Biology subjects

Huber, E.

Publications and source records attributed to Huber, E..

6 recordsLinked to original sources

bioRxiv2018

Applying biophysical models to understand the role of white matter in cognitive development

Diffusion MRI (dMRI) holds great promise for illuminating the biological changes that underpin cognitive development. The diffusion of water molecules probes the cellular structure of brain tissue, and biophysical modeling of the diffusion signal can be used to make inferences about specific tissue properties that vary over development or predict cognitive performance. However, applying these models to study development requires that the parameters can be reliably estimated given the constraints of data collection with children. Here we collect repeated scans using a multi-shell diffusion MRI protocol in a group of children (ages 7-12) and use two popular biophysical models to characterize axonal properties. We first assess the scan-rescan reliability of model parameters and show that axon water faction can be reliably estimated from a relatively fast acquisition, without applying spatial smoothing or de-noising. We then investigate developmental changes in the white matter, and individual differences in white matter that correlate with reading skill. Specifically, we test the hypothesis that previously reported correlations between reading skill and diffusion anisotropy in the corpus callosum reflect increased axon density in poor readers. Both models support this interpretation, highlighting the utility of biophysical models for testing specific hypotheses about cognitive development.

neuroscience↗

bioRxiv2018

Sensitive periods for white matter plasticity in human

As a child matures, some brain circuits stabilize while others remain plastic. However, the literature on maturational changes in the brains capacity for experience-dependent plasticity is primarily based on experiments in animals that mature over dramatically different time-scales than humans. Moreover, while principles of plasticity for sensory and motor systems might be conserved across species, the myriad of late-developing and uniquely human cognitive functions such as literacy cannot be studied with animal models. Here we use an intensive reading intervention program, in combination with longitudinal diffusion MRI measurements in school-aged children with dyslexia, to investigate the sensitive period for white matter plasticity and literacy learning. We find that the intervention induces large-scale changes in white matter diffusion properties, and improvements in reading scores, but that the magnitude and time-course of plasticity does not depend on the subjects age. Thus, we conclude that, for the intensive, one-on-one reading intervention program employed here, if a sensitive period exists, it does not end before middle school.

neuroscience↗

bioRxiv2018

Word selectivity in high-level visual cortex and reading skill

Word-selective neural responses in human ventral occipito-temporal cortex (VOTC) emerge as children learn to read, creating a visual word form area (VWFA) in the literate brain. It has been suggested that the VWFA arises through competition between pre-existing selectivity for other stimulus categories, changing the topography of VOTC to support rapid word recognition. Here, we hypothesized that competition between words and objects would be resolved as children acquire reading skill. Using functional magnetic resonance imaging (fMRI), we examined the relationship between responses to words and objects in VOTC in two ways. First, we defined the VWFA using a words > objects contrast and found that only skilled readers had a region that responded more to words than objects. Second, we defined the VWFA using a words > faces contrast and examined selectivity for words over objects in this region. We found that word selectivity strongly correlated with reading skill, suggesting reading skill-dependent tuning for words. Furthermore, we found that low word selectivity in struggling readers was not due to a lack of response to words, but to a high response to objects. Our results suggest that the fine-tuning of word-selective responses in VOTC is a critical component of skilled reading.

neuroscience↗

bioRxiv2018

White matter plasticity and reading instruction: Widespread anatomical changes track the learning process

White matter tissue properties correlate with childrens performance across domains ranging from reading, to math, to executive function. We use a longitudinal intervention design to examine experience-dependent growth in reading skills and white matter in a group of grade school aged, struggling readers. Diffusion MRI data were collected at regular intervals during an 8-week, intensive reading intervention. These measurements reveal large-scale changes throughout a collection of white matter tracts, in concert with growth in reading skill. Additionally, we identify tracts whose properties predict reading skill but remain fixed throughout the intervention, suggesting that some anatomical properties may stably predict the ease with which a child learns to read, while others dynamically reflect the effects of experience. These results underscore the importance of considering recent experience when interpreting cross-sectional anatomy-behavior correlations. Widespread changes throughout the white matter may be a hallmark of rapid plasticity associated with an intensive learning experience.

neuroscience↗

bioRxiv2018

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

PurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.\n\nMethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.\n\nResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.\n\nConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

genomics↗

bioRxiv2017

Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identified a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We tested 565 pairwise knockdowns in the developing eye, and identified 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppressed or enhanced cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways were also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for genetic interactions within CNVs and identifies potential therapeutic targets for neurodevelopmental disorders.

genomics↗