Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

A framework for quantification and physical modeling of cell mixing applied to oscillator synchronization in vertebrate somitogenesis

In development and disease, cells move as they exchange signals. One example is found in vertebrate development, during which the timing of segment formation is set by a ‘segmentation clock’, in which oscillating gene expression is synchronized across a population of cells by Delta-Notch signaling. Delta-Notch signaling requires local cell-cell contact, but in the zebrafish embryonic tailbud, oscillating cells move rapidly, exchanging neighbors. Previous theoretical studies proposed that this relative movement or cell mixing might alter signaling and thereby enhance synchronization. However, it remains unclear whether the mixing timescale in the tissue is in the right range for this effect, because a framework to reliably measure the mixing timescale and compare it with signaling timescale is lacking. Here, we develop such a framework using a quantitative description of cell mixing without the need for an external reference frame and constructing a physical model of cell movement based on the data. Numerical simulations show that mixing with experimentally observed statistics enhances synchronization of coupled phase oscillators, suggesting that mixing in the tailbud is fast enough to affect the coherence of rhythmic gene expression. Our approach will find general application in analyzing the relative movements of communicating cells during development and disease.Fil: Uriu, Koichiro. Kanazawa University; JapónFil: Bhavna, Rajasekaran. Max Planck Institute of Molecular Cell Biology and Genetics; Alemania. Max Planck Institute for the Physics of Complex Systems; AlemaniaFil: Oates, Andrew C.. Francis Crick Institute; Reino Unido. University College London; Reino UnidoFil: Morelli, Luis Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Max Planck Institute for Molecular Physiology; Alemania. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentin

Deep learning-based parameter mapping for joint relaxation and diffusion tensor MR Fingerprinting

Magnetic Resonance Fingerprinting (MRF) enables the simultaneous quantification of multiple properties of biological tissues. It relies on a pseudo-random acquisition and the matching of acquired signal evolutions to a precomputed dictionary. However, the dictionary is not scalable to higher-parametric spaces, limiting MRF to the simultaneous mapping of only a small number of parameters (proton density, T1 and T2 in general). Inspired by diffusion-weighted SSFP imaging, we present a proof-of-concept of a novel MRF sequence with embedded diffusion-encoding gradients along all three axes to efficiently encode orientational diffusion and T1 and T2 relaxation. We take advantage of a convolutional neural network (CNN) to reconstruct multiple quantitative maps from this single, highly undersampled acquisition. We bypass expensive dictionary matching by learning the implicit physical relationships between the spatiotemporal MRF data and the T1, T2 and diffusion tensor parameters. The predicted parameter maps and the derived scalar diffusion metrics agree well with state-of-the-art reference protocols. Orientational diffusion information is captured as seen from the estimated primary diffusion directions. In addition to this, the joint acquisition and reconstruction framework proves capable of preserving tissue abnormalities in multiple sclerosis lesions

Empirical comparison of diffusion kurtosis imaging and diffusion basis spectrum imaging using the same acquisition in healthy young adults

As diffusion tensor imaging gains widespread use, many researchers have been motivated to go beyond the tensor model and fit more complex diffusion models, to gain a more complete description of white matter microstructure and associated pathology. Two such models are diffusion kurtosis imaging (DKI) and diffusion basis spectrum imaging (DBSI). It is not clear which DKI parameters are most closely related to DBSI parameters, so in the interest of enabling comparisons between DKI and DBSI studies, we conducted an empirical survey of the interrelation of these models in 12 healthy volunteers using the same diffusion acquisition. We found that mean kurtosis is positively associated with the DBSI fiber ratio and negatively associated with the hindered ratio. This was primarily driven by the radial component of kurtosis. The axial component of kurtosis was strongly and specifically correlated with the restricted ratio. The joint spatial distributions of DBSI and DKI parameters are tissue-dependent and stable across healthy individuals. Our contribution is a better understanding of the biological interpretability of the parameters generated by the two models in healthy individuals

A variational approach to the registration of tensor-valued images

We present a variational framework for the registration of tensor valued images. It is based on an energy functional with four terms: a data term based on a diffusion tensor constancy constraint, a compatibility term encoding the physical model linking domain deformations and tensor reorientation, and smoothness terms for deformation and tensor reorientation. Although the tensor deformation model employed here is designed with regard to diffusion tensor MRI data, the separation of data and compatibility term allows to adapt the model easily to different tensor deformation models. We minimise the energy functional with respect to both transformation fields by a multiscale gradient descent. Experiments demonstrate the viability and potential of this approach in the registration of tensor-valued images

Neuroconductor: an R platform for medical imaging analysis

Neuroconductor (https://neuroconductor.org) is an open-source platform for rapid testing and dissemination of reproducible computational imaging software. The goals of the project are to: (i) provide a centralized repository of R software dedicated to image analysis, (ii) disseminate software updates quickly, (iii) train a large, diverse community of scientists using detailed tutorials and short courses, (iv) increase software quality via automatic and manual quality controls, and (v) promote reproducibility of image data analysis. Based on the programming language R (https://www.r-project.org/), Neuroconductor starts with 51 inter-operable packages that cover multiple areas of imaging including visualization, data processing and storage, and statistical inference. Neuroconductor accepts new R package submissions, which are subject to a formal review and continuous automated testing. We provide a description of the purpose of Neuroconductor and the user and developer experience