Faculty Bibliography

The diagnosis of various disorders is hindered by the lack of an imaging technique that reveals the architecture of living tissue at the fine resolution of the associated pathological processes. Indeed, even the most powerful imaging techniques such as MRI can only resolve or visualize biological tissue down to the scale of a cubic millimetre. However, MRI may be able to reveal what happens on a much finer scale, as it is sensitive to the random thermal motion of water molecules and, more importantly, their interactions with surrounding cells constituting the microstructure of the tissue. The gap between being sensitive and specific is bridged by the development of a tissue model that decomposes the MRI signal into components that probe relevant features of the underlying microstructure, typically affected by pathology. Hence, biophysical modelling is potentially a diagnostic tool that allows scientists to identify problems that arise in the unexplored depths of our organs, driving forward treatment and understanding of disease progression. In this chapter, we will introduce the main concepts of multiparametric modelling, lay out a general framework of multi-compartmental models, and discuss limitations and challenges.
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Cross-scanner and cross-protocol variability of diffusion magnetic resonance imaging (dMRI) data are known to be major obstacles in multi-site clinical studies since they limit the ability to aggregate dMRI data and derived measures. Computational algorithms that harmonize the data and minimize such variability are critical to reliably combine datasets acquired from different scanners and/or protocols, thus improving the statistical power and sensitivity of multi-site studies. Different computational approaches have been proposed to harmonize diffusion MRI data or remove scanner-specific differences. To date, these methods have mostly been developed for or evaluated on single b-value diffusion MRI data. In this work, we present the evaluation results of 19 algorithms that are developed to harmonize the cross-scanner and cross-protocol variability of multi-shell diffusion MRI using a benchmark database. The proposed algorithms rely on various signal representation approaches and computational tools, such as rotational invariant spherical harmonics, deep neural networks and hybrid biophysical and statistical approaches. The benchmark database consists of data acquired from the same subjects on two scanners with different maximum gradient strength (80 and 300 mT/m) and with two protocols. We evaluated the performance of these algorithms for mapping multi-shell diffusion MRI data across scanners and across protocols using several state-of-the-art imaging measures. The results show that data harmonization algorithms can reduce the cross-scanner and cross-protocol variabilities to a similar level as scan-rescan variability using the same scanner and protocol. In particular, the LinearRISH algorithm based on adaptive linear mapping of rotational invariant spherical harmonics features yields the lowest variability for our data in predicting the fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK) and the rotationally invariant spherical harmonic (RISH) features. But other algorithms, such as DIAMOND, SHResNet, DIQT, CMResNet show further improvement in harmonizing the return-to-origin probability (RTOP). The performance of different approaches provides useful guidelines on data harmonization in future multi-site studies.

Multi-parametric quantitative MRI (qMRI) of the spinal cord is a promising non-invasive tool to probe early microstructural damage in neurological disorders. It is usually performed in vivo by combining acquisitions with multiple signal readouts, which exhibit different thermal noise levels, geometrical distortions and susceptibility to physiological noise. This ultimately hinders joint multi-contrast modelling and makes the geometric correspondence of parametric maps challenging. We propose an approach to overcome these limitations, by implementing state-of-the-art microstructural MRI of the spinal cord with a unified signal readout in vivo (i.e. with matched spatial encoding parameters across a range of imaging contrasts). We base our acquisition on single-shot echo planar imaging with reduced field-of-view, and obtain data from two different vendors (vendor 1: Philips Achieva; vendor 2: Siemens Prisma). Importantly, the unified acquisition allows us to compare signal and noise across contrasts, thus enabling overall quality enhancement via multi-contrast image denoising methods. As a proof-of-concept, here we provide a demonstration with one such method, known as Marchenko-Pastur (MP) Principal Component Analysis (PCA) denoising. MP-PCA is a singular value (SV) decomposition truncation approach that relies on redundant acquisitions, i.e. such that the number of measurements is large compared to the number of components that are maintained in the truncated SV decomposition. Here we used in vivo and synthetic data to test whether a unified readout enables more efficient MP-PCA denoising of less redundant acquisitions, since these can be denoised jointly with more redundant ones. We demonstrate that a unified readout provides robust multi-parametric maps, including diffusion and kurtosis tensors from diffusion MRI, myelin metrics from two-pool magnetisation transfer, and T1 and T2 from relaxometry. Moreover, we show that MP-PCA improves the quality of our multi-contrast acquisitions, since it reduces the coefficient of variation (i.e. variability) by up to 17% for mean kurtosis, 8% for bound pool fraction (myelin-sensitive), and 13% for T1, while enabling more efficient denoising of modalities limited in redundancy (e.g. relaxometry). In conclusion, multi-parametric spinal cord qMRI with unified readout is feasible and provides robust microstructural metrics with matched resolution and distortions, whose quality benefits from multi-contrast denoising methods such as MP-PCA.

PURPOSE/OBJECTIVE:We aim to illustrate the diagnostic performance of diffusional kurtosis imaging (DKI) in the diagnosis of gliomas. METHODS:A review protocol was developed according to the (PRISMA-P) checklist, registered in the international prospective register of systematic reviews (PROSPERO) and published. A literature search in 4 databases was performed using the keywords 'glioma' and 'diffusional kurtosis'. After applying a robust inclusion/exclusion criteria, included articles were independently evaluated according to the QUADAS-2 tool and data extraction was done. Reported sensitivities and specificities were used to construct 2 × 2 tables and paired forest plots using the Review Manager (RevMan®) software. A random-effect model was pursued using the hierarchical summary receiver operator characteristics. RESULTS: = 73.8%). CONCLUSION/CONCLUSIONS:DKI shows good diagnostic accuracy in the differentiation of high- and low-grade gliomas further supporting its potential role in clinical practice. Further exploration of DKI in differentiating IDH status and in characterising non-glioma CNS tumours is however needed.

Axon caliber plays a crucial role in determining conduction velocity and, consequently, in the timing and synchronization of neural activation. Noninvasive measurement of axon radii could have significant impact on the understanding of healthy and diseased neural processes. Until now, accurate axon radius mapping has eluded in vivo neuroimaging, mainly due to a lack of sensitivity of the MRI signal to micron-sized axons. Here, we show how - when confounding factors such as extra-axonal water and axonal orientation dispersion are eliminated - heavily diffusion-weighted MRI signals become sensitive to axon radii. However, diffusion MRI is only capable of estimating a single metric, the effective radius, representing the entire axon radius distribution within a voxel that emphasizes the larger axons. Our findings, both in rodents and humans, enable noninvasive mapping of critical information on axon radii, as well as resolve the long-standing debate on whether axon radii can be quantified.

Probing microstructure with diffusion magnetic resonance imaging (dMRI) on a scale orders of magnitude below the imaging resolution relies on biophysical modelling of the signal response in the tissue. The vast majority of these biophysical models of diffusion in white matter assume that the measured dMRI signal is the sum of the signals emanating from each of the constituent compartments, each of which exhibits a distinct behaviour in the b-value and/or orientation domain. Many of these models further assume that the dMRI behaviour of the oriented compartments (e.g. the intra-axonal space) is identical between distinct fibre populations, at least at the level of a single voxel. This implicitly assumes that any potential biological differences between fibre populations are negligible, at least as far as is measurable using dMRI. Here, we validate this assumption by means of a voxel-wise, model-free signal decomposition that, under the assumption above and in the absence of noise, is shown to be rank-1. We evaluate the effect size of signal components beyond this rank-1 representation and use permutation testing to assess their significance. We conclude that in the healthy adult brain, the dMRI signal is adequately represented by a rank-1 model, implying that biologically more realistic, but mathematically more complex fascicle-specific microstructure models do not capture statistically significant or anatomically meaningful structure, even in extended high-b diffusion MRI scans.

Diffusion MRI is being used increasingly in studies of the brain and other parts of the body for its ability to provide quantitative measures that are sensitive to changes in tissue microstructure. However, inter-scanner and inter-protocol differences are known to induce significant measurement variability, which in turn jeopardises the ability to obtain 'truly quantitative measures' and challenges the reliable combination of different datasets. Combining datasets from different scanners and/or acquired at different time points could dramatically increase the statistical power of clinical studies, and facilitate multi-centre research. Even though careful harmonisation of acquisition parameters can reduce variability, inter-protocol differences become almost inevitable with improvements in hardware and sequence design over time, even within a site. In this work, we present a benchmark diffusion MRI database of the same subjects acquired on three distinct scanners with different maximum gradient strength (40, 80, and 300 mT/m), and with 'standard' and 'state-of-the-art' protocols, where the latter have higher spatial and angular resolution. The dataset serves as a useful testbed for method development in cross-scanner/cross-protocol diffusion MRI harmonisation and quality enhancement. Using the database, we compare the performance of five different methods for estimating mappings between the scanners and protocols. The results show that cross-scanner harmonisation of single-shell diffusion data sets can reduce the variability between scanners, and highlight the promises and shortcomings of today's data harmonisation techniques.

Tissue microstructure modeling of diffusion MRI signal is an active research area striving to bridge the gap between macroscopic MRI resolution and cellular-level tissue architecture. Such modeling in neuronal tissue relies on a number of assumptions about the microstructural features of axonal fiber bundles, such as the axonal shape (e.g., perfect cylinders) and the fiber orientation dispersion. However, these assumptions have not yet been validated by sufficiently high-resolution 3-dimensional histology. Here, we reconstructed sequential scanning electron microscopy images in mouse brain corpus callosum, and introduced a random-walker (RaW)-based algorithm to rapidly segment individual intra-axonal spaces and myelin sheaths of myelinated axons. Confirmed by a segmentation based on human annotations initiated with conventional machine-learning-based carving, our semi-automatic algorithm is reliable and less time-consuming. Based on the segmentation, we calculated MRI-relevant estimates of size-related parameters (inner axonal diameter, its distribution, along-axon variation, and myelin g-ratio), and orientation-related parameters (fiber orientation distribution and its rotational invariants; dispersion angle). The reported dispersion angle is consistent with previous 2-dimensional histology studies and diffusion MRI measurements, while the reported diameter exceeds those in other mouse brain studies. Furthermore, we calculated how these quantities would evolve in actual diffusion MRI experiments as a function of diffusion time, thereby providing a coarse-graining window on the microstructure, and showed that the orientation-related metrics have negligible diffusion time-dependence over clinical and pre-clinical diffusion time ranges. However, the MRI-measured inner axonal diameters, dominated by the widest cross sections, effectively decrease with diffusion time by ~ 17% due to the coarse-graining over axonal caliber variations. Furthermore, our 3d measurement showed that there is significant variation of the diameter along the axon. Hence, fiber orientation dispersion estimated from MRI should be relatively stable, while the "apparent" inner axonal diameters are sensitive to experimental settings, and cannot be modeled by perfectly cylindrical axons.