White matter connections : developmental neuroimaging studies of the associations between genes, brain and behavior

Abstract: Development of cognitive abilities across childhood and adulthood parallels brain maturation in typically developing samples. Cognitive abilities such as reading and working memory have been linked to neuroimaging measures in relevant brain regions. Though the correlations between inter-individual brain differences and their related cognitive abilities are well established, the cause of this inter-individual variability is still not fully known. This thesis aims to understand the neural bases of the inter-individual variability in reading ability by studying the associations between dyslexia susceptibility genes and white and gray matter brain structures, and determine whether the measures of associated regions correlate with variability in reading ability. Moreover, it aims to identify the brain measures that correlate with concurrent measures of working memory and those that are predictive of future working memory, using a longitudinal cohort of typically developing children and young adults. Studies I and II: Three genes, DYX1C1, DCDC2 and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. We investigated whether the polymorphisms within these genes would affect variability in white and gray matter brain structures. Rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) were associated with left temporo-parietal white matter volume connecting middle temporal cortex to angular and supramarginal gyri as well as lateral occipital cortex. Rs793842 was significantly associated with thickness of left parietal areas and the lateral occipital cortex. Both white and gray matter measures correlated with current reading ability, but only white matter predicted future reading. Study III: We aimed to investigate whether MRPL19/C2ORF3 dyslexia genes, found to be correlated with verbal and non-verbal IQ, have a significant influence on white matter brain structures. Rs917235 showed a significant association with white matter volume in bilateral posterior parts of the corpus callosum and the cingulum, with connections to parietal, occipital and temporal cortices that are involved in both language and general cognitive abilities. Study IV: ROBO1 is a dyslexia gene that has been associated with axonal guidance and midline crossing. We assessed whether the polymorphisms within this gene have an influence on structure of the corpus callosum. Rs7631357 was associated with probability of connections within the fibers extending through the body of corpus callosum to parietal brain regions. The results fit well with previous reports on the role of Robo1 in axonal path finding in mice. Study V: Working memory has been associated with greater brain activity, thinner cortex, and white matter maturation in cross-sectional studies of children and young adults. Here, we aimed to investigate the role of differences in brain structure and function in the development of working memory. We assessed the concurrent and predictive relationships between working memory performance and neuroimaging measures in the fronto-parietal and fronto-striatal networks important for working memory. Working memory performance correlated with brain activity in frontal and parietal regions, cortical thickness in parietal cortex, and white matter volume of fronto-parietal and fronto-striatal tracts. White matter microstructure and brain activity in the caudate predicted future working memory. This work highlights the impact of imaging genetics research, revealing important associations between genes, brain and behavior. The results identify the neural mechanism underlying two cognitive abilities, reading and working memory. Specifically, the findings identify the important role of white matter in driving the development of working memory and reading ability, connecting the related cortical areas, as well as bridging the gap between genes and behavior.