Comparing single-shell and multi-shell free-water fraction estimation algorithms

Tese de mestrado, Engenharia Biomédica e Biofísica , 2022, Universidade de Lisboa, Faculdade de CiênciasDiffusion Weighted (DW) MRI is a medical imaging modality which can be used to model the dis placement of water molecules as they diffuse through the brain, allowing the microstructural architecture of brain tissues to be explored in vivo. This technique has been widely applied to the study of many brain pathologies. However, the presence of extracellular free water affects the diffusion measurements, potentially leading to wrong interpretation about the underlying microstructural changes. Free-water elimination (FWE) is an alternative to more traditional approaches to model DWI data, which divides the signal into an extracellular compartment (which depending on tissue type can be isotropic) representing free water and another compartment representing tissue (usually anisotropic). A recent method by Neto Henriques, et al, to estimate free water fraction using multiple diffusion weighting shells has been shown to reduce the bias in parameter estimates. However, as clinical protocols often use a single diffusion-weighting (single-shell data) to reduce exam times, it becomes relevant to investigate if introducing prior knowledge in the estimation, as proposed in the work of Pasternak, et al, could enable reliable free water elimination when applied to single-shell data. The goal of this project is to compare the performance of these two free water elimination algorithms when applied to the same data. A large dataset of multi-shell DWI data was acquired as part of a longitudinal study led by the Norwegian University of Science and Technology (NTNU) in Trondheim. This dataset includes 78 healthy controls. The data was pre-processed and the multi-shell algorithm applied to eliminate free water contamination. In this project, the same data was processed after removal of the high diffusion-weighting shell, by applying an open-source implementation of the single-shell algorithm presented on the work of Golub, et al. The methods used are fully detailed in this work, including the participants, image acquisition and image preprocessing phases. Tract-based spatial statistics (TBSS) were used for registration and align ment of images for all studied parameters and voxelwise statistics was performed in order to learn which voxels were significantly different between images processed with the two a l gorithms. White matter, cerebral cortex and subcortical masks were used to understand how the algorithms behave at a regional level. The results include a comparison of the original data used, where differences can be observed and discussed. The statistical results - corrected p-value images for each parameter - are presented and dis cussed: considering the multishell algorithm as gold standard, for both fractional anysotropy (FA) and free water (FW) the singleshell algorithm seems to underestimate the white matter values and overes timate the gray matter values. For mean diffusivity (MD), it is the opposite: the single-shell algorithm seems to overestimate the white matter values and underestimate the gray matter values. These results are supported by further analysis, where each subject images for all parameters (FA, MD and FW) and for both algorithms (single and multi-shell) was used to get an average value of the voxels (excluding null values from this average), in order to understand how these values differ according to the algorithm used. These results, presented as boxplots for the regions being studied, also indicate that the values for both algorithms are significantly different in almost all regions and parameters. This study allows to understand the FWE-DTI application in single-shell data. The comparison with the multi-shell algorithm for FA and FW showed an underestimaion of WM values and overestimation of GM values. For MD, the values are conditioned by the prior and overestimated for all tissue type. Besides, the values obtained with the single-shell algorithm are considered significantly different from the ones obtained with multi-shell agorithm for both WM and GM in most parameters and regions

Diffusion-Weighted Imaging: Recent Advances and Applications

Quantitative diffusion imaging techniques enable the characterization of tissue microstructural properties of the human brain “in vivo”, and are widely used in neuroscientific and clinical contexts. In this review, we present the basic physical principles behind diffusion imaging and provide an overview of the current diffusion techniques, including standard and advanced techniques as well as their main clinical applications. Standard diffusion tensor imaging (DTI) offers sensitivity to changes in microstructure due to diseases and enables the characterization of single fiber distributions within a voxel as well as diffusion anisotropy. Nonetheless, its inability to represent complex intravoxel fiber topologies and the limited biological specificity of its metrics motivated the development of several advanced diffusion MRI techniques. For example, high-angular resolution diffusion imaging (HARDI) techniques enabled the characterization of fiber crossing areas and other complex fiber topologies in a single voxel and supported the development of higher-order signal representations aiming to decompose the diffusion MRI signal into distinct microstructure compartments. Biophysical models, often known by their acronym (e.g., CHARMED, WMTI, NODDI, DBSI, DIAMOND) contributed to capture the diffusion properties from each of such tissue compartments, enabling the computation of voxel-wise maps of axonal density and/or morphology that hold promise as clinically viable biomarkers in several neurological and neuroscientific applications; for example, to quantify tissue alterations due to disease or healthy processes. Current challenges and limitations of state-of-the-art models are discussed, including validation efforts. Finally, novel diffusion encoding approaches (e.g., b-tensor or double diffusion encoding) may increase the biological specificity of diffusion metrics towards intra-voxel diffusion heterogeneity in clinical settings, holding promise in neurological applications

Effects of Multi-Shell Free Water Correction on Glioma Characterization.

Diffusion MRI is a useful tool to investigate the microstructure of brain tumors. However, the presence of fast diffusing isotropic signals originating from non-restricted edematous fluids, within and surrounding tumors, may obscure estimation of the underlying tissue characteristics, complicating the radiological interpretation and quantitative evaluation of diffusion MRI. A multi-shell regularized free water (FW) elimination model was therefore applied to separate free water from tissue-related diffusion components from the diffusion MRI of 26 treatment-naïve glioma patients. We then investigated the diagnostic value of the derived measures of FW maps as well as FW-corrected tensor-derived maps of fractional anisotropy (FA). Presumed necrotic tumor regions display greater mean and variance of FW content than other parts of the tumor. On average, the area under the receiver operating characteristic (ROC) for the classification of necrotic and enhancing tumor volumes increased by 5% in corrected data compared to non-corrected data. FW elimination shifts the FA distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy (p ≤ 0.003), whereas skewness is decreased (p ≤ 0.004). Kurtosis is significantly decreased (p < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of FA, which helps to disentangle the cancer heterogeneity

Assessment of Precision and Accuracy of Brain White Matter Microstructure using Combined Diffusion MRI and Relaxometry

Joint modeling of diffusion and relaxation has seen growing interest due to its potential to provide complementary information about tissue microstructure. For brain white matter, we designed an optimal diffusion-relaxometry MRI protocol that samples multiple b-values, B-tensor shapes, and echo times (TE). This variable-TE protocol (27 min) has as subsets a fixed-TE protocol (15 min) and a 2-shell dMRI protocol (7 min), both characterizing diffusion only. We assessed the sensitivity, specificity and reproducibility of these protocols with synthetic experiments and in six healthy volunteers. Compared with the fixed-TE protocol, the variable-TE protocol enables estimation of free water fractions while also capturing compartmental $T_2$ relaxation times. Jointly measuring diffusion and relaxation offers increased sensitivity and specificity to microstructure parameters in brain white matter with voxelwise coefficients of variation below 10%.Comment: 8 figure

Effects of Multi-Shell Free Water Correction on Glioma Characterization.

Diffusion MRI is a useful tool to investigate the microstructure of brain tumors. However, the presence of fast diffusing isotropic signals originating from non-restricted edematous fluids, within and surrounding tumors, may obscure estimation of the underlying tissue characteristics, complicating the radiological interpretation and quantitative evaluation of diffusion MRI. A multi-shell regularized free water (FW) elimination model was therefore applied to separate free water from tissue-related diffusion components from the diffusion MRI of 26 treatment-naïve glioma patients. We then investigated the diagnostic value of the derived measures of FW maps as well as FW-corrected tensor-derived maps of fractional anisotropy (FA). Presumed necrotic tumor regions display greater mean and variance of FW content than other parts of the tumor. On average, the area under the receiver operating characteristic (ROC) for the classification of necrotic and enhancing tumor volumes increased by 5% in corrected data compared to non-corrected data. FW elimination shifts the FA distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy (p ≤ 0.003), whereas skewness is decreased (p ≤ 0.004). Kurtosis is significantly decreased (p < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of FA, which helps to disentangle the cancer heterogeneity

Spherical means-based free-water volume fraction from diffusion MRI increases non-linearly with age in the white matter of the healthy human brain

Producción CientíficaThe term free-water volume fraction (FWVF) refers to the signal fraction that could be found as the cerebrospinal fluid of the brain, which has been demonstrated as a sensitive measure that correlates with cognitive performance and various neuropathological processes. It can be quantified by properly fitting the isotropic component of the magnetic resonance (MR) signal in diffusion-sensitized sequences. Using healthy subjects (178F/109M) aged 25-94, this study examines in detail the evolution of the FWVF obtained with the spherical means technique from multi-shell acquisitions in the human brain white matter across the adult lifespan, which has been previously reported to exhibit a positive trend when estimated from single-shell data using the bi-tensor signal representation. We found evidence of a noticeably non-linear gain after the sixth decade of life, with a region-specific variate and varying change rate of the spherical means-based multi-shell FWVF parameter with age, at the same time, a heteroskedastic pattern across the adult lifespan is suggested. On the other hand, the FW corrected diffusion tensor imaging (DTI) leads to a region-dependent flattened age-related evolution of the mean diffusivity (MD) and fractional anisotropy (FA), along with a considerable reduction in their variability, as compared to the studies conducted over the standard (single-component) DTI. This way, our study provides a new perspective on the trajectory-based assessment of the brain and explains the conceivable reason for the variations observed in FA and MD parameters across the lifespan with previous studies under the standard diffusion tensor imaging.Ministerio de Ciencia e Innovación (MCIN-AEI) y FEDER-UE (grant PID2021-124407NB-I00)Ministerio de Ciencia e Innovación (MCIN-AEI) - Unión Europea “NextGenerationEU/PRTR” (grant TED2021-130758B-I00)Ministry of Science and Higher Education (Poland) - Bekker programme (grant PPN/BEK/2019/1/00421)Norwegian ExtraFoundation for Health and Rehabilitation (2015/FO5146)European Union's Horizon 2020 research and Innovation program (ERC 802998

Quantitative Magnetic Resonance Imaging of Tissue Microvasculature and Microstructure in Selected Clinical Applications

This thesis is based on four papers and aims to establish perfusion and diffusion measurements with magnetic resonance imaging (MRI) in selected clinical applications. While structural imaging provides invaluable geometric and anatomical information, new disease relevant information can be obtained from measures of physiological processes inferred from advanced modelling. This study is motivated by clinical questions pertaining to diagnosis and treatment effects in particular patient groups where inflammatory processes are involved in the disease. Paper 1 investigates acquisition parameters in dynamic contrast enhanced (DCE)-MRI of the temporomandibular joint (TMJ) with possible involvement of juvenile idiopathic arthritis. High level elastic motion correction should be applied to DCE data from the TMJ, and the DCE data should be acquired with a sample rate of at least 4 s. Paper 2 investigates choices of arterial input functions (AIFs) in dynamic susceptibility contrast (DSC)-MRI in brain metastases. AIF shapes differed across patients. Relative cerebral blood volume estimates differentiated better between perfusion in white matter and grey matter when scan-specific AIFs were used than when patient-specific AIFs and population-based AIFs were used. Paper 3 investigates DSC-MRI perfusion parameters in relation to outcome after stereotactic radiosurgery (SRS) in brain metastases. Low perfusion prior to SRS may be related to unfavourable outcome. Paper 4 applies free water (FW) corrected diffusion MRI to characterise glioma. Fractional anisotropy maps of the tumour region were significantly impacted by FW correction. The estimated FW maps may also contribute to a better description of the tumour. Although there are challenges related to post-processing of MRI data, it was shown that the advanced MRI methods applied can add to a more accurate description of the TMJ and of brain lesions.Doktorgradsavhandlin

Correction for fast pseudo-diffusive fluid motion contaminations in diffusion tensor imaging

In this prospective study, we quantified the fast pseudo-diffusion contamination by blood perfusion or cerebrospinal fluid (CSF) intravoxel incoherent movements on the measurement of the diffusion tensor metrics in healthy brain tissue. Diffusion-weighted imaging (TR/TE = 4100 ms/90 ms; b-values: 0, 5, 10, 20, 35, 55, 80, 110, 150, 200, 300, 500, 750, 1000, 1300 s/mm2, 20 diffusion-encoding directions) was performed on a cohort of five healthy volunteers at 3 Tesla. The projections of the diffusion tensor along each diffusion-encoding direction were computed using a two b-value approach (2b), by fitting the signal to a monoexponential curve (mono), and by correcting for fast pseudo-diffusion compartments using the biexponential intravoxel incoherent motion model (IVIM) (bi). Fractional Anisotropy (FA) and Mean Diffusivity (MD) of the diffusion tensor were quantified in regions of interest drawn over white matter areas, gray matter areas, and the ventricles. A significant dependence of the MD from the evaluation method was found in all selected regions. A lower MD was computed when accounting for the fast-diffusion compartments. A larger dependence was found in the nucleus caudatus (bi: median 0.86 10-3 mm2/s, Δ2b: -11.2%, Δmono: -14.4%; p = 0.007), in the anterior horn (bi: median 2.04 10-3 mm2/s, Δ2b: -9.4%, Δmono: -11.5%, p = 0.007) and in the posterior horn of the lateral ventricles (bi: median 2.47 10-3 mm2/s, Δ2b: -5.5%, Δmono: -11.7%; p = 0.007). Also for the FA, the signal modeling affected the computation of the anisotropy metrics. The deviation depended on the evaluated region with significant differences mainly in the nucleus caudatus (bi: median 0.15, Δ2b: +39.3%, Δmono: +14.7%; p = 0.022) and putamen (bi: median 0.19, Δ2b: +3.1%, Δmono: +17.3%; p = 0.015). Fast pseudo-diffusive regimes locally affect diffusion tensor imaging (DTI) metrics in the brain. Here, we propose the use of an IVIM-based method for correction of signal contaminations through CSF or perfusion

Comprehensive Brain Tumour Characterisation with VERDICT-MRI: Evaluation of Cellular and Vascular Measures Validated by Histology

The aim of this work was to extend the VERDICT-MRI framework for modelling brain tumours, enabling comprehensive characterisation of both intra- and peritumoural areas with a particular focus on cellular and vascular features. Diffusion MRI data were acquired with multiple b-values (ranging from 50 to 3500 s/mm2), diffusion times, and echo times in 21 patients with brain tumours of different types and with a wide range of cellular and vascular features. We fitted a selection of diffusion models that resulted from the combination of different types of intracellular, extracellular, and vascular compartments to the signal. We compared the models using criteria for parsimony while aiming at good characterisation of all of the key histological brain tumour components. Finally, we evaluated the parameters of the best-performing model in the differentiation of tumour histotypes, using ADC (Apparent Diffusion Coefficient) as a clinical standard reference, and compared them to histopathology and relevant perfusion MRI metrics. The best-performing model for VERDICT in brain tumours was a three-compartment model accounting for anisotropically hindered and isotropically restricted diffusion and isotropic pseudo-diffusion. VERDICT metrics were compatible with the histological appearance of low-grade gliomas and metastases and reflected differences found by histopathology between multiple biopsy samples within tumours. The comparison between histotypes showed that both the intracellular and vascular fractions tended to be higher in tumours with high cellularity (glioblastoma and metastasis), and quantitative analysis showed a trend toward higher values of the intracellular fraction (fic) within the tumour core with increasing glioma grade. We also observed a trend towards a higher free water fraction in vasogenic oedemas around metastases compared to infiltrative oedemas around glioblastomas and WHO 3 gliomas as well as the periphery of low-grade gliomas. In conclusion, we developed and evaluated a multi-compartment diffusion MRI model for brain tumours based on the VERDICT framework, which showed agreement between non-invasive microstructural estimates and histology and encouraging trends for the differentiation of tumour types and sub-regions