Altered organization of the visual cortex in FHONDA syndrome.

A fundamental scheme in the organization of the early visual cortex is the retinotopic representation of the contralateral visual hemifield on each hemisphere. We determined the cortical organization in a novel congenital visual pathway disorder, FHONDA-syndrome, where the axons from the temporal retina abnormally cross to the contralateral hemisphere. Using ultra-high field fMRI at 7 T, the population receptive field (pRF) properties of the primary visual cortex were modeled for two affected individuals and two controls. The cortical activation in FHONDA was confined to the hemisphere contralateral to the stimulated eye. Each cortical location was found to contain a pRF in each visual hemifeld and opposing hemifields were represented as retinotopic cortical overlays of mirror-symmetrical locations across the vertical meridian. Since, the enhanced crossing of the retinal fibers at the optic chiasm observed in FHONDA has been previously assumed to be exclusive to the pigment-deficiency in albinism, our direct evidence of abnormal mapping in FHONDA highlights the independence of pigmentation and development of the visual cortex. These findings thus provide fundamental insights into the developmental mechanisms of the human visual system and underline the general relevance of the interplay of subcortical stability and cortical plasticity.

Neural mechanisms of oculomotor abnormalities in the infantile strabismus syndrome.

Infantile strabismus is characterized by numerous visual and oculomotor abnormalities. Recently nonhuman primate models of infantile strabismus have been established, with characteristics that closely match those observed in human patients. This has made it possible to study the neural basis for visual and oculomotor symptoms in infantile strabismus. In this review, we consider the available evidence for neural abnormalities in structures related to oculomotor pathways ranging from visual cortex to oculomotor nuclei. These studies provide compelling evidence that a disturbance of binocular vision during a sensitive period early in life, whatever the cause, results in a cascade of abnormalities through numerous brain areas involved in visual functions and eye movements.

[Formula: see text]Dorsal and ventral visual streams: Typical and atypical development.

The literature on visuospatial processing describes two distinct pathways within the brain: a dorsal route extending from the visual cortex into the parietal lobes that is critical for spatial processing and a ventral route extending from the visual cortex into the temporal lobes that is critical for form perception. These visual streams appear to differ in their developmental trajectories and their vulnerabilities to diverse neurodevelopmental conditions. The present work aims to investigate development and vulnerability in two aspects of dorsal and ventral visual-stream function, namely attention to location and attention to identity. In Study 1, we compare typically-developing (TD) youth aged 9 to 16 years with young adults aged 18 to 22 years on computerized location and identity tasks. In Study 2, we compare children and adolescents who have congenital hypothyroidism (CH), a pediatric endocrine disorder, with age-matched TD controls on the same tasks. The results from Study 1 show that the youths were less accurate than the adults at judging identity, whereas both groups were equally accurate at judging location. The results from Study 2 show that the youths with CH were slower but not less accurate than the TD youths in making both identity and location judgments. The results are interpreted as signifying later development of ventral (identity) stream functions compared to dorsal (location) but equal vulnerability of both functions in CH.

Nondecussating retinal-fugal fiber syndrome: Clinical and neuroimaging clues to diagnosis.

We report the clinical details and imaging findings for a case of nondecussating retinal-fugal fiber syndrome or isolated achiasma in a 4-year-old female child. Findings included the isolated absence of optic chiasm with unremarkable rest of the optic pathway and midline structures in a child presenting clinically with see-saw nystagmus. Clinically congenital see-saw nystagmus, "mirror reversal" of visual field representation and interocular ipsilateral asymmetry on monocular visual evoked potential point toward achiasma and warrant further evaluation with magnetic resonance imaging (MRI). Isolated achiasma is a rare condition that may remain undiagnosed unless MRI is done.

Congenital visual pathway abnormalities: a window onto cortical stability and plasticity.

Sensory systems project information in a highly organized manner to the brain, where it is preserved in maps of the sensory structures. These sensory projections are altered in congenital abnormalities, such as anophthalmia, albinism, achiasma, and hemihydranencephaly. Consequently, these abnormalities, profoundly affect the organization of the visual system. Surprisingly, visual perception remains largely intact, except for anophthalmia. Recent brain imaging advances shed light on the mechanisms that underlie this phenomenon. In contrast to animal models, in humans the plasticity of thalamocortical connections appears limited, thus demonstrating the importance of cortical adaptations. We suggest that congenital visual pathway abnormalities provide a valuable model to investigate the principles of plasticity that make visual representations available for perception and behavior in humans.

Dysfunctional uveoscleral pathway in a rat model of congenital glaucoma.

UNLABELLED: The purpose of the study was to investigate the presence of the uveoscleral pathway in the normotensive rat (NR) and in a rat model of congenital glaucoma (CGR). We injected the fluorescent tracer 70-kDa dextran rhodamine B in the anterior chamber of four NRs and four CGRs. At 10 and 60 minutes after injection, rats were euthanized by CO2 inhalation and eyes were enucleated. Cryosections were prepared and analyzed using fluorescent microscopy. Hematoxylin-eosin staining and electron microscopy of the anterior chamber angle (ACA) were performed. At 10 minutes after injection, fluorescent tracer was detected in the iris root and ciliary processes of NRs and CGRs. At 60 minutes, NRs showed prominent signal in the suprachoroidal, whereas, in the CGRs, tracer was barely detectable. Histology of the anterior chamber revealed the presence of an open ACA and electron microscopy confirmed the normal structure of the ciliary body in CGRs. CONCLUSIONS: Our results document the presence of an uveoscleral pathway in the normotensive rat. The rat model of congenital glaucoma shows severe impairment of the uveoscleral pathway, suggesting that alterations of the uveoscleral outflow might play a role in the pathogenesis of CG.

Role of retinal input on the development of striate-extrastriate patterns of connections in the rat.

Previous studies have shown that retinal input plays an important role in the development of interhemispheric callosal connections, but little is known about the role retinal input plays on the development of ipsilateral striate-extrastriate connections and the interplay that might exist between developing ipsilateral and callosal pathways. We analyzed the effects of bilateral enucleation performed at different ages on both the distribution of extrastriate projections originating from restricted loci in medial, acallosal striate cortex, and the overall pattern of callosal connections revealed following multiple tracer injections. As in normal rats, striate-extrastriate projections in rats enucleated at birth consisted of multiple, well-defined fields that were largely confined to acallosal regions throughout extrastriate cortex. However, these projections were highly irregular and variable, and they tended to occupy correspondingly anomalous and variable acallosal regions. Moreover, area 17, but not area 18a, was smaller in enucleates compared to controls, resulting in an increase in the divergence of striate projections. Anomalies in patterns of striate-extrastriate projections were not observed in rats enucleated at postnatal day (P)6, although the size of area 17 was still reduced in these rats. These results indicate that the critical period during which the eyes influence the development of striate-extrastriate, but not the size of striate cortex, ends by P6. Finally, enucleation did not change the time course and definition of the initial invasion of axons into gray matter, suggesting that highly variable striate projections patterns do not result from anomalous pruning of exuberant distributions of 17-18a fibers in gray matter.

Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity.

Although the organization of neuronal circuitry is shaped by activity patterns, the capacity to modify and/or optimize the structure and function of whole projection pathways using external stimuli is poorly defined. We investigate whether neuronal activity induced by pulsed magnetic fields (PMFs) alters brain structure and function. We delivered low-intensity PMFs to the posterior cranium of awake, unrestrained mice (wild-type and ephrin-A2A5(-/-)) that have disorganized retinocollicular circuitry and associated visuomotor deficits. Control groups of each genotype received sham stimulation. Following daily stimulation for 14 d, we measured biochemical, structural (anterograde tracing), and functional (electrophysiology and behavior) changes in the retinocollicular projection. PMFs induced BDNF, GABA, and nNOS expression in the superior colliculus and retina of wild-type and ephrin-A2A5(-/-) mice. Furthermore, in ephrin-A2A5(-/-) mice, PMFs corrected abnormal neuronal responses and selectively removed inaccurate ectopic axon terminals to improve structural and functional organization of their retinocollicular projection and restore normal visual tracking behavior. In contrast, PMFs did not alter the structure or function of the normal projection in wild-type mice. Sham PMF stimulation had no effect on any mice. Thus, PMF-induced biochemical changes are congruent with its capacity to facilitate beneficial reorganization of abnormal neural circuits without disrupting normal connectivity and function.

Comparison of infantile nystagmus syndrome in achiasmatic zebrafish and humans.

Infantile nystagmus syndrome (INS; formerly called congenital nystagmus) is an ocular motor disorder characterized by several typical nystagmus waveforms. To date, restrictions inherent to human research and the absence of a handy animal model have impeded efforts to identify the underlying mechanism of INS. Displaying INS-like spontaneous eye oscillations, achiasmatic zebrafish belladonna (bel) mutants may provide new insights into the mystery of INS. In this study, we demonstrate that these spontaneous eye oscillations match the diagnostic waveforms of INS. As a result, zebrafish bel mutants can be used as an animal model for the study of INS. In zebrafish bel mutants, visual pathway abnormalities may contribute to the spontaneous nystagmus via an inverted signal to the pretectal area. We hypothesized that human INS may also be linked to visual pathway abnormalities (possibly underdiagnosed in INS patients) in a similar way.

Role of three-dimensional ultrasound measurement of the optic tract in fetuses with agenesis of the septum pellucidum.

OBJECTIVES: To construct reference ranges for fetal optic tract mean diameter and to report measurements in fetuses with agenesis of the septum pellucidum (SP). METHODS: Three-dimensional volumes of the optic chiasm were acquired in 98 normal fetuses during routine sonographic examination at 21-36 weeks' gestation and the diameters of the posterior left and right optic tracts were measured offline. A polynomial regression approach (mean and SD model) was used to compute reference charts for the mean fetal optic tract diameter measurements. In addition, 23 volumes were acquired in fetuses with SP agenesis for offline measurement of optic tract diameter. Complete follow-up was obtained in 13 of these 23 cases. RESULTS: In normal fetuses, the optic tract diameter increased linearly throughout gestation. There was no evidence of increased variability with gestational age (constant SD). Normal charts and equations for Z-score calculation were constructed. Among the 13 fetuses with SP agenesis and complete follow-up, nine had normal measurements, of which eight had normal vision postnatally. Four had hypoplastic optic tract, defined as mean optic tract diameter Z-score below - 3. Of these, two underwent termination of pregnancy and pathological examination confirmed hypoplasia of the tract, one showed signs of hypoplasia at magnetic resonance imaging and postnatal examination confirmed blindness, and one had a hypoplastic measurement for only one tract and was born with poor vision and abnormal bilateral eye movements. CONCLUSION: We present new reference charts for mean fetal optic tract diameter. In fetuses with agenesis of the SP, sonography of the optic tract might be a useful tool to assess its development and may help in prenatal counseling.

Cortical maps and white matter tracts following long period of visual deprivation and retinal image restoration.

Abnormal visual input during development has dramatic effects on the visual system. How does the adult visual system respond when input is corrected? MM lost his left eye and became blind in the right due to corneal damage at the age of 3. At age 46, MM regained his retinal image, but his visual abilities, even seven years following the surgery, remain severely limited, and he does not rely on vision for daily life. Neuroimaging measurements reveal several differences among MM, sighted controls, sighted monocular, and early blind subjects. We speculate that these differences stem from damage during the critical period in development of retinal neurons with small, foveal receptive fields. In this case, restoration of functional vision requires more than improving retinal image contrast. In general, visual restoration will require accounting for the developmental trajectory of the individual and the consequences of the early deprivation on cortical circuitry.

Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

Switching retinogeniculate axon laterality leads to normal targeting but abnormal eye-specific segregation that is activity dependent.

Partial decussation of sensory pathways allows neural inputs from both sides of the body to project to the same target region where these signals will be integrated. Here, to better understand mechanisms of eye-specific targeting, we studied how retinal ganglion cell (RGC) axons terminate in their thalamic target, the dorsal lateral geniculate nucleus (dLGN), when crossing at the optic chiasm midline is altered. In models with gain- and loss-of-function of EphB1, the receptor that directs the ipsilateral projection at the optic chiasm, misrouted RGCs target the appropriate retinotopic zone in the opposite dLGN. However, in EphB1(-/-) mice, the misrouted axons do not intermingle with normally projecting RGC axons and segregate instead into a distinct patch. We also revisited the role of retinal activity on eye-specific targeting by blocking correlated waves of activity with epibatidine into both eyes. We show that, in wild-type mice, retinal waves are necessary during the first postnatal week for both proper distribution and eye-specific segregation of ipsilateral axons in the mature dLGN. Moreover, in EphB1(-/-) mice, refinement of ipsilateral axons is perturbed in control conditions and is further impaired after epibatidine treatment. Finally, retinal waves are required for the formation of the segregated patch of misrouted axons in EphB1(-/-) mice. These findings implicate molecular determinants for targeting of eye-specific zones that are independent of midline guidance cues and that function in concert with correlated retinal activity to sculpt retinogeniculate projections.

Distance perception in autism and typical development.

Children with autism and typically developing children walked blindfolded to a previously seen target (blindwalking task) and matched the frontal to the sagittal extent of a pattern formed by ropes on the ground (L-matching task). All participants were accurate in the blindwalking task. Children with autism were also very accurate in the matching task. By contrast, in the matching task typically developing children made substantial underestimations that were inversely correlated with age. These findings support models that posit independent representations for the egocentric distance to a target location and for the spatial extent to a target object relative to the other spatial extents. These latter representations involve a form of large-scale pattern perception that may mature more slowly than representations of egocentric distance and develop atypically in autism.

Phr1 regulates retinogeniculate targeting independent of activity and ephrin-A signalling.

Proper functioning of the mammalian visual system requires that connections between the eyes and their central targets develop precisely. At birth, axons from the two eyes project to broad, overlapping regions of the dorsal-lateral geniculate nucleus (dLGN). In the adult, retinal axons segregate into distinct monocular regions at stereotyped locations within the dLGN. This process is driven by both molecular cues and activity-dependent synaptic competition. Here we demonstrate that Phr1, an evolutionarily conserved regulator of synapse formation and axon guidance, defines a novel molecular pathway required for proper localization of retinogeniculate projections. Following conditional excision of Phr1 in the retina, eye-specific domains within the dLGN are severely disturbed, despite normal spontaneous retinal wave activity and monocular segregation. Although layer placement is dramatically altered, Phr1 mutant retinal axons respond to ephrin-A in vitro. These findings indicate that Phr1 is a key presynaptic regulator of retinogeniculate layer placement independent of activity, segregation, or ephrin-A signaling.

Conditional inactivation of the NBS1 gene in the mouse central nervous system leads to neurodegeneration and disorganization of the visual system.

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of the human NBS1, Nbs1, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. Here we report that conditional targeted disruption of the murine NBS1 gene in the CNS results in mal-development, degeneration, disorganization and dysfunction of the murine visual system, especially in the optic nerve. Nbs1 deletion resulted in reduced diameters of Nbs1-CNS-Delta eye and optic nerve. MRI analysis revealed defective white matter development and organization. Nbs1 inactivation altered the morphology and organization of the glial cells. Interestingly, at the age of two-month-old the levels of the axonal guidance molecule semaphorin-3A and its receptor neuropilin-1 were up-regulated in the retina of the mutant mice, a typical injury response. Electroretinogram analysis revealed marked reduction in a- and b-waves, indicative of decreased retinal function. Our study points to a novel role for Nbs1 in the development, organization and function of the visual system.

[Morphology of the optic chiasm in albinism]. / Morphologie des Chiasma opticum bei Albinismus.

Albinism is associated with a misrouting of fibers at the optic chiasm where the majority of fibers cross to the contralateral side. The cause of this abnormal decussation pattern reflects a disturbance of cell cycle regulation in the development of the retina which is in part controlled by melanin. Growing axons from retinal ganglion cells therefore arrive later than usual at the optic chiasm and are misrouted contralaterally. This atypical decussation leads to morphological changes of the optic chiasm including a reduced chiasm width with larger angles between optic nerves and tracts which can be shown by magnetic resonance imaging.

Isolated absence of the optic chiasm: a rare cause of congenital nystagmus.

The cases presented are rare examples of congenital nystagmus associated with isolated absence of the optic chiasm. MR imaging in both patients demonstrated unremarkable anterior optic pathways and optic tracts. No additional midline central nervous system abnormalities, migrational anomalies, space-occupying lesions, or destructive processes were noted. These cases demonstrate that the achiasmatic syndrome should be included in the differential diagnosis of congenital nystagmus and may be overlooked without careful MR imaging evaluation.

Vesicular glutamate transport at a central synapse limits the acuity of visual perception in zebrafish.

The neural circuitry that constrains visual acuity in the CNS has not been experimentally identified. We show here that zebrafish blumenkohl (blu) mutants are impaired in resolving rapid movements and fine spatial detail. The blu gene encodes a vesicular glutamate transporter expressed by retinal ganglion cells. Mutant retinotectal synapses release less glutamate, per vesicle and per terminal, and fatigue more quickly than wild-type in response to high-frequency stimulation. In addition, mutant axons arborize more extensively, thus increasing the number of synaptic terminals and effectively normalizing the combined input to postsynaptic cells in the tectum. This presumably homeostatic response results in larger receptive fields of tectal cells and a degradation of the retinotopic map. As predicted, mutants have a selective deficit in the capture of small prey objects, a behavior dependent on the tectum. Our studies successfully link the disruption of a synaptic protein to complex changes in neural circuitry and behavior.

Early experience with 3-T magnetic resonance tractography in the surgery of cerebral arteriovenous malformations in and around the visual pathway.

OBJECTIVE: To evaluate of the role of magnetic resonance (MR) tractography on the optic radiation with a 3-T MR unit in the surgery of cerebral arteriovenous malformation (AVM) in and around the visual pathway. METHODS: Of the 322 patients with cerebral AVMs admitted to our clinic between 1978 and 2005, a study of MR tractography was made on 29 patients. Ten of those patients had AVMs in and around the visual pathway and were included in this study. There were two men and eight women ranging in age from 15 to 64 years (mean age, 34.5 +/- 14.8 yr). All of the patients underwent 3-T tractography of optic radiation (OR) and neuro-ophthalmologic evaluation. Four of the 10 patients underwent surgical resection of the AVM. A postoperative 3-T MR study and a neuro-ophthalmologic evaluation was performed 1 month after surgery in most patients. RESULTS: The preoperative patients for whom tractography demonstrated a continuous bundle of OR from the medial temporal region to the primary visual cortex had minimal or no visual field loss, whereas the patients for whom the tractography did not show a continuous bundle of OR had significant visual loss. The patients for whom tractography in the postoperative study demonstrated a bundle of OR experienced no postoperative deterioration of the visual field loss, whereas the patients for whom tractography did not demonstrate a bundle of OR exhibited significant visual field loss. CONCLUSION: This technique is thought to be useful in confirming the integrity of and localizing deviated tract and in evaluating the surgical risk, especially for nonhemorrhagic AVMs in and around the visual pathways, taking some limitations of this method into consideration.