Fahimeh Darki

Three Dyslexia Susceptibility Genes, DYX1C1, DCDC2, and KIAA0319, Affect Temporo-Parietal White Matter Structure

BACKGROUND Volume and integrity of white matter correlate with reading ability, but the underlying factors contributing to this variability are unknown. METHODS We investigated single nucleotide polymorphisms in three genes previously associated with dyslexia and implicated in neuronal migration (DYX1C1, DCDC2, KIAA0319) and white matter volume in a cohort of 76 children and young adults from the general population. RESULTS We found that all three genes contained polymorphisms that were significantly associated with white matter volume in the left temporo-parietal region and that white matter volume influenced reading ability. CONCLUSIONS The identified region contained white matter pathways connecting the middle temporal gyrus with the inferior parietal lobe. The finding links previous neuroimaging and genetic results and proposes a mechanism underlying variability in reading ability in both normal and impaired readers.

The Role of Fronto-Parietal and Fronto-Striatal Networks in the Development of Working Memory: A Longitudinal Study

The increase in working memory (WM) capacity is an important part of cognitive development during childhood and adolescence. Cross-sectional analyses have associated this development with higher activity, thinner cortex, and white matter maturation in fronto-parietal networks. However, there is still a lack of longitudinal data showing the dynamics of this development and the role of subcortical structures. We included 89 individuals, aged 6-25 years, who were scanned 1-3 times at 2-year intervals. Functional magnetic resonance imaging (fMRI) was used to identify activated areas in superior frontal, intraparietal cortices, and caudate nucleus during performance on a visuo-spatial WM task. Probabilistic tractography determined the anatomical pathways between these regions. In the cross-sectional analysis, WM capacity correlated with activity in frontal and parietal regions, cortical thickness in parietal cortex, and white matter structure [both fractional anisotropy (FA) and white matter volume] of fronto-parietal and fronto-striatal tracts. However, in the longitudinal analysis, FA in white matter tracts and activity in caudate predicted future WM capacity. The results show a dynamic of neural networks underlying WM development in which cortical activity and structure relate to current capacity, while white matter tracts and caudate activity predict future WM capacity.

Music practice is associated with development of working memory during childhood and adolescence

Practicing a musical instrument is associated with cognitive benefits and structural brain changes in correlational and interventional trials; however, the effect of musical training on cognition during childhood is still unclear. In this longitudinal study of child development we analyzed the association between musical practice and performance on reasoning, processing speed and working memory (WM) during development. Subjects (n = 352) between the ages of 6 and 25 years participated in neuropsychological assessments and neuroimaging investigations (n = 64) on two or three occasions, 2 years apart. Mixed model regression showed that musical practice had an overall positive association with WM capacity (visuo-spatial WM, F = 4.59, p = 0.033, verbal WM, F = 9.69, p = 0.002), processing speed, (F = 4.91, p = 0.027) and reasoning (Raven’s progressive matrices, F = 28.34, p < 0.001) across all three time points, after correcting for the effect of parental education and other after school activities. Music players also had larger gray matter volume in the temporo-occipital and insular cortex (p = 0.008), areas previously reported to be related to musical notation reading. The change in WM between the time points was proportional to the weekly hours spent on music practice for both WM tests (VSWM, β = 0.351, p = 0.003, verbal WM, β = 0.261, p = 0.006) but this was not significant for reasoning ability (β = 0.021, p = 0.090). These effects remained when controlling for parental education and other after school activities. In conclusion, these results indicate that music practice positively affects WM development and support the importance of practice for the development of WM during childhood and adolescence.

The Dyslexia Candidate Locus on 2p12 Is Associated with General Cognitive Ability and White Matter Structure

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.

DCDC2 Polymorphism Is Associated with Left Temporoparietal Gray and White Matter Structures during Development

Three genes, DYX1C1, DCDC2, and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth.

CTNND2—a candidate gene for reading problems and mild intellectual disability

Background Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders. Methods and results Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patients mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon. Conclusions Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.

Quantitative susceptibility mapping of striatum in children and adults, and its association with working memory performance

Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique in which the magnetic susceptibility characteristic of molecular and cellular components, including iron and myelin, is quantified. Rapid iron accumulation in subcortical nuclei and myelination of the white matter tracts are two important developmental processes that contribute to cognitive functions. Both also contribute to the magnetic susceptibility of the brain tissues. Here, we used the QSM as indirect measures of iron in subcortical nuclei and myelin in caudo-frontal white matter pathways. We included two groups of participants; 21 children aged 6-7years and 25 adults aged 21-40years. All subjects also performed tests estimating their visuo-spatial working memory capacity. Adults had higher magnetic susceptibility in all subcortical nuclei, compared to children. The magnetic susceptibility of these nuclei highly correlated with their previously reported iron content. Moreover, working memory performance correlated significantly with the magnetic susceptibility in caudate nucleus in both children and adults, while the correlation was not significant for gray matter density. QSM of white matter in the caudo-frontal tract also differed between children and adults, but did not correlate with working memory scores. These results indicate that QSM is a feasible technique to measure developmental aspects of changes in the striatum, possibly related to iron content that is relevant to cognition.

False positive control of activated voxels in single fMRI analysis using bootstrap resampling in comparison to spatial smoothing

Functional magnetic resonance imaging (fMRI) is an effective tool for the measurement of brain neuronal activities. To date, several statistical methods have been proposed for analyzing fMRI datasets to select true active voxels among all the voxels appear to be positively activated. Finding a reliable and valid activation map is very important and becomes more crucial in clinical and neurosurgical investigations of single fMRI data, especially when pre-surgical planning requires accurate lateralization index as well as a precise localization of activation map. Defining a proper threshold to determine true activated regions, using common statistical processes, is a challenging task. This is due to a number of variation sources such as noise, artifacts, and physiological fluctuations in time series of fMRI data which affect spatial distribution of noise in an expected uniform activated region. Spatial smoothing methods are frequently used as a preprocessing step to reduce the effect of noise and artifacts. The smoothing may lead to a shift and enlargement of activation regions, and in some extend, unification of distinct regions. In this article, we propose a bootstrap resampling technique for analyzing single fMRI dataset with the aim of finding more accurate and reliable activated regions. This method can remove false positive voxels and present high localization accuracy in activation map without any spatial smoothing and statistical threshold setting.

Accurate activation map detection using bootstrap resampling of single fMRI data

Functional magnetic resonance imaging (fMRI) is an effective method for measuring the brain neuronal activities. Numerous statistical methods are used for fMRI analyzing. However, determining the true activated regions among the whole apparent activated voxels is a vital but challenging task. The activation pattern of fMRI data analysis is affected under the presence of source of variations such as noise, artifacts, and physiological fluctuations. Finding an accurate and reliable activation map from a single data analysis is essential for true interpretation of an individual data especially when it should be used in neurosurgical planning. We introduced a resampling process (called Bootstrapping) through the original EPI data, with the aim of evaluating the reproducibility of the activation changes throughout a task-related signal variation.

Identification of NCAN as a candidate gene for developmental dyslexia

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.