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The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher signal-to-noise ratio and spatial resolution compared to in vivo studies, and more advanced diffusion contrasts for improved microstructure and connectivity characterization. Another major advantage is direct comparison with histological data as a crucial methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging, but ultimately affect what questions can be answered using the data. This work represents 'Part 2' of a series of recommendations and considerations for preclinical dMRI, where we focus on best practices for dMRI of ex vivo tissue. We first describe the value that ex vivo imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We then give guidelines for ex vivo protocols, including tissue preparation, imaging sequences and data processing including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available ex vivo dMRI datasets and dedicated software packages. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist, and where future work should lie. An overarching goal herein is to enhance the rigor and reproducibility of ex vivo dMRI acquisitions and analyses, and thereby advance biomedical knowledge., Comment: 59 pages, 12 figures, part of ongoing efforts on ISMRM Diffusion Study Group initiative 'Best Practices (Consensus) for diffusion MRI'. arXiv admin note: text overlap with arXiv:2209.12994

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the resultant data. This work aims to present selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. We describe the general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss why some may be more or less appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, and imaging sequences, followed by advice for data processing including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. In each section, we attempt to provide guides and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should focus. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge., Comment: 45 pages, 5 figures, 1 table

Combining multi-site data can strengthen and uncover trends, but is a task that is marred by the influence of site-specific covariates that can bias the data and therefore any downstream analyses. Post-hoc multi-site correction methods exist but have strong assumptions that often do not hold in real-world scenarios. Algorithms should be designed in a way that can account for site-specific effects, such as those that arise from sequence parameter choices, and in instances where generalisation fails, should be able to identify such a failure by means of explicit uncertainty modelling. This body of work showcases such an algorithm, that can become robust to the physics of acquisition in the context of segmentation tasks, while simultaneously modelling uncertainty. We demonstrate that our method not only generalises to complete holdout datasets, preserving segmentation quality, but does so while also accounting for site-specific sequence choices, which also allows it to perform as a harmonisation tool., Comment: 25 pages, 8 figures

Being able to adequately process and combine data arising from different sites is crucial in neuroimaging, but is difficult, owing to site, sequence and acquisition-parameter dependent biases. It is important therefore to design algorithms that are not only robust to images of differing contrasts, but also be able to generalise well to unseen ones, with a quantifiable measure of uncertainty. In this paper we demonstrate the efficacy of a physics-informed, uncertainty-aware, segmentation network that employs augmentation-time MR simulations and homogeneous batch feature stratification to achieve acquisition invariance. We show that the proposed approach also accurately extrapolates to out-of-distribution sequence samples, providing well calibrated volumetric bounds on these. We demonstrate a significant improvement in terms of coefficients of variation, backed by uncertainty based volumetric validation., Comment: 10 pages, 3 figures, published in: Simulation and Synthesis in Medical Imaging 6th International Workshop, SASHIMI 2021, Held in Conjunction with MICCAI 2021, Strasbourg, France, September 27, 2021, Proceedings

Magnetic Resonance Imaging (MRI) is one of the most flexible and powerful medical imaging modalities. This flexibility does however come at a cost; MRI images acquired at different sites and with different parameters exhibit significant differences in contrast and tissue appearance, resulting in downstream issues when quantifying brain anatomy or the presence of pathology. In this work, we propose to combine multiparametric MRI-based static-equation sequence simulations with segmentation convolutional neural networks (CNN), to make these networks robust to variations in acquisition parameters. Results demonstrate that, when given both the image and their associated physics acquisition parameters, CNNs can produce segmentations that exhibit robustness to acquisition variations. We also show that the proposed physics-informed methods can be used to bridge multi-centre and longitudinal imaging studies where imaging acquisition varies across a site or in time., Comment: Accepted at SASHIMI2019

The intra-axonal water exchange time {\tau}i, a parameter associated with axonal permeability, could be an important biomarker for understanding demyelinating pathologies such as Multiple Sclerosis. Diffusion-Weighted MRI is sensitive to changes in permeability, however, the parameter has remained elusive due to the intractability of the mathematical models that incorporate it. Machine learning based computational models can potentially be used to estimate such parameters, and recently, a theoretical framework using a random forest (RF) suggests this is a promising approach. In this study, we adopt such an RF approach and experimentally investigate its suitability as a biomarker for demyelinating pathologies through direct comparison with histology. For this, we use an in-vivo cuprizone (CPZ) mouse model of demyelination with available ex-vivo electron microscopy (EM) data. We test our model on noise-free simulations and find very strong correlations between the predicted and ground truth parameters. For realistic noise levels as in our in-vivo data, the performance is affected, however, the parameters are still well estimated. We apply our RF model on in-vivo data from 8 CPZ and 8 wild-type (WT) mice and validate the RF estimates using histology. We find a strong correlation between the in-vivo RF estimates of {\tau}i and the EM measurements of myelin thickness ({\rho_\tau}i = 0.82), and between RF estimates and EM measurements of intra-axonal volume fraction ({\rho_f} = 0.98). When comparing {\tau}i in CPZ and WT mice we find a statistically significant decrease in the corpus callosum of the CPZ compared to the WT mice, in line with our expectations that {\tau}i is lower in regions where the myelin sheath is damaged. Overall, these results demonstrate the suitability of machine learning compartment models with permeability as a potential biomarker for demyelinating pathologies.

Microscopic diffusion anisotropy ({\mu}A) has been recently gaining increasing attention for its ability to decouple the average compartment anisotropy from orientation dispersion. Advanced diffusion MRI sequences, such as double diffusion encoding (DDE) and double oscillating diffusion encoding (DODE) have been used for mapping {\mu}A. However, the time-dependence of {\mu}A has not been investigated insofar, and furthermore, the accuracy of {\mu}A estimation vis-\`a-vis different b-values was not assessed. Here, we investigate both these concepts using theory, simulation, and experiments in the mouse brain. In the first part, simulations and experimental results show that the conventional estimation of microscopic anisotropy from the difference of D(O)DE sequences with parallel and orthogonal gradient directions yields values that highly depend on the choice of b-value. To mitigate this undesirable bias, we propose a multi-shell approach that harnesses a polynomial fit of the signal difference up to third order terms in b-value. In simulations, this approach yields more accurate {\mu}A metrics, which are similar to the ground truth values. The second part of this work uses the proposed multi-shell method to estimate the time/frequency dependence of {\mu}A. The data shows either an increase or no change in {\mu}A with frequency depending on the region of interest, both in white and gray matter. When comparing the experimental results with simulations, it emerges that simple geometric models such as infinite cylinders with either negligible or finite radii cannot replicate the measured trend, and more complex models, which, for example, incorporate structure along the fibre direction are required. Thus, measuring the time dependence of microscopic anisotropy can provide valuable information for characterizing tissue microstructure.

In this paper we use a continuous model to describe the development of a single cell lineage following the committal of stem cells. Three separate controls are implemented in the model, namely the proliferative control of stem cells, the proliferative control of developing blast cells, and the peripheral control of stem cell committal by circulating blood cell density. We show that variation of parameters in all three control systems can cause oscillations, and that the characters of these oscillations are very different. This allows us some potential insight into the mechanisms that may be operative in some of the dynamic blood diseases like cyclical neutropenia and periodic chronic myelogenous leukemia., Comment: 24 pages, 11 figures