Towards non-parametric reconstruction of axon diameter distributions using diffusion MRI and regularized discrete linear modeling

The distribution of axon diameters (ADD) is an important white matter feature: it influences action potential speed, it has been shown to evolve during development, and also to be affected during pathological processes. Diffusion Magnetic Resonance Imaging is a powerful non-invasive tool that is sensitive to the displacement of water molecules. In theory, as axon diameters are well bellow the imaging resolution, the ADD can be estimated indirectly by fitting a biophysical model to the measured signal. Such an approach is the basis of microstructure imaging. Microstructure imaging usually relies on compartment models, splitting the signal into the intra-axonal or the extra-axonal compartments. However, in practice, ADD reconstruction remains a challenging problem, mainly due to model degeneracy (different solutions can have similar signals), the diameter lower bound which dictates the smallest diameter visible by the scanner, and the difficulty in modeling properly the extra-axonal signal. In this thesis, we addressed the challenges at stake by focusing on the intra-axonal and extra-axonal compartments separately. Model performance was evaluated by comparing estimates with the ground-truth provided by Monte Carlo simulations. Model degeneracy was addressed by introducing Laplacian regularization, which was shown to provide better ADD estimates when considering the intra-axonal signal only. Sensitivity to small diameters was improved by using a richer diffusion protocol designed to maximize sensitivity to a set of diameters, which was shown to provide reconstruction of unimodal and bimodal distributions, with sensitivity to population specific changes. Regarding the extra-axonal space, using a mixture of higher order tensors improved reconstruction of the signal compared to standard models. The proposed model is flexible enough to adapt to a variety of simulated signals, outperforming current models of hindered diffusion. Combining the results for both compartments slightly improved estimates for some of the simulated signals. We highlighted the similarity between the intra-axonal and extra-axonal signals, which might be the main limiting factor when using single Pulsed Gradient Spin Echo sequences

Genomic Study of RNA Polymerase II and III SNAPc-Bound Promoters Reveals a Gene Transcribed by Both Enzymes and a Broad Use of Common Activators

SNAP(c) is one of a few basal transcription factors used by both RNA polymerase (pol) II and pol III. To define the set of active SNAP(c)-dependent promoters in human cells, we have localized genome-wide four SNAP(c) subunits, GTF2B (TFIIB), BRF2, pol II, and pol III. Among some seventy loci occupied by SNAP(c) and other factors, including pol II snRNA genes, pol III genes with type 3 promoters, and a few un-annotated loci, most are primarily occupied by either pol II and GTF2B, or pol III and BRF2. A notable exception is the RPPH1 gene, which is occupied by significant amounts of both polymerases. We show that the large majority of SNAP(c)-dependent promoters recruit POU2F1 and/or ZNF143 on their enhancer region, and a subset also recruits GABP, a factor newly implicated in SNAP(c)-dependent transcription. These activators associate with pol II and III promoters in G1 slightly before the polymerase, and ZNF143 is required for efficient transcription initiation complex assembly. The results characterize a set of genes with unique properties and establish that polymerase specificity is not absolute in vivo

Widespread occurrence of non-canonical transcription termination by human RNA polymerase III

Human RNA polymerase (Pol) III-transcribed genes are thought to share a simple termination signal constituted by four or more consecutive thymidine residues in the coding DNA strand, just downstream of the RNA 3′-end sequence. We found that a large set of human tRNA genes (tDNAs) do not display any T≥4 stretch within 50 bp of 3′-flanking region. In vitro analysis of tDNAs with a distanced T≥4 revealed the existence of non-canonical terminators resembling degenerate T≥5 elements, which ensure significant termination but at the same time allow for the production of Pol III read-through pre-tRNAs with unusually long 3′ trailers. A panel of such non-canonical signals was found to direct transcription termination of unusual Pol III-synthesized viral pre-miRNA transcripts in gammaherpesvirus 68-infected cells. Genome-wide location analysis revealed that human Pol III tends to trespass into the 3′-flanking regions of tDNAs, as expected from extensive terminator read-through. The widespread occurrence of partial termination suggests that the Pol III primary transcriptome in mammals is unexpectedly enriched in 3′-trailer sequences with the potential to contribute novel functional ncRNA

Accelerated Microstructure Imaging via Convex Optimisation for regions with multiple fibres (AMICOx)

This paper reviews and extends our previous work to enable fast axonal diameter mapping from diffusion MRI data in the presence of multiple fibre populations within a voxel. Most of the existing microstructure imaging techniques use non-linear algorithms to fit their data models and consequently, they are computationally expensive and usually slow. Moreover, most of them assume a single axon orientation while numerous regions of the brain actually present more complex configurations, e.g. fiber crossing. We present a flexible framework, based on convex optimisation, that enables fast and accurate reconstructions of the microstructure organisation, not limited to areas where the white matter is coherently oriented. We show through numerical simulations the ability of our method to correctly estimate the microstructure features (mean axon diameter and intra-cellular volume fraction) in crossing regions

Widespread occurrence of non-canonical transcription termination by human RNA polymerase III

Human RNA polymerase (Pol) III-transcribed genes are thought to share a simple termination signal constituted by four or more consecutive thymidine residues in the coding DNA strand, just downstream of the RNA 3′-end sequence. We found that a large set of human tRNA genes (tDNAs) do not display any T≥4 stretch within 50 bp of 3′-flanking region. In vitro analysis of tDNAs with a distanced T≥4 revealed the existence of non-canonical terminators resembling degenerate T≥5 elements, which ensure significant termination but at the same time allow for the production of Pol III read-through pre-tRNAs with unusually long 3′ trailers. A panel of such non-canonical signals was found to direct transcription termination of unusual Pol III-synthesized viral pre-miRNA transcripts in gammaherpesvirus 68-infected cells. Genome-wide location analysis revealed that human Pol III tends to trespass into the 3′-flanking regions of tDNAs, as expected from extensive terminator read-through. The widespread occurrence of partial termination suggests that the Pol III primary transcriptome in mammals is unexpectedly enriched in 3′-trailer sequences with the potential to contribute novel functional ncRNAs

Learning <i>by</i> Heart or <i>with</i> Heart: Brain Asymmetry Reflects Pedagogical Practices

Brain hemispheres develop rather symmetrically, except in the case of pathology or intense training. As school experience is a form of training, the current study tested the influence of pedagogy on morphological development through the cortical thickness (CTh) asymmetry index (AI). First, we compared the CTh AI of 111 students aged 4 to 18 with 77 adults aged > 20. Second, we investigated the CTh AI of the students as a function of schooling background (Montessori or traditional). At the whole-brain level, CTh AI was not different between the adult and student groups, even when controlling for age. However, pedagogical experience was found to impact CTh AI in the temporal lobe, within the parahippocampal (PHC) region. The PHC region has a functional lateralization, with the right PHC region having a stronger involvement in spatiotemporal context encoding, while the left PHC region is involved in semantic encoding. We observed CTh asymmetry toward the left PHC region for participants enrolled in Montessori schools and toward the right for participants enrolled in traditional schools. As these participants were matched on age, intelligence, home-life and socioeconomic conditions, we interpret this effect found in memory-related brain regions to reflect differences in learning strategies. Pedagogy modulates how new concepts are encoded, with possible long-term effects on knowledge transfer

On evaluating the accuracy and biological plausibility of diffusion MRI tractograms

In diffusion MRI, traditional tractography algorithms do not recover truly quantitative tractograms and the structural connectivity has to be estimated indirectly by counting the number of fiber tracts or averaging scalar maps along them. Recently, global and efficient methods have emerged to estimate more quantitative tractograms by combining tractography with local models for the diffusion signal, like the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) framework. In this abstract, we show the importance of using both (i) proper multi-compartment diffusion models and (ii) adequate multi-shell acquisitions, in order to evaluate the accuracy and the biological plausibility of the tractograms

When does a volume of a bundle achieve saturation? A microstructure informed tractography study

Volumetric analysis of bundles derived from tractography is a popular statistical measure used in neurological disorder studies. Recent research performed by Gauvin shows that different bundles saturate with different tractography parameters, however, to achieve that saturation millions of streamlines need to be computed. In this investigation, the aim was to use microstructure informed tractography, a novel technique that combine tractography and microstructure models, to study the saturation of the bundles. This study has found that generally microstructure informed tractography makes the volume estimation less sensitive to tracking parameters. The findings may have profound implications in volumetric analysis in group studies