Human ROBO1 regulates white matter structure in corpus callosum

The axon guidance receptor, Robo1, controls the pathfinding of callosal axons in mice. To determine whether the orthologous ROBO1 gene is involved in callosal development also in humans, we studied polymorphisms in the ROBO1 gene and variation in the white matter structure in the corpus callosum using both structural magnetic resonance imaging and diffusion tensor magnetic resonance imaging. We found that five polymorphisms in the regulatory region of ROBO1 were associated with white matter density in the posterior part of the corpus callosum pathways. One of the polymorphisms, rs7631357, was also significantly associated with the probability of connections to the parietal cortical regions. Our results demonstrate that human ROBO1 may be involved in the regulation of the structure and connectivity of posterior part of corpus callosum.Peer reviewe

Connectivity of the Human Number Form Area Reveals Development of a Cortical Network for Mathematics

The adult brain contains cortical areas thought to be specialized for the analysis of numbers (the putative number form area, NFA) and letters (the visual word form area, VWFA). Although functional development of the VWFA has been investigated, it is largely unknown when and how the NFA becomes specialized and connected to the rest of the brain. One hypothesis is that NFA and VWFA derive their special functions through differential connectivity, but the development of this differential connectivity has not been shown. Here, we mapped the resting state connectivity of NFA and VWFA to the rest of the brain in a large sample (n = 437) of individuals (age 3.2–21 years). We show that within NFA-math network and within VWFA-reading network the strength of connectivity increases with age. The right NFA is significantly connected to the right intraparietal cortex already at the earliest age tested (age 3), before formal mathematical education has begun. This connection might support or enable an early understanding of magnitude or numerosity In contrast, the functional connectivity from NFA to the left anterior intraparietal cortex and to the right dorsolateral prefrontal cortex is not different from the functional connectivity of VWFA to these regions until around 12–14 years of age. The increase in connectivity to these regions was associated with a gradual increase in mathematical ability in an independent sample. In contrast, VWFA connects significantly to Broca’s region around age 6, and this connectivity is correlated with reading ability. These results show how the differential connectivity of the networks for mathematics and reading slowly emerges through years of training and education

Microstructure of Temporo-Parietal White Matter as a Basis for Reading Ability Evidence from Diffusion Tensor Magnetic Resonance Imaging

AbstractDiffusion tensor magnetic resonance imaging (MRI) was used to study the microstructural integrity of white matter in adults with poor or normal reading ability. Subjects with reading difficulty exhibited decreased diffusion anisotropy bilaterally in temporo-parietal white matter. Axons in these regions were predominantly anterior–posterior in direction. No differences in T1-weighted MRI signal were found between poor readers and control subjects, demonstrating specificity of the group difference to the microstructural characteristics measured by diffusion tensor imaging (DTI). White matter diffusion anisotropy in the temporo-parietal region of the left hemisphere was significantly correlated with reading scores within the reading-impaired adults and within the control group. The anisotropy reflects microstructure of white matter tracts, which may contribute to reading ability by determining the strength of communication between cortical areas involved in visual, auditory, and language processing

Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family

Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.Peer reviewe

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.Peer reviewe

Was ist "Populäre Musik"? : Überlegungen in eigener Sache

Many common disorders across the lifespan feature impaired working memory (WM). Reported benefits of a WM training program include improving inattention in daily life, but this has not been evaluated in a meta-analysis. This study aimed to evaluate whether one WM training method has benefits for inattention in daily life by conducting a systematic review and meta-analysis.We searched Medline and PsycINFO, relevant journals and contacted authors for studies with an intervention and control group reporting post-training estimates of inattention in daily life. To reduce the influence of different WM training methods on the findings, the review was restricted to trials evaluating the Cogmed method. A meta-analysis calculated the pooled standardised difference in means (SMD) between intervention and control groups.A total of 622 studies were identified and 12 studies with 13 group comparisons met inclusion criteria. The meta-analysis showed a significant training effect on inattention in daily life, SMD=-0.47, 95% CI -0.65, -0.29, p<.00001. Subgroup analyses showed this significant effect was observed in groups of children and adults as well as users with and without ADHD, and in studies using control groups that were active and non-adaptive, wait-list and passive as well as studies using specific or general measures. Seven of the studies reported follow-up assessment and a meta-analysis showed persisting training benefits for inattention in daily life, SMD=-0.33, 95% CI -0.57 -0.09, p=.006. Additional meta-analyses confirmed improvements after training on visuospatial WM, SMD=0.66, 95% CI 0.43, 0.89, p<.00001, and verbal WM tasks, SMD=0.40, 95% CI 0.18, 0.62, p=.0004.Benefits of a WM training program generalise to improvements in everyday functioning. Initial evidence shows that the Cogmed method has significant benefits for inattention in daily life with a clinically relevant effect size

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

Peer reviewe

The neurophysiology of working memory : functional mapping of the human brain with positron emission tomography

Working memory (WM) refers to the retention, or keeping on-line, of informationover short periods of time. WMis thought to be important for a variety of cognitivefunctions, including problem solving, learning and reading. Previous studies in nonhuman primates have mainly implicated sustained neural activity in the prefrontalcortex as the neural correlate of WM. In the present series of experiments, positronemission tomography was used to measure regional cerebral blood flow, a marker ofregional metabolic activity, in the brain of human subjects during performance ofWM tasks. In paper I, we found that WM for visual, auditory and somatosensory stimuli activatedcortical areas with WMspecific activity, independent of the sensory modality of thestimulus. These areas were located in the prefrontal, inferior parietal, cingulateand frontal opercular cortex. We hypothesized that activation of the same part ofcortex by two different tasks would be associated with interference when these tasksare performed simultaneously. This hypothesis was supported by the results of a seriesof psychological experiments (paper II). In paper V, both single and dual-task performanceof WM tasks was studied. We could show that no additional areas were activated duringdual-task performance compared to single task performance. This also implies thatthere was no area with activation specifically related to divided attention or task-coordinationrequirements, which has previously been suggested. In paper III,WM for abstract visualstimuli was studied in two delayed matching to sample tasks. In the second matchingtask the WM load was increased by introducing additional contingencies in the instruction.Both matching tasks activated prefrontal and inferior parietal cortex in the lefthemisphere, and the activity in these areas was correlated. The cingulate cortexwas activated in the same location as in paper I and V. This cingulate activity islikely due to the planning of a motor response in delayed response tasks such asWM tasks. The increasing WM load in the second matching task induced additional activationin the right prefrontal and inferior parietal cortex. Schizophrenic patients performingthis task show impaired performance, and reduced frontal metabolism, compared tocontrol subjects. In paper IV we studied encoding and retrieval from long-term memory,the results suggesting that WM may be necessary to perform tasks involving encodinginto long-term memory. In conclusion: a consistent finding in the WM tasks was the coactivation of dorsolateralprefrontal cortex and the middle part of the inferior parietal cortex. This activitywas significantly higher during WM tasks than during control tasks involving selectiveattention. While the prefrontal activation was expected from studies in non humanprimates, the inferior parietal involvement in WMis a relatively new finding. Thisarea probably has no functionally corresponding area in the non-human primate. Ourresults also show that two different WM tasks, with memoranda from different sensorymodalities, activate overlapping parts of the cortex. This means that informationprocessing during WM tasks is not entirely parallel, but depends on the activationof parts of the cortex which has no modality specificity. Furthermore, we have associatedsuch overlap in activity between tasks with limitations of simultaneous informationprocessing in the brain