The form of reference frames in vision: The case of intermediate shape-centered representations.

Although a great deal is known about the early sensory and the later, perceptual, stages of visual processing, far less is known about the nature of intermediate representational units and reference frames. Progress in understanding intermediate levels of representations in vision is hindered by the complexity of interactions among multiple levels of representation in the visual system, making it difficult to isolate and study the nature of each particular level. Nature occasionally provides the opportunity to peer inside complex systems by isolating components of a system through accidental damage or genetic modification of neural components. We have recently reported the case of a young woman who perceives 2D bounded regions of space as if they were plane-rotated by 90, 180 or 270° around their center, mirrored across their own axes, or both. This suggested that an intermediate stage of processing consists in representing mutually exclusive 2D bounded regions extracted from the retinal image in their own "shape-centered" perceptual frame. We proposed to refer to this level of representation as "intermediate shape-centered representation" (ISCR). Here, we used Davida's pattern of errors across 9 experiments as a tool for specifying in greater detail the geometrical properties of the reference frame in which elongated and/or symmetrical shapes are represented at the level of the ISCR. The nature of Davida's errors in these experiments suggests that ISCRs are represented in reference frames composed of orthogonal axes aligned with and centered on the most elongated segment of elongated shapes and, for symmetrical shapes deprived of a straight segment, aligned with their axis of symmetry, and centered on their centroid.

Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability.

Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing (RAP), visual attention and working memory. Genetic variants in Doublecortin domain-containing protein 2 (DCDC2) have been associated with dyslexia, impairments in phonological processing and in short-term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre-pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working vs. reference memory) and rotarod (to examine sensorimotor ability and motor learning), were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in RAP, working memory and reference memory in Dcdc2(del2/del2) mice when compared with matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability.

Genetic mapping of brain plasticity across development in Williams syndrome: ERP markers of face and language processing.

In Williams Syndrome (WS), a known genetic deletion results in atypical brain function with strengths in face and language processing. We examined how genetic influences on brain activity change with development. In three studies, event-related potentials (ERPs) from large samples of children, adolescents, and adults with the full genetic deletion for WS were compared to typically developing controls, and two adults with partial deletions for WS. Studies 1 and 2 identified ERP markers of brain plasticity in WS across development. Study 3 suggested that, in adults with partial deletions for WS, specific genes may be differentially implicated in face and language processing.

Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders.

Developmental dyslexia, the most common childhood learning disorder, is highly heritable, and recent studies have identified KIAA0319-Like (KIAA0319L) as a candidate dyslexia susceptibility gene at the 1p36-34 (DYX8) locus. In this experiment, we investigated the anatomical effects of knocking down this gene during rat corticogenesis. Cortical progenitor cells were transfected using in utero electroporation on embryonic day (E) 15.5 with plasmids encoding either: (1) Kiaa0319l small hairpin RNA (shRNA), (2) an expression construct for human KIAA0319L, (3) Kiaa0319l shRNA+KIAA0319L expression construct (rescue), or (4) controls (scrambled Kiaa0319l shRNA or empty expression vector). Mothers were injected with 5-bromo-2-deoxyuridine (BrdU) at either E13.5, E15.5, or E17.5. Disruption of Kiaa0319l function (by knockdown, overexpression, or rescue) resulted in the formation of large nodular periventricular heterotopia in approximately 25% of the rats, which can be seen as early as postnatal day 1. Only a small subset of heterotopic neurons had been transfected, indicating non-cell autonomous effects of the transfection. Most heterotopic neurons were generated in mid- to late-gestation, and laminar markers suggest that they were destined for upper cortical laminae. Finally, we found that transfected neurons in the cerebral cortex were located in their expected laminae. These results indicate that KIAA0319L is the fourth of four candidate dyslexia susceptibility genes that is involved in neuronal migration, which supports the association of abnormal neuronal migration with developmental dyslexia.

Dcdc2 knockout mice display exacerbated developmental disruptions following knockdown of doublecortin.

The dyslexia-associated gene DCDC2 is a member of the DCX family of genes known to play roles in neurogenesis, neuronal migration, and differentiation. Here we report the first phenotypic analysis of a Dcdc2 knockout mouse. Comparisons between Dcdc2 knockout mice and wild-type (wt) littermates revealed no significant differences in neuronal migration, neocortical lamination, neuronal cilliogenesis or dendritic differentiation. Considering previous studies showing genetic interactions and potential functional redundancy among members of the DCX family, we tested whether decreasing Dcx expression by RNAi would differentially impair neurodevelopment in Dcdc2 knockouts and wild-type mice. Consistent with this hypothesis, we found that deficits in neuronal migration, and dendritic growth caused by RNAi of Dcx were more severe in Dcdc2 knockouts than in wild-type mice with the same transfection. These results indicate that Dcdc2 is not required for neurogenesis, neuronal migration or differentiation in mice, but may have partial functional redundancy with Dcx.

The effects of embryonic knockdown of the candidate dyslexia susceptibility gene homologue Dyx1c1 on the distribution of GABAergic neurons in the cerebral cortex.

Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1, KIAA0319, and DCDC2. Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these genes dramatically disrupts neuronal migration to the cerebral cortex by both cell autonomous and non-cell autonomous effects. Here we sought to investigate the extent of non-cell autonomous effects following in utero disruption of the candidate dyslexia susceptibility gene homolog Dyx1c1 by assessing the effects of this disruption on GABAergic neurons. We transfected the ventricular zone of embryonic day (E) 15.5 rat pups with either Dyx1c1 shRNA, DYX1C1 expression construct, both Dyx1c1 shRNA and DYX1C1 expression construct, or a scrambled version of Dyx1c1 shRNA, and sacrificed them at postnatal day 21. The mothers of these rats were injected with BrdU at either E13.5, E15.5, or E17.5. Neurons transfected with Dyx1c1 shRNA were bi-modally distributed in the cerebral cortex with one population in heterotopic locations at the white matter border and another migrating beyond their expected location in the cerebral cortex. In contrast, there was no disruption of migration following transfection with the DYX1C1 expression construct. We found untransfected GABAergic neurons (parvalbumin, calretinin, and neuropeptide Y) in the heterotopic collections of neurons in Dyx1c1 shRNA treated animals, supporting the hypothesis of non-cell autonomous effects. In contrast, we found no evidence that the position of the GABAergic neurons that made it to the cerebral cortex was disrupted by the embryonic transfection with any of the constructs. Taken together, these results support the notion that neurons within heterotopias caused by transfection with Dyx1c1 shRNA result from both cell autonomous and non-cell autonomous effects, but there is no evidence to support non-cell autonomous disruption of neuronal position in the cerebral cortex itself.

Spectral processing deficits in belt auditory cortex following early postnatal lesions of somatosensory cortex.

Induced or genetically based cortical laminar malformations in somatosensory cortex have been associated with perceptual and acoustic processing deficits in mammals. Perinatal freeze-lesions of developing rat primary somatosensory (S1) cortex induce malformations resembling human microgyria. Induced microgyria located in parietal somatosensory cortex have been linked to reduced behavioral detection of rapid sound transitions and altered spectral processing in primary auditory cortex (A1). Here we asked whether belt auditory cortex function would be similarly altered in rats with S1 microgyria (MG+). Pure-tone acoustic response properties were assessed in A1 and ventral auditory (VAF) cortical fields with Fourier optical imaging and multi-unit recordings. Three changes in spectral response properties were observed in both A1 and VAF in MG+ rats: 1) multi-unit response magnitudes were reduced 2) optical and multi-unit frequency responses were more variable; 3) at high sound levels units responded to a broader range of pure-tone frequencies. Optical and multi-unit pure-tone response magnitudes were both reduced for low sound levels in VAF but not A1. Sound level "tuning" was reduced in VAF but not in A1. Finally, in VAF frequency tuning and spike rates near best frequency were both altered for mid- but not high-frequency recording sites. These data suggest that VAF belt auditory cortex is more vulnerable than A1 to early postnatal induction of microgyria in neighboring somatosensory cortex.

Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat.

Embryonic knockdown of candidate dyslexia susceptibility gene (CDSG) homologs in cerebral cortical progenitor cells in the rat results in acute disturbances of neocortical migration. In the current report we investigated the effects of embryonic knockdown and overexpression of the homolog of DCDC2, one of the CDSGs, on the postnatal organization of the cerebral cortex. Using a within-litter design, we transfected cells in rat embryo neocortical ventricular zone around embryonic day (E) 15 with either 1) small hairpin RNA (shRNA) vectors targeting Dcdc2, 2) a DCDC2 overexpression construct, 3) Dcdc2 shRNA along with DCDC2 overexpression construct, 4) an overexpression construct composed of the C terminal domain of DCDC2, or 5) an overexpression construct composed of the DCX terminal domain of DCDC2. RNAi of Dcdc2 resulted in pockets of heterotopic neurons in the periventricular region. Approximately 25% of the transfected brains had hippocampal pyramidal cell migration anomalies. Dcdc2 shRNA-transfected neurons migrated in a bimodal pattern, with approximately 7% of the neurons migrating a short distance from the ventricular zone, and another 30% migrating past their expected lamina. Rats transfected with Dcdc2 shRNA along with the DCDC2 overexpression construct rescued the periventricular heterotopia phenotype, but did not affect the percentage of transfected neurons that migrate past their expected laminar location. There were no malformations associated with any of the overexpression constructs, nor was there a significant laminar disruption of migration. These results support the claim that knockdown of Dcdc2 expression results in neuronal migration disorders similar to those seen in the brains of dyslexics.

Early cortical damage in rat somatosensory cortex alters acoustic feature representation in primary auditory cortex.

Early postnatal freeze-lesions to the cortical plate result in malformations resembling human microgyria. Microgyria in primary somatosensory cortex (S1) of rats are associated with a reduced behavioral detection of rapid auditory transitions and the loss of large cells in the thalamic nucleus projecting to primary auditory cortex (A1). Detection of slow transitions in sound is intact in animals with S1 microgyria, suggesting dissociation between responding to slow versus rapid transitions and a possible dissociation between levels of auditory processing affected. We hypothesized that neuronal responses in primary auditory cortex (A1) would be differentially reduced for rapid sound repetitions but not for slow sound sequences in animals with S1 microgyria. We assessed layer IV cortical responses in primary auditory cortex (A1) to single pure-tones and periodic noise bursts (PNB) in rats with and without S1 microgyria. We found that responses to both types of acoustic stimuli were reduced in magnitude in animals with microgyria. Furthermore, spectral resolution was degraded in animals with microgyria. The cortical selectivity and temporal precision were then measured with conventional methods for PNB and tone-stimuli, but no significant changes were observed between microgyric and control animals. Surprisingly, the observed spike rate reduction was similar for rapid and slow temporal modulations of PNB stimuli. These results suggest that acoustic processing in A1 is indeed altered with early perturbations of neighboring cortex. However, the type of deficit does not affect the temporal dynamics of the cortical output. Instead, acoustic processing is altered via a systematic reduction in the driven spike rate output and spectral integration resolution in A1. This study suggests a novel form of plasticity, whereas early postnatal lesions of one sensory cortex can have a functional impact on processing in neighboring sensory cortex.

DYX1C1 functions in neuronal migration in developing neocortex.

Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1's function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.

The neurobiology of Williams syndrome: cascading influences of visual system impairment?

Williams syndrome (WS) is characterized by a unique pattern of cognitive, behavioral, and neurobiological findings that stem from a microdeletion of genes on chromosome 7. Visuospatial ability is particularly affected in WS and neurobiological studies of WS demonstrate atypical function and structure in posterior parietal, thalamic, and cerebellar regions that are important for performing space-based actions. This review summarizes the neurobiological findings in WS, and, based on these findings, we suggest that people with WS have a primary impairment in neural systems that support the performance of space-based actions. We also examine the question of whether impaired development of visual systems could affect the development of atypical social-emotional and language function in people with WS. Finally, we propose developmental explanations for the visual system impairments in WS. While hemizygosity for the transcription factor II-I gene family probably affects the development of visual systems, we also suggest that Lim-kinase 1 hemizygosity exacerbates the impairments in performing space-based actions.

Histometric changes and cell death in the thalamus after neonatal neocortical injury in the rat.

Freezing injury to the developing cortical plate results in a neocortical malformation resembling four-layered microgyria. Previous work has demonstrated that following freezing injury to the somatosensory cortex, males (but not females) have more small and fewer large cells in the medial geniculate nucleus. In the first experiment, we examined the effects of induced microgyria to the somatosensory cortex on neuronal numbers, neuronal size, and nuclear volume of three sensory nuclei: ventrobasal complex, dorsal lateral geniculate nucleus, and medial geniculate nucleus. We found that there was a decrease in neuronal number and nuclear volume in ventrobasal complex of microgyric rats when compared with shams, whereas there were no differences in these variables in the dorsal lateral geniculate nucleus or medial geniculate nucleus. We also found that there were more small and fewer large neurons in both ventrobasal complex and medial geniculate nucleus. In experiment 2, we attempted to determine the role of cell death in the thalamus on these histometric measures. We found that cell death peaked within 24 h of the freezing injury and was concentrated mostly in ventrobasal complex. In addition, there was evidence of greater cell death in males at this age. Taken together, these results support the notion that males are more severely affected by early injury to the cerebral cortex than females.

Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia.

OBJECTIVE: To define the behavioral profile of periventricular nodular heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. METHODS: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. RESULTS: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. CONCLUSION: The neuronal migration disorder of periventricular nodular heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence.

Evidence for superior parietal impairment in Williams syndrome.

Parietal lobe impairment is hypothesized to contribute to the dramatic visual-spatial deficits in Williams syndrome (WS). The authors examined the superior and inferior parietal lobule in 17 patients with WS and 17 control female adults (CNLs). The right and left superior parietal lobule gray matter volumes were significantly smaller in patients with WS than in CNLs, even after controlling for total cerebral gray matter. Impaired superior parietal function could explain WS visual-spatial and visual-motor problems.

[Developmental dyslexia]. / Dislexia del desarrollo.

Developmental dyslexia makes up an important proportion of the known learning disorders. Until the late 1970s most research on dyslexia was carried out by educators and educational psychologists, but soon after the publication of some dyslexic cases with focal disorders of neuronal migration to the cerebral cortex, interest in the neurobiological and neurocognitive underpinnings of dyslexia grew, especially in Europe and North America. There are at least two types of developmental dyslexia--phonological and surface. Surface dyslexia refers to a disorder in which the difficulty lies in reading irregular words, whereas phonological dyslexia is characterized by difficulty with pseudowords. Phonological dyslexia is the more common of the two types. Surface dyslexia does not present a major problem in a language such as Spanish, where the number of irregular words is indeed very small. Still, in languages such as English, where irregular words are common, the phonological type of developmental dyslexia is much more common. Phonologic dyslexics have problems with phonological awareness, that is, the conscious knowledge and manipulation of speech sounds, which is the most proximate explanation for their difficulty in reading pseudowords. Many, but not all, phonologic dyslexics also have problems processing rapidly changing sounds, even if not linguistic, and some slow sounds, too. The same group tends to have visual problems, especially involving the so-called magnocellular pathway of the visual system, which, among others, has the role of analyzing movement. Accompanying these perceptual and cognitive deficits, phonologic dyslexics also show abnormal brain activation to phonological tasks, as shown in functional magnetic resonance studies (figure). In addition, dyslexic brains show focal malformations, ectopias and microgyria, of the cerebral cortex, involving mainly the left perisylvian region and the word form area in the temporo-occipital junction. There are also changes in the composition of neurons in the lateral and medial geniculate nuclei of the thalamus. Experimental studies indicate that the thalamic changes are a consequence of the focal malformations, and that they are responsible for the sound processing deficits. None of these discoveries have changed the therapeutic modalities in this condition, but it is hoped that this will be the next area of progress.

[Williams syndrome. A summary of cognitive, electrophysiological, anatomofunctional, microanatomical and genetic findings]. / El síndrome de Williams. Un resumen de hallazgos cognitivos, electrofisiológicos, anatomofuncionales, microanatómicos y genéticos.

Williams syndrome (WS) is the result of a hemideletion of about 17 genes in the q11.22-23 region of chromosome 7. Patients with WS show unique phenotypic features that include elfin face, heart malformations, calcium metabolism problems and learning disorders. The latter consist of mental retardation that is characterised by serious difficulties with processing visuospatial tasks, a striking ability to easily recognise faces, a relatively developed linguistic capacity and sensitiveness to sound, a strong need to establish affective ties with other people and a fondness for music. Anatomical studies show a decrease in the postero-dorsal parts of both hemispheres of the brain, malformation in the central dorsal region and an expansion of the superior temporal gyrus, of the amygdala and of the frontal lobe. These macroscopic anomalies are accompanied by microscopic anomalies, which consist of changes in the number and size of the neurons. Studies on evoked potentials show acoustic hyperexcitability and abnormal waves related to language and to faces. Genetic studies in our laboratories show that the exact size of the deletion can vary, which means partial cases also exist and have partial phenotypes. Combining behavioural, electrophysiological, anatomical and genetic reports suggests a problem with the posterior dorsal region of the brain, possibly resulting from mistakes in establishing the dorsoventral and caudorostral genetico-molecular gradients, which specify the cortical regions during development.

Dorsal forebrain anomaly in Williams syndrome.

BACKGROUND: Williams syndrome (WMS) is a rare neurogenetic condition with a behavioral phenotype that suggests a dorsal and/or ventral developmental dissociation, with deficits in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus has been observed in autopsy specimens. OBJECTIVE: To compare gross anatomical features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in brain magnetic resonance images from a sample of subjects with WMS and age- and sex-matched control subjects. SUBJECTS: Twenty-one subjects having clinically and genetically diagnosed WMS (mean +/- SD age, 28.9 +/- 7.9 years) were compared with 21 age- and sex-matched typically developing controls (mean +/- SD age, 28.8 +/- 7.9 years). DESIGN: High-resolution structural magnetic resonance images were acquired. The extent of the central sulcus was qualitatively assessed via surface projections of the cerebral cortex. RESULTS: The dorsal central sulcus is less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both left (P< .001, chi(2) = 15.79) and right (P< .001, chi(2) = 12.95) hemispheres. No differences between the groups were found in the ventral extent of the central sulcus. CONCLUSIONS: Anomalies in the dorsal region in patients with WMS are indicative of early neurodevelopmental problems affecting the development of the dorsal forebrain and are most likely related to the deficits in visuospatial ability and behavioral timing often observed in this condition.

Unilateral induced neocortical malformation and the formation of ipsilateral and contralateral barrel fields.

Freezing lesions to the developing cortical plate of rodents results in a focal malformation resembling human 4-layered microgyria, and this malformation has been shown to result in local and widespread disruptions of neuronal architecture, connectivity, and physiology. Because we had previously demonstrated that microgyria caused disruptions in callosal connections, we hypothesized that freeze lesions to the postero-medial barrel sub-field (PMBSF) in one hemisphere would affect the organization of this barrel field contralaterally. We placed freeze lesions in the presumptive PMBSF of neonatal rats and, in adulthood, assessed the architecture of the ipsilateral and contralateral barrel fields. Malformations in the PMBSF resulted in a substantial decrease in the number of barrels as identified by cytochrome oxidase activity. More importantly, we found an increase in the total area of the contralateral PMBSF, although there was no difference in individual barrel cross-sectional areas, indicating an increase in the area of inter-barrel septae. This increase in the septal area of the contralateral PMBSF is consistent with changes in callosal and/or thalamic connectivity in the contralateral hemisphere. These results are another example of both local and widespread disruption of connectional architecture following induction of focal microgyria.

Single cause, polymorphic neuronal migration disorders: an animal model.

Injury to the developing cortical plate can result in a variety of neuronal migration disorders. The results are reported of experimental research aimed at determining whether these different types of neocortical malformations are the consequence of comparable injury of varying intensity. Freezing probes were placed on the skulls of 44 newborn rats (age equivalent to 4 to 5 months of gestation in humans) and induced either one or two freezing injuries of durations ranging from 2 to 20 seconds. A variety of cortical malformations including minor laminar dysplasias, molecular layer ectopias, microgyria, and porencephalic cysts were seen in the brains of these animals when they were examined on postnatal day (P)2, P21, and P60. The severity of the malformation was directly related to the strength (number of hits and duration) of the freezing injury. These results suggest that a single etiologic event of varying severity during neuronal migration to the neocortex can induce widely disparate malformations of the cortex.

Connectivity of ectopic neurons in the molecular layer of the somatosensory cortex in autoimmune mice.

Approximately 50% of New Zealand Black mice (NZB/BINJ) and 80% of NXSM-D/EiJ mice prenatally develop neocortical layer I ectopias, mostly in somatosensory cortices. These cortical anomalies are similar to those seen in the brains of individuals with dyslexia. Neurofilament staining revealed a radial column of tightly packed fiber bundles in the layers underlying ectopias. This suggested that the connectivity of the ectopic neurons was aberrant. The present study used the tracers 1,1'-dioctadecyl- 3,3,3',3'-tetramethylindo- carbocyanine perchlorate (DiI) and biotinylated dextran amine (BDA) to more thoroughly explore the cortical and thalamic connectivity of the ectopias. DiI placement into ectopias again revealed a distinct bundle of fibers extending from the ectopic neurons to the deep cortical layers. This bundle split in the white matter with some fibers traveling to the corpus callosum and others to the internal capsule. Thalamic connections were concentrated in the ventrobasal com- plex (VB) and posterior thalamic nucleus group (Po). Injections of BDA into VB revealed reciprocal connections between VB and the ectopic cortical neurons. Ipsilateral corticocortical projections were seen between ectopias in primary somatosensory and motor and secondary somatosensory cortices, but no contralateral connections of the ectopic neurons were seen. These findings confirm the notion that layer I ectopias are anomalously connected by comparison to neurons in homologous cortex, which may underlie widespread dysfunction of brains containing ectopias.