Orthographic Depth May Influence the Degree of Severity of Maze Learning Performance in Children at Risk for Reading Disorder.

Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most prevalent form of learning disability, and is associated with underactivation of a universal reading network in children. However, recent research suggests there are differences in learning rates on cognitive predictors of reading performance, as well as differences in activation patterns within the reading neural network, based on orthographic depth (i.e., transparent/shallow vs. deep/opaque orthographies) in children with RD. Recently, we showed that native English-speaking children with RD exhibit impaired performance on a maze learning task that taps into the same neural networks that are activated during reading. In addition, we demonstrated that genetic risk for RD strengthens the relationship between reading impairment and maze learning performance. However, it is unclear whether the results from these studies can be broadly applied to children from other language orthographies. In this study, we examined whether low reading skill was associated with poor maze learning performance in native English-speaking and native German-speaking children, and the influence of genetic risk for RD on cognition and behavior. In addition, we investigated the link between genetic risk and performance on this task in an orthographically diverse sample of children attending an English-speaking international school in Germany. The results from our data suggest that children with low reading skill, or with a genetic risk for reading impairment, exhibit impaired performance on the maze learning task, regardless of orthographic depth. However, these data also suggest that orthographic depth influences the degree of impairment on this task. The maze learning task requires the involvement of various cognitive processes and neural networks that underlie reading, but is not influenced by potential differences in reading experience due to lack of text or oral reporting. As a fully automated tool, it does not require specialized training to administer, and current results suggest it may be a practicable screening tool for early identification of reading impairment across orthographies.

Identifying Dyslexia: Link between Maze Learning and Dyslexia Susceptibility Gene, DCDC2, in Young Children.

Dyslexia is a common learning disability that affects processing of written language despite adequate intelligence and educational background. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which influence future success in all aspects of their life. Dyslexia has a 60% heritability rate, and genetic studies have identified multiple dyslexia susceptibility genes (DSGs). DSGs, such as DCDC2, are consistently associated with the risk and severity of reading disability (RD). Altered neural connectivity within temporoparietal regions of the brain is associated with specific variants of DSGs in individuals with RD. Genetically altering DSG expression in mice results in visual and auditory processing deficits as well as neurophysiological and neuroanatomical disruptions. Previously, we demonstrated that learning deficits associated with RD can be translated across species using virtual environments. In this 2-year longitudinal study, we demonstrate that performance on a virtual Hebb-Williams maze in pre-readers is able to predict future reading impairment, and the genetic risk strengthens, but is not dependent on, this relationship. Due to the lack of oral reporting and use of letters, this easy-to-use tool may be particularly valuable in a remote working environment as well as working with vulnerable populations such as English language learners.

Cellular and axonal constituents of neocortical molecular layer heterotopia.

Human neocortical molecular layer heterotopia consist of aggregations of hundreds of neurons and glia in the molecular layer (layer I) and are indicative of neuronal migration defect. Despite having been associated with dyslexia, epilepsy, cobblestone lissencephaly, polymicrogyria, and Fukuyama muscular dystrophy, a complete understanding of the cellular and axonal constituents of molecular layer heterotopia is lacking. Using a mouse model, we identify diverse excitatory and inhibitory neurons as well as glia in heterotopia based on molecular profiles. Using immunocytochemistry, we identify diverse afferents in heterotopia from subcortical neuromodulatory centers. Finally, we document intracortical projections to/from heterotopia. These data are relevant toward understanding how heterotopia affect brain function in diverse neurodevelopmental disorders.

Neuronal migration defect of the developing cerebellar vermis in substrains of C57BL/6 mice: cytoarchitecture and prevalence of molecular layer heterotopia.

Abnormal development of the cerebellum is often associated with disorders of movement, postural control, and motor learning. Rodent models are widely used to study normal and abnormal cerebellar development and have revealed the roles of many important genetic and environmental factors. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia, a malformation of neuronal migration, in the cerebellar vermis of C57BL/6 mice and closely-related strains. In particular, we found a diverse number of cell-types affected by these malformations including Purkinje cells, granule cells, inhibitory interneurons (GABAergic and glycinergic), and glia. Heterotopia were not observed in a sample of wild-derived mice, outbred mice, or inbred mice not closely related to C57BL/6 mice. These data are relevant to the use of C57BL/6 mice as models in the study of brain and behavior relationships and provide greater understanding of human cerebellar dysplasia.

Progress towards a cellular neurobiology of reading disability.

Reading Disability (RD) is a significant impairment in reading accuracy, speed and/or comprehension despite adequate intelligence and educational opportunity. RD affects 5-12% of readers, has a well-established genetic risk, and is of unknown neurobiological cause or causes. In this review we discuss recent findings that revealed neuroanatomic anomalies in RD, studies that identified 3 candidate genes (KIAA0319, DYX1C1, and DCDC2), and compelling evidence that potentially link the function of candidate genes to the neuroanatomic anomalies. A hypothesis has emerged in which impaired neuronal migration is a cellular neurobiological antecedent to RD. We critically evaluate the evidence for this hypothesis, highlight missing evidence, and outline future research efforts that will be required to develop a more complete cellular neurobiology of RD.

A feasibility study of using event-related potential as a biometrics.

The use of an individual's neural response to stimuli (the event-related potential or ERP) has potential as a biometric because it is highly resistant to fraud relative to other conventional authentication systems. P300 is an ERP in human electroencephalography (EEG) that occurs in response to an oddball stimulus when an individual is actively engaged in a target detection task. Because P300 is consistently detectable from almost every subject, it is considered a potential signal for biometric applications. This paper presents a feasibility study of using topological plots of P300 as a biometric in subject authentication. The variation in latency and location of P300 response of 24 participants performing the P300Speller task were studied. Data sets from four participants were used for algorithm training; data from the other 20 participants were used as imposters for algorithm validation. The result showed that the algorithm was able to correctly identify three out of these four participants. Validation test also proved that the algorithm was able to reject 95% of the imposters for those three authenticated participants.

Translating dyslexia across species.

Direct relationships between induced mutation in the DCDC2 candidate dyslexia susceptibility gene in mice and changes in behavioral measures of visual spatial learning have been reported. We were interested in determining whether performance on a visual-spatial learning and memory task could be translated across species (study 1) and whether children with reading impairment showed a similar impairment to animal models of the disorder (study 2). Study 1 included 37 participants who completed six trials of four different virtual Hebb-Williams maze configurations. A 2 × 4 × 6 mixed factorial repeated measures ANOVA indicated consistency in performance between humans and mice on these tasks, enabling us to translate across species. Study 2 included a total of 91 participants (age range = 8-13 years). Eighteen participants were identified with reading disorder by performance on the Woodcock-Johnson III Tests of Achievement. Participants completed six trials of five separate virtual Hebb-Williams maze configurations. A 2 × 5 × 6 mixed factorial ANCOVA (gender as covariate) indicated that individuals with reading impairment demonstrated impaired visuo-spatial performance on this task. Overall, results from this study suggest that we are able to translate behavioral deficits observed in genetic animal models of dyslexia to humans with reading impairment. Future studies will utilize the virtual environment to further explore the underlying basis for this impairment.

Visual experience regulates transient expression and dendritic localization of fragile X mental retardation protein.

Fragile X syndrome is the most common form of inherited mental retardation and is caused by the loss of function of the Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein thought to play a key role in protein synthesis-dependent synaptic plasticity. The regulation of FMRP expression itself is also likely to be an important control point in this process. Here we used dark-reared/light-exposed rats to determine the role of experience in regulating FMRP levels in the visual cortex. We find that FMRP levels increase in the cell bodies and dendrites of visual cortical neurons after as little as 15 min of light exposure. Remarkably, FMRP expression in these neurons returns to baseline levels by 30 min of light exposure. These changes were post-transcriptional because the FMR1 mRNA levels remained constant over this time period. A transient increase in FMRP levels was also observed in synaptic fractions prepared from visual cortices of light-exposed animals. In contrast, alpha-calcium/calmodulin-dependent kinase II expression showed a sustained upregulation under these conditions. Finally, the increase in FMRP expression was inhibited by blockade of NMDA receptors. This tight temporal-spatial regulation suggests that FMRP plays a dynamic role in a distinct epoch of experience-dependent synaptic plasticity.

Differential seizure response in two models of cortical heterotopia.

Malformations of cortical development (MCD) are linked to epilepsy in humans. MCD encompass a broad spectrum of malformations, which occur as the principal pathology or a secondary disruption. Recently, Rosen et al. (2012) reported that BXD29-Trl4(lps-2J)/J mice have subcortical nodular heterotopias with partial agenesis of the corpus callosum (p-ACC). Additionally Ramos et al. (2008) demonstrated that C57BL/10J mice exhibit cortical heterotopias with no additional cortical abnormalities. We examined the seizure susceptibility of these mice to determine if the presence (BXD29-Trl4(lps-2J)/J) or absence (C57BL/10J) of p-ACC, in strains with MCD, confers a differential response to chemi-convulsive treatment. Our results indicate that C57BL/10J mice with layer I heterotopia are more susceptible, whereas BXD29-Trl4(lps-2J)/J mice with more severe subcortical nodular heterotopia and p-ACC are more resistant to seizure behavior induced by pentylenetetrazole. These data suggest that p-ACC may confer seizure resistance in models of MCD.

Neocortical molecular layer heterotopia in substrains of C57BL/6 and C57BL/10 mice.

Abnormal development of the neocortex is often associated with cognitive deficits and epilepsy. Rodent models are widely used to study normal and abnormal cortical development and have revealed the roles of many important genetic and environmental factors. Interestingly, several inbred mouse strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations including C57BL/6J mice, which are among the most widely utilized mice. In the present report we describe the prevalence and cytoarchitecture of molecular-layer heterotopia in C57BL/6J mice and related strains obtained from three commercial vendors as well as mice bred in academic vivaria from founders obtained commercially. In particular, we found that the prevalence of molecular-layer heterotopia vaired according to the sex as well as the vendor-of-origin of the mouse. These data are relevant to the use of this strain as a mouse-model in the study of brain-behavior relationships.

Layer I ectopias and increased excitability in murine neocortex.

Cortical dysplasias are associated with both epilepsy and cognitive impairments in humans. Similarly, several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo and increased levels of excitability in vitro. As most current animal models involve either global disruptions in cortical architecture or the induction of lesions, it is not yet clear whether small spontaneous neocortical malformations are also associated with increased excitability or seizure susceptibility. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory-processing deficits. In a previous study, we characterized the physiology of cells within neocortical ectopias, in one of the inbred lines (NXSM-D/Ei) and showed that the presence of multiple ectopias is associated with the generation of spontaneous epileptiform activity in slices. In this study, we use extracellular recordings from brain slices to show that even single-layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of the GABA(A) receptor antagonist bicuculline than do slices without ectopias (either from opposite hemispheres or animals without ectopias). Moreover, because removal of ectopias from slices does not restore normal excitability, enhanced excitability is not generated within the ectopia. Finally, we show that in vivo, mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias. Together these results suggest that alterations in cortical hemispheres containing focal layer I malformations increase cortical excitability and that even moderately small spontaneous cortical dysplasias are associated with increased excitability in vitro and in vivo.