Evidence for the late MMN as a neurophysiological endophenotype for dyslexia.

Dyslexia affects 5-10% of school-aged children and is therefore one of the most common learning disorders. Research on auditory event related potentials (AERP), particularly the mismatch negativity (MMN) component, has revealed anomalies in individuals with dyslexia to speech stimuli. Furthermore, candidate genes for this disorder were found through molecular genetic studies. A current challenge for dyslexia research is to understand the interaction between molecular genetics and brain function, and to promote the identification of relevant endophenotypes for dyslexia. The present study examines MMN, a neurophysiological correlate of speech perception, and its potential as an endophenotype for dyslexia in three groups of children. The first group of children was clinically diagnosed with dyslexia, whereas the second group of children was comprised of their siblings who had average reading and spelling skills and were therefore "unaffected" despite having a genetic risk for dyslexia. The third group consisted of control children who were not related to the other groups and were also unaffected. In total, 225 children were included in the study. All children showed clear MMN activity to/da/-/ba/contrasts that could be separated into three distinct MMN components. Whilst the first two MMN components did not differentiate the groups, the late MMN component (300-700 ms) revealed significant group differences. The mean area of the late MMN was attenuated in both the dyslexic children and their unaffected siblings in comparison to the control children. This finding is indicative of analogous alterations of neurophysiological processes in children with dyslexia and those with a genetic risk for dyslexia, without a manifestation of the disorder. The present results therefore further suggest that the late MMN might be a potential endophenotype for dyslexia

What does the brain of children with developmental dyslexia tell us about reading improvement? ERP evidence from an intervention study

Intervention is key to managing developmental dyslexia (DD), but not all children with DD benefit from treatment. Some children improve (improvers, IMP), whereas others do not improve (non-improvers, NIMP). Neurobiological differences between IMP and NIMP have been suggested, but studies comparing IMP and NIMP in childhood are missing. The present study examined whether ERP patterns change with treatment and differ between IMP and NIMP. We investigated the ERPs of 28 children with DD and 25 control children (CON) while performing a phonological lexical decision (PLD) task before and after a 6-month intervention. After intervention children with DD were divided into IMP (n = 11) and NIMP (n = 17). In the PLD-task children were visually presented with words, pseudohomophones, pseudowords, and false fonts and had to decide whether the presented stimulus sounded like an existing German word or not. Prior to intervention IMP showed higher N300 amplitudes over fronto-temporal electrodes compared to NIMP and CON and N400 amplitudes were attenuated in both IMP and NIMP compared to CON. After intervention N300 amplitudes of IMP were comparable to those of CON and NIMP. This suggests that the N300, which has been related to phonological access of orthographic stimuli and integration of orthographic and phonological representations, might index a compensatory mechanism or precursor that facilitates reading improvement. The N400, which is thought to reflect grapheme-phoneme conversion or the access to the orthographic lexicon increased in IMP from pre to post and was comparable to CON after intervention. Correlations between N300 amplitudes pre, growth in reading ability and N400 amplitudes post indicated that higher N300 amplitudes might be important for reading improvement and increase in N400 amplitudes showing the same cognitive profile might differ regarding their neuronal profile which could further influence reading improvement

The time course of reading processes in children with and without dyslexia: an ERP study

The main diagnostic criterion for developmental dyslexia (DD) in transparent orthographies is a remarkable reading speed deficit, which is often accompanied by spelling difficulties. These deficits have been traced back to both deficits in orthographic and phonological processing. For a better understanding of the reading speed deficit in DD it is necessary to clarify which processing steps are degraded in children with DD during reading. In order to address this question the present study used EEG to investigate three reading related ERPs: the N170, N400 and LPC. Twenty-nine children without DD and 52 children with DD performed a phonological lexical decision (PLD)-task, which tapped both orthographic and phonological processing. Children were presented with words, pseudohomophones, pseudowords and false fonts and had to decide whether the presented stimulus sounded like an existing German word or not. Compared to control children, children with DD showed deficits in all the investigated ERPs. Firstly, a diminished mean area under the curve for the word material-false font contrasts in the time window of the N170 was observed, indicating a reduced degree of print sensitivity; secondly, N400 amplitudes, as suggested to reflect the access to the orthographic lexicon and grapheme-phoneme conversion, were attenuated; and lastly, phonological access as indexed by the LPC was degraded in children with DD. Processing differences dependent on the linguistic material in children without DD were observed only in the LPC, suggesting that similar reading processes were adopted independent of orthographic familiarity. The results of this study suggest that effective treatment should include both orthographic and phonological training. Furthermore, more longitudinal studies utilizing the same task and stimuli are needed to clarify how these processing steps and their time course change during reading development

Does the late positive component reflect successful reading acquisition? A longitudinal ERP study

Developmental dyslexia is a reading disorder that is associated with deficits in phonological processing, where the exact neural basis for those processing deficits remains unclear. In particular, disagreement exists whether degraded phonological representations or an impaired access to the phonological representations causes these deficits. To investigate this question and to trace changes in neurophysiology during the process of reading acquisition, we designed a longitudinal study with event related potentials (ERPs) in children between kindergarten and second grade. We used an explicit word processing task to elicit the late positive component (LPC), which has been shown to reflect phonological processing. A brain-wide analysis of the LPC with an electrode-wise application of mixed effects models showed significantly attenuated amplitudes in the left temporo-parietal region in dyslexic children. Since these differences were only present in the word and not in the picture (i.e. control) condition, the attenuated amplitudes might reflect impaired access to the phonological representations of words. This was further confirmed by the longitudinal development, which showed a rapid increase in amplitude at the beginning of reading instruction and a decrease with continuing automatization, possibly pointing to a progression from grapheme-phoneme parsing to whole word reading. Our longitudinal study provides the first evidence that it is possible to detect neurophysiological differences in the LPC between children with dyslexia and control children in both preliterate and very early stages of reading acquisition, providing new insights about the neurophysiological development and a potential marker of later reading problems

Reproducibility of Brain Responses: High for Speech Perception, Low for Reading Difficulties

Neuroscience findings have recently received critique on the lack of replications. To examine the reproducibility of brain indices of speech sound discrimination and their role in dyslexia, a specific reading difficulty, brain event-related potentials using EEG were measured using the same cross-linguistic passive oddball paradigm in about 200 dyslexics and 200 typically reading 8-12-year-old children from four countries with different native languages. Brain responses indexing speech and non-speech sound discrimination were extremely reproducible, supporting the validity and reliability of cognitive neuroscience methods. Significant differences between typical and dyslexic readers were found when examined separately in different country and language samples. However, reading group differences occurred at different time windows and for different stimulus types between the four countries. This finding draws attention to the limited generalizability of atypical brain response findings in children with dyslexia across language environments and raises questions about a common neurobiological factor for dyslexia. Our results thus show the robustness of neuroscience methods in general while highlighting the need for multi-sample studies in the brain research of language disorders

Development of a Surface Plasmon Resonance Biosensor for Real-Time Detection of Osteogenic Differentiation in Live Mesenchymal Stem Cells

Surface plasmon resonance (SPR) biosensors have been recognized as a useful tool and widely used for real-time dynamic analysis of molecular binding affinity because of its high sensitivity to the change of the refractive index of tested objects. The conventional methods in molecular biology to evaluate cell differentiation require cell lysis or fixation, which make investigation in live cells difficult. In addition, a certain amount of cells are needed in order to obtain adequate protein or messenger ribonucleic acid for various assays. To overcome this limitation, we developed a unique SPR-based biosensing apparatus for real-time detection of cell differentiation in live cells according to the differences of optical properties of the cell surface caused by specific antigen-antibody binding. In this study, we reported the application of this SPR-based system to evaluate the osteogenic differentiation of mesenchymal stem cells (MSCs). OB-cadherin expression, which is up-regulated during osteogenic differentiation, was targeted under our SPR system by conjugating antibodies against OB-cadherin on the surface of the object. A linear relationship between the duration of osteogenic induction and the difference in refractive angle shift with very high correlation coefficient was observed. To sum up, the SPR system and the protocol reported in this study can rapidly and accurately define osteogenic maturation of MSCs in a live cell and label-free manner with no need of cell breakage. This SPR biosensor will facilitate future advances in a vast array of fields in biomedical research and medical diagnosis

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy

Sequence comparison of prefrontal cortical brain transcriptome from a tame and an aggressive silver fox (Vulpes vulpes)

<p>Abstract</p> <p>Background</p> <p>Two strains of the silver fox (<it>Vulpes vulpes</it>), with markedly different behavioral phenotypes, have been developed by long-term selection for behavior. Foxes from the tame strain exhibit friendly behavior towards humans, paralleling the sociability of canine puppies, whereas foxes from the aggressive strain are defensive and exhibit aggression to humans. To understand the genetic differences underlying these behavioral phenotypes fox-specific genomic resources are needed.</p> <p>Results</p> <p>cDNA from mRNA from pre-frontal cortex of a tame and an aggressive fox was sequenced using the Roche 454 FLX Titanium platform (> 2.5 million reads & 0.9 Gbase of tame fox sequence; >3.3 million reads & 1.2 Gbase of aggressive fox sequence). Over 80% of the fox reads were assembled into contigs. Mapping fox reads against the fox transcriptome assembly and the dog genome identified over 30,000 high confidence fox-specific SNPs. Fox transcripts for approximately 14,000 genes were identified using SwissProt and the dog RefSeq databases. An at least 2-fold expression difference between the two samples (p < 0.05) was observed for 335 genes, fewer than 3% of the total number of genes identified in the fox transcriptome.</p> <p>Conclusions</p> <p>Transcriptome sequencing significantly expanded genomic resources available for the fox, a species without a sequenced genome. In a very cost efficient manner this yielded a large number of fox-specific SNP markers for genetic studies and provided significant insights into the gene expression profile of the fox pre-frontal cortex; expression differences between the two fox samples; and a catalogue of potentially important gene-specific sequence variants. This result demonstrates the utility of this approach for developing genomic resources in species with limited genomic information.</p

Global Patterns and Controls of Nutrient Immobilization On Decomposing Cellulose In Riverine Ecosystems

Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature