Changes in brain metabolite levels across childhood.

Metabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N = 101 children, 112 observations; LTP: N = 95 children, 318 observations). We found that tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only. Glx did not show linear age effects in either region, but a follow-up analysis in participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.

Reading intervention and neuroplasticity: A systematic review and meta-analysis of brain changes associated with reading intervention.

Behavioral research supports the efficacy of intervention for reading disability, but the brain mechanisms underlying improvement in reading are not well understood. Here, we review 39 neuroimaging studies of reading intervention to characterize links between reading improvement and changes in the brain. We report evidence of changes in activation, connectivity, and structure within the reading network, and right hemisphere, frontal and sub-cortical regions. Our meta-analysis of changes in brain activation from pre- to post- reading intervention in eight studies did not yield any significant effects. Methodological heterogeneity among studies may contribute to the lack of significant meta-analytic findings. Based on our qualitative synthesis, we propose that brain changes in response to intervention should be considered in terms of interactions among distributed cognitive, linguistic and sensory systems, rather than via a "normalized" vs. "compensatory" dichotomy. Further empirical research is needed to identify effects of moderating factors such as features of intervention programs, neuroimaging tasks, and individual differences among participants.

Widespread effects of dMRI data quality on diffusion measures in children.

Diffusion magnetic resonance imaging (dMRI) datasets are susceptible to several confounding factors related to data quality, which is especially true in studies involving young children. With the recent trend of large-scale multicenter studies, it is more critical to be aware of the varied impacts of data quality on measures of interest. Here, we investigated data quality and its effect on different diffusion measures using a multicenter dataset. dMRI data were obtained from 691 participants (5-17 years of age) from six different centers. Six data quality metrics-contrast to noise ratio, outlier slices, and motion (absolute, relative, translation, and rotational)-and four diffusion measures-fractional anisotropy, mean diffusivity, tract density, and length-were computed for each of 36 major fiber tracts for all participants. The results indicated that four out of six data quality metrics (all except absolute and translation motion) differed significantly between centers. Associations between these data quality metrics and the diffusion measures differed significantly across the tracts and centers. Moreover, these effects remained significant after applying recently proposed harmonization algorithms that purport to remove unwanted between-site variation in diffusion data. These results demonstrate the widespread impact of dMRI data quality on diffusion measures. These tracts and measures have been routinely associated with individual differences as well as group-wide differences between neurotypical populations and individuals with neurological or developmental disorders. Accordingly, for analyses of individual differences or group effects (particularly in multisite dataset), we encourage the inclusion of data quality metrics in dMRI analysis.

Neurite density and arborization is associated with reading skill and phonological processing in children.

BACKGROUND: Studies exploring neuroanatomic correlates of reading have associated white matter tissue properties with reading disability and related componential skills (e.g., phonological and single-word reading skills). Mean diffusivity (MD) and fractional anisotropy (FA) are widely used surrogate measures of tissue microstructure with high sensitivity; however, they lack specificity for individual microstructural features. Here we investigated neurite features with higher specificity in order to explore the underlying microstructural architecture. METHODS: Diffusion weighted images (DWI) and a battery of behavioral and neuropsychological assessments were obtained from 412 children (6 - 16 years of age). Neurite indices influenced by orientation and density were attained from 23 major white matter tracts. Partial correlations were calculated between neurite indices and indicators of phonological processing and single-word reading skills using age, sex, and image quality metrics as covariates. In addition, mediation analysis was performed using structural equation modeling (SEM) to evaluate the indirect effect of phonological processing on reading skills. RESULTS: We observed that orientation dispersion index (ODI) and neurite density index (NDI) were negatively correlated with single-word reading and phonological processing skills in several tracts previously shown to have structural correlates with reading efficiency. We also observed a significant and substantial effect in which phonological processing mediated the relationship between neurite indices and reading skills in most tracts. CONCLUSIONS: In sum, we established that better reading and phonological processing skills are associated with greater tract coherence (lower ODI) and lower neurite density (lower NDI). We interpret these findings as evidence that reading is associated with neural architecture and its efficiency.

Neuroimaging genetic associations between SEMA6D, brain structure, and reading skills.

Specific reading disability (SRD) is defined by genetic and neural risk factors that are not fully understood. The current study used imaging genetics methodology to investigate relationships between SEMA6D, brain structure, and reading. SEMA6D, located on SRD risk locus DYX1, is involved in axon guidance, synapse formation, and dendrite development. SEMA6D's associations with brain structure in reading-related regions of interest (ROIs) were investigated in a sample of children with a range of reading performance, from sites in Connecticut, CT (n = 67, 6-13 years, mean age = 9.07) and San Francisco, SF (n = 28, 5-8 years, mean age = 6.5). Multiple regression analyses revealed significant associations between SEMA6D's rs16959669 and cortical thickness in the fusiform gyrus and rs4270119 and gyrification in the supramarginal gyrus in the CT sample, but this was not replicated in the SF sample. Significant clusters were not associated with reading. For white matter volume, combined analyses across both samples revealed associations between reading and the left transverse temporal gyrus, left pars triangularis, left cerebellum, and right cerebellum. White matter volume in the left transverse temporal gyrus was nominally related to rs1817178, rs12050859, and rs1898110 in SEMA6D, and rs1817178 was significantly related to reading. Haplotype analyses revealed significant associations between the whole gene and brain phenotypes. Results suggest SEMA6D likely has an impact on multiple reading-related neural structures, but only white matter volume in the transverse temporal gyrus was significantly related to reading in the current sample. As the sample was young, the transverse temporal gyrus, involved in auditory perception, may be more strongly involved in reading because phonological processing is still being learned. The relationship between SEMA6D and reading may change as different brain regions are involved during reading development. Future research should examine mediating effects, use additional brain measures, and use an older sample to better understand effects.

From BDNF to reading: Neural activation and phonological processing as multiple mediators.

The BDNF gene is a prominent promoter of neuronal development, maturation and plasticity. Its Val66Met polymorphism affects brain morphology and function within several areas and is associated with several cognitive functions and neurodevelopmental disorder susceptibility. Recently, it has been associated with reading, reading-related traits and altered neural activation in reading-related brain regions. However, it remains unknown if the intermediate phenotypes (IPs, such as brain activation and phonological skills) mediate the pathway from gene to reading or reading disability. By conducting a serial multiple mediation model in a sample of 94 children (age 5-13), our findings revealed no direct effects of genotype on reading. Instead, we found that genotype is associated with brain activation in reading-related and more domain general regions which in turn is associated with phonological processing which is associated with reading. These findings suggest that the BDNF-Val66Met polymorphism is related to reading via phonological processing and functional activation. These results support brain imaging data and neurocognitive traits as viable IPs for complex behaviors.

Gray Matter Structure Is Associated with Reading Skill in Typically Developing Young Readers.

Research using functional and structural magnetic resonance imaging has identified areas of reduced brain activation and gray matter volume in children and adults with reading disability, but associations between cortical structure and individual differences in reading in typically developing children remain underexplored. Furthermore, the majority of research linking gray matter structure to reading ability quantifies gray matter in terms of volume, and cannot specify unique contributions of cortical surface area and thickness to these relationships. Here, we applied a continuous analytic approach to investigate associations between distinct surface-based properties of cortical structure and individual differences in reading-related skills in a sample of typically developing young children. Correlations between cortical structure and reading-related skills were conducted using a surface-based vertex-wise approach. Cortical thickness in the left superior temporal cortex was positively correlated with word and pseudoword reading performance. The observed positive correlation between cortical thickness in the left superior temporal cortex and reading may have implications for the patterns of brain activation that support reading.

Putative protective neural mechanisms in prereaders with a family history of dyslexia who subsequently develop typical reading skills.

Developmental dyslexia affects 40-60% of children with a familial risk (FHD+) compared to a general prevalence of 5-10%. Despite the increased risk, about half of FHD+ children develop typical reading abilities (FHD+Typical). Yet the underlying neural characteristics of favorable reading outcomes in at-risk children remain unknown. Utilizing a retrospective, longitudinal approach, this study examined whether putative protective neural mechanisms can be observed in FHD+Typical at the prereading stage. Functional and structural brain characteristics were examined in 47 FHD+ prereaders who subsequently developed typical (n = 35) or impaired (n = 12) reading abilities and 34 controls (FHD-Typical). Searchlight-based multivariate pattern analyses identified distinct activation patterns during phonological processing between FHD+Typical and FHD-Typical in right inferior frontal gyrus (RIFG) and left temporo-parietal cortex (LTPC) regions. Follow-up analyses on group-specific classification patterns demonstrated LTPC hypoactivation in FHD+Typical compared to FHD-Typical, suggesting this neural characteristic as an FHD+ phenotype. In contrast, RIFG showed hyperactivation in FHD+Typical than FHD-Typical, and its activation pattern was positively correlated with subsequent reading abilities in FHD+ but not controls (FHD-Typical). RIFG hyperactivation in FHD+Typical was further associated with increased interhemispheric functional and structural connectivity. These results suggest that some protective neural mechanisms are already established in FHD+Typical prereaders supporting their typical reading development.

Common variation within the SETBP1 gene is associated with reading-related skills and patterns of functional neural activation.

Epidemiological population studies highlight the presence of substantial individual variability in reading skill, with approximately 5-10% of individuals characterized as having specific reading disability (SRD). Despite reported substantial heritability, typical for a complex trait, the specifics of the connections between reading and the genome are not understood. Recently, the SETBP1 gene has been implicated in several complex neurodevelopmental syndromes and disorders that impact language. Here, we examined the relationship between common polymorphisms in this gene, reading, and reading associated behaviors using data from an ongoing project on the genetic basis of SRD (n = 135). In addition, an exploratory analysis was conducted to examine the relationship between SETBP1 and brain activation using functional magnetic resonance imaging (fMRI; n = 73). Gene-based analyses revealed a significant association between SETBP1 and phonological working memory, with rs7230525 as the strongest associated single nucleotide polymorphism (SNP). fMRI analysis revealed that the rs7230525-T allele is associated with functional neural activation during reading and listening to words and pseudowords in the right inferior parietal lobule (IPL). These findings suggest that common genetic variation within SETBP1 is associated with reading behavior and reading-related brain activation patterns in the general population.

Neural correlates of phonological processing: Disrupted in children with dyslexia and enhanced in musically trained children.

Phonological processing has been postulated as a core area of deficit among children with dyslexia. Reduced brain activation during phonological processing in children with dyslexia has been observed in left-hemispheric temporoparietal regions. Musical training has shown positive associations with phonological processing abilities, but the neural mechanisms underlying this relationship remain unspecified. The present research aims to distinguish neural correlates of phonological processing in school-age typically developing musically trained children, musically untrained children, and musically untrained children with dyslexia utilizing fMRI. A whole-brain ANCOVA, accounting for gender and nonverbal cognitive abilities, identified a main effect of group in bilateral temporoparietal regions. Subsequent region-of-interest analyses replicated temporoparietal hypoactivation in children with dyslexia relative to typically developing children. By contrast, musically trained children showed greater bilateral activation in temporoparietal regions when compared to each musically untrained group. Therefore, musical training shows associations with enhanced bilateral activation of left-hemispheric regions known to be important for reading. Findings suggest that engagement of these regions through musical training may underlie the putative positive effects of music on reading development. This supports the hypothesis that musical training may facilitate the development of a bilateral compensatory neural network, which aids children with atypical function in left-hemispheric temporoparietal regions.

Emergence of the neural network underlying phonological processing from the prereading to the emergent reading stage: A longitudinal study.

Numerous studies have shown that phonological skills are critical for successful reading acquisition. However, how the brain network supporting phonological processing evolves and how it supports the initial course of learning to read is largely unknown. Here, for the first time, we characterized the emergence of the phonological network in 28 children over three stages (prereading, beginning reading, and emergent reading) longitudinally. Across these three time points, decreases in neural activation in the left inferior parietal cortex (LIPC) were observed during an audiovisual phonological processing task, suggesting a specialization process in response to reading instruction/experience. Furthermore, using the LIPC as the seed, a functional network consisting of the left inferior frontal, left posterior occipitotemporal, and right angular gyri was identified. The connection strength in this network co-developed with the growth of phonological skills. Moreover, children with above-average gains in phonological processing showed a significant developmental increase in connection strength in this network longitudinally, while children with below-average gains in phonological processing exhibited the opposite trajectory. Finally, the connection strength between the LIPC and the left posterior occipitotemporal cortex at the prereading level significantly predicted reading performance at the emergent reading stage. Our findings highlight the importance of the early emerging phonological network for reading development, providing direct evidence for the Interactive Specialization Theory and neurodevelopmental models of reading.