From vision to cognition: potential contributions of cerebral visual impairment to neurodevelopmental disorders.

Vision has a crucial role to play in human development and functioning. It is, therefore, not surprising that vision plays a fundamental role in the development of the child. As a consequence, an alteration in visual function is, therefore, likely to hinder the child's development. Although ocular disorders are well known, diagnosed and taken into account, cerebral visual impairments (CVI) resulting from post-chiasmatic damage are largely underdiagnosed. However, among the disorders resulting from an episode of perinatal asphyxia and/or associated with prematurity, or neonatal hypoglycaemia, CVIs are prominent. In this article, we focus on the role of the possible effects of CVI on a child's learning abilities, leading to major difficulty in disentangling the consequences of CVI from other neurodevelopmental disorders (NDD) such as dyslexia, dyscalculia, dysgraphia, attention-deficit/hyperactivity disorder (ADHD), developmental coordination disorder (DCD) and autism spectrum disorders (ASD). Although we focus here on the possible overlap between children with CVI and children with other NDD, De Witt et al. (Wit et al. Ear Hear 39:1-19, 2018) have raised exactly the same question regarding children with auditory processing disorders (the equivalent of CVI in the auditory modality). We underline how motor, social and cognitive development as well as academic success can be impaired by CVI and raise the question of the need for systematic evaluation for disorders of vision, visual perception and cognition in all children presenting with a NDD and/or previously born under adverse neurological conditions.

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.

Cerebral cortical hypoplasia with abnormal morphology of pyramidal neuron in growth-retarded mouse (grt/grt).

The purpose of this study was to quantitatively characterize structural abnormalities of the cerebrum in a growth-retarded mouse (grt/grt) with a tyrosylprotein sulfotransferase 2 gene defect. Three-dimensional computed tomography (CT) images were obtained from fixed brains of male homogenous grt/grt (n=5) and heterozygous grt/+ (n=5) mice at 15 weeks of age, and volumes of representative cerebral regions were calculated on the basis of those images. Following CT measurements, cryosections of the brain were made, and immunohistochemistry for NeuN and SMI-32 was carried out. By CT-based volumetry, region-specific reductions in volumes were marked in the cerebral cortex and white matter, but not in other cerebral regions of grt/grt. When quantitatively evaluating the shape of the cerebral cortex, the frontooccipital length of the cortex was significantly smaller in grt/grt than in grt/+, whereas the cortical width was not altered in grt/grt. On the other hand, both cortical thickness and density of NeuN-immunopositive neurons in three distinctive cortical regions, i.e., the primary motor cortex, barrel field of primary somatosensory cortex and primary visual cortex, were not different between grt/grt and grt/+. By semi-quantitative immunohistochemical analysis, the intensity of SMI-32 immunostaining was significantly weaker in grt/grt than in grt/+ in the three cortical areas examined. SMI-32 staining was reduced, particularly in layer III pyramidal neurons in grt/grt, while it was sustained in multipolar neurons. The present results suggest that cerebral abnormalities in grt/grt mice are characterized by cortical hypoplasia at the frontooccipital axis with immature pyramidal neurons and insufficient development of callosal fibers.

Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in mice.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders. Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n = 22) and ephrin-A2A5(-/-) (n = 22) mice, the latter possessing visuotopic anomalies. Mice were treated with LI-rTMS or sham (handling control) daily for 14 d, then fluorojade and fluororuby were injected into visual cortex. The distribution of dorsal LGN (dLGN) neurons and corticotectal terminal zones (TZs) was mapped and disorder defined by comparing their actual location with that predicted by injection sites. In the afferent geniculocortical projection, LI-rTMS decreased the abnormally high dispersion of retrogradely labeled neurons in the dLGN of ephrin-A2A5(-/-) mice, indicating geniculocortical map refinement. In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5(-/-) mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5(-/-) mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.

Structural brain abnormalities in patients with primary open-angle glaucoma: a study with 3T MR imaging.

PURPOSE: We examined changes of the central nervous system in patients with advanced primary open-angle glaucoma (POAG). METHODS: The clinical observational study included 15 patients with bilateral advanced POAG and 15 healthy normal control subjects, matched for age and sex with the study group. Retinal nerve fiber layer (RNFL) thickness was measured by optical coherence tomography (OCT). Using a 3-dimensional magnetization-prepared rapid gradient-echo sequence (3D-MP-RAGE) of magnetic resonance imaging (MRI) and optimized voxel-based morphometry (VBM), we measured the cross-sectional area of the optic nerve and optic chiasm, and the gray matter volume of the brain. RESULTS: Patients in the POAG group compared to the subjects in the control group showed a significant (P < 0.001) decrease in the bilateral gray-matter volume in the lingual gyrus, calcarine gyrus, postcentral gyrus, superior frontal gyrus, inferior frontal gyrus, and rolandic operculum, as well as in the right cuneus, right inferior occipital gyrus, left paracentral lobule, and right supramarginal gyrus. Patients in the study group showed a significant increase in the bilateral gray matter volume in the middle temporal gyrus, inferior parietal gyrus, and angular gyrus, and in the left gray matter volume in the superior parietal gyrus, precuneus, and middle occipital gyrus. In addition, the cross-sectional area of the optic nerve and optic chiasm, and RNFL thickness were significantly decreased in the POAG group. CONCLUSIONS: In patients with POAG, three-dimensional MRI revealed widespread abnormalities in the central nervous system beyond the visual cortex.

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.

Visual cortex abnormalities in adults with ADHD: a structural MRI study.

OBJECTIVES: Most structural imaging studies in ADHD have focused on prefronto-striatal circuits. However, findings remained inconsistent while recent reports point to the posterior parietal cortex as an additional target for research. Moreover, although adult ADHD clinically differs from the childhood presentation little is known about the structural correlates of ADHD in adults. The aim of this study was to clarify the involvement of prefronto-striatal and posterior parietal areas in adult ADHD. METHODS: Voxel-based morphometry of high resolution MRI scans was applied to analyze volumetric brain differences between 31 adult patients with ADHD and 31 control subjects. RESULTS: The volume of prefrontal, striatal and parietal gray matter was normal. ADHD patients displayed a significant reduction of gray matter volume bilaterally in the early visual cortex (P<0.04). CONCLUSIONS: The unexpected finding of visual cortex abnormalities might be related to impairments in early-stage, 'subexecutive" attentional mechanisms. The results support the notion that executive dysfunction may not be the dominant neurobiological characteristic of ADHD at least in adult patients. The visual cortex deserves more consideration as a potentially important site of dysfunction in adult and possibly childhood ADHD.

Reduced cortical folding in mental retardation.

BACKGROUND AND PURPOSE: MR is a developmental disorder associated with impaired cognitive functioning and deficits in adaptive behavior. With a 2D region of interest-based GI, a preliminary study reported significantly reduced gyrification in the prefrontal lobe in MR. The purpose of this study was to further investigate the abnormalities of cortical gyrification in MR and to explore the possible causes of these abnormalities. MATERIALS AND METHODS: Thirteen patients with MR and 26 demographically matched healthy controls were included in this study. A 3D surface-based lGI was calculated as a measure to quantify gyrification. Then vertex-by-vertex contrasts of lGI were performed between patients with MR and healthy controls. RESULTS: Statistical analysis showed that patients with MR had significantly reduced lGI in multiple brain regions compared with healthy controls. These regions include the lateral and medial prefrontal cortices, the right superior temporal gyrus, the left superior parietal lobe, the bilateral insular and adjacent cortices, and the visual and motor cortices. CONCLUSIONS: The observed abnormal pattern of cortical gyrification revealed by significant reduction of lGI in multiple brain regions might reflect the developmental disturbance in intracortical organization and cortical connectivities in MR.

Visual maps: To merge or not to merge.

A recent study of a child born with one cerebral hemisphere has revealed an extreme developmental reorganization of visual cortex. Self-organizing visual maps demonstrate a surprisingly flexible restructuring in response to cortical loss.

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.

The layout of functional maps in area 18 of strabismic cats.

Strabismus (or squint) is both a well-established model for developmental plasticity and a frequent clinical symptom. To analyze experience-dependent plasticity of functional maps in the brain we used optical imaging of intrinsic signals to visualize both orientation and ocular dominance domains in cat area 18. In strabismic animals, iso-orientation domains exhibited a pinwheel-like organization, as previously described for area 18 of normally raised animals and for area 17 of both normally raised and strabismic cats. In area 18, mean pinwheel density was similar in the experimental (2.2 pinwheel centers per mm2 cortical surface) and control animals (2.3/mm2 in normally raised animals), but significantly lower than in area 17 of both normally raised and strabismic cats (2.7-3.4/mm2). A comparison of orientation and ocular dominance domains revealed that iso-orientation domains were continuous across the borders of ocular dominance domains and tended to cross these borders at steep angles. Thus, the orientation map does not seem to be modified by experience-dependent changes in afferent activity. Together with our recent observation that strabismus does not enhance the segregation of ocular dominance domains in cat area 18, the present data indicate that the layout of functional maps in area 18 is less susceptible to experience-dependent manipulations than in area 17.

Callosal agenesis and absence of primary visual cortex induced by prenatal X rays impair navigation's strategy and learning in tasks involving visuo-spatial working but not reference memory in mice.

This study was designed for the identification of possible and distinct abilities for behavioral recovery after prenatal cerebral damage. We adopted an interesting tool for promotion of cell's death. Due to the fact that neuroblastic cells and early postmitotic neurons on the beginning of differentiation are particularly sensible for the promotion of apoptosis, we used a low whole-body dose of X radiation on pregnant female mice on E16 (sixteenth gestational day) to promote damage on specific cerebral areas of the progeny, given that the pattern of cerebral neurogenesis is not homogeneous. The morphological results were previously described by our team. Here we noticed that the recovery of behavioral functions after prenatal damage seems to be related to specific factors of local cortical circuitry organization. The deficits found on visual navigation and working memory contrast with the recovery of primary visual functions and also with reference memory, where the mice have a delay on acquisition of learning but get it. As a conclusion we reasoning that changes on laminar organization on frontal cortex as well as the inter hemispheric cortical integration through the corpus callosum could promote relatively fixed cognitive dysfunctions, as those observed on performances that require strategies for navigation (decision making) and working memory, with consequences also observed on the subsequent learning.

Cortical intercorrelations of temporal area volumes in schizophrenia.

BACKGROUND: Abnormal temporal connections with other cortical areas may underlie some of the most prominent cognitive deficits described in schizophrenia. In order to evaluate the relationship between temporal and other cortical regions in schizophrenia, we examined the intercorrelations of volumetric measures of gray and white matter for each Brodmann's area of the temporal lobe with volumes in the rest of the cortex in patients with schizophrenia and normal comparison subjects. METHODS: MR images were acquired in normal subjects (n=46) and patients with schizophrenia (n=106), divided into good-outcome (n=52) and poor-outcome (Kraepelinian; n=54) subtypes; and correlational patterns between the volumes of individual Brodmann's areas were compared and examined in relation to outcome. RESULTS: Positive frontotemporal intercorrelations were significantly stronger while negative frontotemporal intercorrelations were weaker in schizophrenia patients as compared to normal subjects. Correlations between the right temporal pole and other temporal regions were significantly weaker in schizophrenia patients than in controls. When compared to normal controls and good-outcome patients, schizophrenia patients with poor outcomes showed a selective pattern of stronger gray matter correlations between the medial temporal vs. primary visual and between primary auditory vs. dorsolateral prefrontal cortices, all in the left hemisphere. CONCLUSIONS: Strengthening of positive associations among the temporal and extratemporal (mainly frontal and occipital) regions as well as weakening of regional intercorrelations within the temporal lobe in patients appear to constitute the major differences of correlational patterns in schizophrenia patients and normal subjects. Present findings may be implicated in object recognition deficits seen in patients with schizophrenia, as well as in purportedly deficient spatial and semantic processing of both auditory and visual information that may be associated with poor outcome.

Neural basis of genetically determined visuospatial construction deficit in Williams syndrome.

A unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of visual processing with fMRI showed isolated hypoactivation in WS in the parietal portion of the dorsal stream. In the immediately adjacent parietooccipital/intraparietal sulcus, structural neuroimaging showed a gray matter volume reduction in participants with WS. Path analysis demonstrated that the functional abnormalities could be attributed to impaired input from this structurally altered region. Our observations confirm a longstanding hypothesis about dorsal stream dysfunction in WS, demonstrate effects of a localized abnormality on visual information processing in humans, and define a systems-level phenotype for mapping genetic determinants of visuoconstructive function.

Efficacy of sodium valproate in the treatment of photosensitive epilepsy (PSE) and the probable reasons for the persistence of occipital spikes.

Intermittent photic stimulation (IPS) in patients with photosensitive epilepsy (PSE) leads to EEG abnormalities, which include generalized discharges with spike and wave activity. This paper investigates 33 PSE patients, 14 (42%) males and 19 (58%) females. The age range was between 8 and 45 years. After the treatment of the patients with sodium valproate (VPA), the EEG examinations showed that the generalized discharges disappeared, while the occipital spikes persisted. The mechanism of action of VPA was re-evaluated in order to ascertain whether or not the persistent occipital was due to a failure in inhibitory postsynaptic potential (IPSP). It was concluded that the possible causes of VPA's inefficacy in abolishing occipital spikes in PSE was not necessarily due to a failure in IPSP, but rather it could be due to a time-dependent failure of certain cells of the visual system to respond positively to the VPA's modulatory activity, probably involving the ionic channels, neurotransmitters, and the second messenger systems. The relationship between occipital spikes and visual evoked response is discussed. The extent to which metabolic processes and neurotransmitters are involved is also evaluated.

Early visual cortex organization in autism: an fMRI study.

Autism is a neurodevelopmental disorder characterized by preserved visual abilities as well as a special profile for visual cognition. We examined the visual cortex of high-ability individuals with autism in order to assess whether the presence of abnormalities at the primary sensory level in autism could be the basis of their unusual pattern of visual cognitive abilities. We found that the early sensory visual areas are normally organized in individuals with autism, with a normal ratio between central versus peripheral visual field representation. We conclude that the differences observed in the visual capacities of individuals with autism are likely to arise from higher-level cognitive areas and functions, and are the result of top-down processes.

Absence of cross-modal reorganization in the primary auditory cortex of congenitally deaf cats.

To investigate possible cross-modal reorganization of the primary auditory cortex (field A1) in congenitally deaf cats, after years of auditory deprivation, multiunit activity and local field potentials were recorded in lightly anesthetized animals and compared with responses obtained in hearing cats. Local field potentials were also used for current source-density analyses. For visual stimulation, phase-reversal gratings of three to five different spatial frequencies and three to five different orientations were presented at the point of central vision. Peripheral visual field was tested using hand-held stimuli (light bar-shaped stimulus of different orientations, moved in different directions and flashed) typically used for neurophysiological characterization of visual fields. From 200 multiunit recordings, no response to visual stimuli could be found in A1 of any of the investigated animals. Using the current source-density analysis of local field potentials, no local generators of field potentials could be found within A1, despite of the presence of small local field potentials. No multiunit responses to somatosensory stimulation (whiskers, face, pinna, head, neck, all paws, back, tail) could be obtained. In conclusion, there were no indications for a cross-modal reorganization (visual, somatosensory) of area A1 in congenitally deaf cats.

Immature cortex lesions alter retinotopic maps and interhemispheric connections.

Unilateral lesions of the occipital visual areas performed on postnatal day 5 (P5) in the ferret are not compensated by the appearance, in the lesioned hemisphere, of visual responses at ectopic locations. Instead, when parts of the visual areas are spared, they show abnormal retinotopic organizations; furthermore, callosal connections are abnormally distributed in relation to the retinotopic maps. Lesions that completely eliminate the visual areas including the posterior parietal cortex cause the appearance of abnormal callosal connections from the primary somatosensory cortex on the lesion side to the contralateral, intact, posterior parietal cortex. The occipital visual areas (17, 18, 19, and 21) of the intact hemisphere show a normal retinotopy but lose callosal connections in territories homotopic to the lesions. These findings clarify the nature and limits of structural developmental plasticity in the visual cortex. Early in life, certain regions of cortex have been irreversibly allocated to the visual areas, but two properties defining the areas, that is, retinotopy and connections, remain modifiable. The findings might be relevant for understanding the consequences of early-onset visual cortical lesions in humans.

[Anatomical differences in optic nerve, chiasma and tractus opticus in human albinism as demonstrated by standardised clinical and MRI evaluation]. / Anatomische Unterschiede der Nervi optici, des Chiasmas und der Tractus optici bei normal- und hypopigmentierten Personen: eine standardisierte MRI- und fMRI-Untersuchung.

BACKGROUND: There has been long-standing clinical and electrophysiological evidence that in patients with albinism the visual pathways cross atypically: most fibres from one eye cross to the contralateral visual cortex. PURPOSE OF THE STUDY: to determine whether the size and configuration of the optic chiasm in human albinos is different from normally pigmented controls. PATIENTS AND METHODS: 17 patients (11 female, mean age 35.8 years) with oculocutaneous albinism underwent a standardised graded morphological and functional evaluation. Magnetic resonance images were reformatted to the region of the optic chiasm and analysed using observer-independent morphometry. In addition, fMRI of the visual cortex was performed during VEP analysis (1.5 Tesla Siemens Vision). Morphological and fMRT results were compared to an age-correlated group of n = 16 normally pigmented healthy volunteers with normal visual acuity and stereopsis. RESULTS: 65 % of the patients (n = 10) showed signs of dysplasia of the optic nerve head. Statistical morphometry showed distinct differences in chiasmal morphology between albinos and normally pigmented probands (smaller optic nerves, different angles of optical entry into the chiasm and of the beginning of the Tractus optici leaving the chiasm, overall chiasmal width and height). CONCLUSIONS: Optic nerve head anomalies are frequent in albinism and influence visual outcome. Size and configuration of the optic chiasm in human albinos is distinctly different from normally pigmented control persons and reflects the atypical crossing of optic fibres.

Relay of visual information to the lateral geniculate nucleus and the visual cortex in albino ferrets.

The abnormal organization of the central visual pathways in the albino ferret has been characterized anatomically and physiologically. Recordings in dorsal lateral geniculate nucleus of the albino ferret show that lamina A1, which receives an aberrant projection from the contralateral eye, contains an extensive representation of the ipsilateral visual hemifield with receptive fields located up to 35 degrees from the vertical meridian. This is not the case in pigmented ferrets, for which the vast majority of units, activated through either the contralateral or ipsilateral eye, have receptive fields confined to the contralateral hemifield. The few fields found in the ipsilateral hemifield are driven through the contralateral eye and none is more than 10 degrees from the midline. Cortical topography was studied by making closely spaced electrode penetrations across the area 17/18 border. In pigmented animals, the reversal of topography at the border is characterized by units with receptive fields centered a few degrees into the ipsilateral hemifield. In 22 of 25 albinos, the "Boston" aberrant topography was found: the representation of the vertical meridian is within area 17, rather than at the area 17/18 border. Instead, at the area 17/18 border, there is a reversal in the topographic progression at up to 30 degrees into the ipsilateral hemifield. This pattern was most pronounced in the upper visual field. In agreement with the "Boston" physiology, injections of retrograde tracer made in area 17 usually label neurons in either lamina A or the part of lamina A1 that is aberrantly innervated by the contralateral eye. A column of labeled cells extending through all geniculate layers is rarely seen in albinos, although this is commonly the pattern in pigmented ferrets.