. Similarly, useful vision in young rd/rd mice shows that there is visual pathway function before photoreceptor degeneration and suggests the potential for early therapy. Together, these findings recommend observation of masking responses in the assessment of gene and cell replacement therapies.

Retinal Waves Trigger Spindle Bursts in the Neonatal Rat Visual Cortex

During visual system development, the light-insensitive retina spontaneously generates waves of activity, which are transmitted to the lateral geniculate nucleus. The crucial question is whether retinal waves are further transmitted to the cortex and influence the early cortical patterns of activity. Using simultaneous recordings from the rat retina and visual cortex during the first postnatal week in vivo, we found that spontaneous retinal bursts are correlated with spindle bursts (intermittent network bursts associated with spindle-shape field oscillations) in the contralateral visual cortex (V1). V1 spindle bursts could be evoked by electrical stimulation of the optic nerve. Intraocular injection of forskolin, which augments retinal waves, increased the occurrence of V1 spindle bursts. Blocking propagation of retinal activity, or removal of the retina reduced the frequency, but did not completely eliminate the cortical spindle bursts. These results indicate that spontaneous retinal waves are transmitted to the visual cortex and trigger endogenous spindle bursts. We propose that the interaction between retinal waves and spindle bursts contributes to the development of visual pathways to the cortex.

Latent Nystagmus

Latent nystagmus is a horizontal binocular oscillation that is evoked by unequal visual input to the 2 eyes. It develops primarily in humans with congenital esotropia. To investigate the interrelationship between latent and peripheral vestibular nystagmus and their corollary neuroanatomical pathways. Examination of subcortical neuroanatomical pathways producing latent nystagmus and review of the neurophysiological mechanisms by which they become activated in congenital esotropia. The vestibular nucleus presides over motion input from the eyes and labyrinths. Latent nystagmus corresponds to the optokinetic component of ocular rotation that is driven monocularly by nasal optic flow during a turning movement of the body in lateral-eyed animals. Congenital esotropia alters visual pathway development from the visual cortex to subcortical centers that project to the vestibular nucleus, allowing this primitive subcortical motion detection system to generate latent nystagmus under conditions of monocular fixation. Latent nystagmus is the ocular counterpart of peripheral vestibular nystagmus. Its clinical expression in humans proclaims the evolutionary function of the eyes as sensory balance organs.

Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial

Aim: To test the hypothesis that maternal docosahexaenoic acid (DHA) supplementation during pregnancy enhances maturation of the visual evoked potential (VEP) in healthy term infants. Methods: One hundred women were...