Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

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 data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and 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. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Quantifying age-related differences in diffusion tensor imaging biomarkers for the male urethral sphincter of prostate cancer patients

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas) Universidade de Lisboa, Faculdade de Ciências, 2019For the past years, radical prostatectomy (RP) has been the treatment of choice for locally advanced prostate cancer (PC) because of its high accuracy in tumor removal. However, the surgical techniques performed tend to be invasive, with a complete removal of the proximal lisso-sphincter and partial removal of the distal rhabdosphincter. Whereas the former has been related with maintenance of continence at rest, the latter is related with active continence. Between 4 to 69 % [1] of patients undergoing RP develop urinary incontinence, with a reported decrease in quality of life. This can be a consequence, not only from the surgical technique used, but from other factors including the competence of the sphincter function, that it is expected to decrease with age [2]. It is important to find preoperative imaging biomarkers that can help predict the risk of the patient developing postoperative urinary incontinence. The TransDouglas project, approved by the Ethics Committee of Champalimaud Foundation since July 2018, aims at validating the implementation of a new surgical procedure for RP, which is an improved version of the robotic-assisted laparoscopic radical prostatectomy (RALRP) procedure. Preoperative anatomical parameters are extracted from the T2-weighted magnetic resonance imaging (MRI) that can be related with urinary incontinence after the new surgical technique, and to construct a model that can help predict the likely time until urinary continence recovery. Diffusion tensor imaging (DTI) is a MRI-based technique that allows the quantification of anisotropic movement of water molecules. It has been proven [3] that this technique can be used to visualize the microarchitecture of the urethral sphincters, and to extract relevant diffusion metrics. DTI metrics can be incorporated in the model to predict urinary incontinence recovery after RP. Considering this, an addendum to the TransDouglas project that requests the acquisition of an additional DTI sequence to the standard multiparametric (mpMRI) of the prostate has been approved this January, enabling the use of DTI to study the microarchitecture of the urethral sphincters in vivo and non-invasively. However, since parameters of sphincter function significantly change with age [2], it is important to study the influence of patient age at scan on these parameters prior to predicting the likely chance of continence recovery after RP. Therefore, the main goal of this thesis was to investigate age-related differences in DTI metrics of the male urethral sphincter complex. Furthermore, the influence of a prostate condition, including PC and benign prostatic hyperplasia (BPH), was studied. The proximal and distal sphincters, as well as the membranous urethra, were reconstructed for 95 subjects by using the deterministic tractography algorithm in DSIStudio software [4]. DTI metrics were extracted including tract length and density, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) and additional histogram parameters for each DTI metric, namely standard deviation, median, trimmed mean, median absolute deviation, minimum, maximum, range, skewness, kurtosis, standard error and the 5th, 25th, 75th and 95th percentiles. The influence of subject motion and eddy currents corrections on the extracted DTI metrics was investigated. Linear regressions and Pearson or Spearman correlations were performed between age and each of the DTI metrics. Additionally, analysis of variance (ANOVA), or the non-parametric Kruskal-Wallis test, were used to compare DTI metrics between four age groups (from 50 to 59, 60 to 69, 70 to 79 and 80 to 89 years old). For a subset of the 69 subjects with a confirmed diagnosis for PC, BPH and the absence of any of both, ANOVA testing was used to compare between disease groups, and t-tests, or the nonparametric Wilcoxon test, to compare between cancer status. For statistically significant ANOVA test results, post-hoc t-tests were used to investigate the groups between which the difference lied. No statistically significant differences were found on DTI metrics with and without motion and eddy currents corrections, so the non-corrected DTI data was used for the subsequent analysis. In this study, it was found that MD and RD distributions statistical significantly changed with age. In particular, older subjects evidenced lower RD kurtosis in the proximal sphincter, lower MD maximum in the distal sphincter and higher MD median absolute deviation in the membranous urethra. On the other hand, further investigations are needed to understand if the presence of a prostate condition affects the DTI metrics of the sphincters and membranous urethra. This project was the first to examine age related differences in the urethral sphincter complex using DTI, as well as, the first time a DTI sequence for the prostate was implemented at Champalimaud Centre for the Unknown (CCU). It was concluded that age should be used as a covariate in a model that makes use of DTI biomarkers representative of the male urethral complex microstructure to predict the likely time of post-surgical continence recovery. Ultimately, this investigation should be a starting point for helping clinicians in the prediction of the risk of complications for each patient before undergoing RP, and balance the advantages and disadvantages comparing with other available treatment options for PC.Segundo dados de 2016, no sexo masculino e em paises desenvolvidos, o cancro da prostata foi o cancro que registou maior incidencia [5]. Apos uma detecao atraves do aumento da evolucao dos niveis do antigenio especifico da prostata (PSA) no sangue e/ou de realizacao do teste do toque retal, o método de diagnostico mais comum e a biopsia, que pode ser auxiliada por ultrassons ou por ressonância magnetica multiparametrica. A escolha do tratamento adequado para cada paciente depende do estadio da doenca e das suas preferencias individuais, que geralmente pretendem equiponderar a esperanca de vida para o paciente e a qualidade de vida apos tratamento. Geralmente, as opcoes de tratamento mais adequadas para um paciente com PSA > 10 ng/mL e nodulos palpaveis sao: acompanhamento e tratamento dos sintomas a medida que estes surgem, radioterapia ou braquiterapia, e cirurgia [6]. A ultima opcao, em particular a prostatectomia radical, tem demonstrado maior precisao na remocao de tecido maligno e no aumento da esperanca media de vida para os pacientes operados [7]. Mais recentemente, tecnicas laparoscopicas convencionais tem vindo a ser substituidas por tecnicas robóticas que oferecem maiores vantagens no pos-operatorio. No entanto, a incontinencia urinaria e a disfunção eretil continuam a ser complicacoes reportadas por uma percentagem significativa de pacientes submetidos a cirurgia. Relativamente ao primeiro, afeta cerca de 4 a 69 % dos pacientes [1], e a sua ocorrencia esta intimamente ligada a remocao do esfincter proximal ou liso, que ocorre aquando da remocao da prostata, e consequente dano no esfincter distal ou rabdoesfincter. A construcao de um modelo preditivo da recuperacao da continencia pos-cirurgica com base na utilizacao de biomarcadores do esfincter, pode permitir aos prospetivos pacientes uma escolha ponderada do tipo de tratamento. No entanto, e sabido que a microestrutura do esfincter varia com a idade [2], logo e necessario conhecer o padrao de variacao dos biomarcadores do esfincter com a idade, no sentido de avaliar a recuperacao pos-cirurgica da continencia. Para estudar a microestrutura do esfincter tem sido utilizadas diversas tecnicas in vivo [8]–[13] que, no entanto, nao fornecem informacao tridimensional da estrutura e orientacao das fibras que o compoem. Contrariamente, imagem por tensor de difusao (DTI) e uma tecnica nao invasiva baseada em ressonância magnetica que permite quantificar o movimento das moleculas de agua nos tecidos, atraves da aplicação de gradientes em varias direcoes nao colineares [14]. Relacionando o gradiente aplicado com o sinal medido, obtem-se em cada voxel informacao sobre a magnitude e direcao da difusao. A partir da diagonalizacao do tensor de difusao e possivel calcular eigenvalues e eigenvectors. Enquanto que os ultimos refletem a direccionalidade, os primeiros quantificam a magnitude da difusao e combinados entre si permitem obter um conjunto de metricas – que inclui a anisotropia fracional (FA), difusibilidade axial (AD), difusibilidade media (MD) e difusibilidade radial (RD) – que permitem estudar a organizacao estrutural das fibras. Apesar das aplicacoes de DTI se focarem essencialmente em estudos de conectividade da substancia branca do cerebro, tem progressivamente sido alargadas ao estudo de outros orgaos, como o rim [15], o coracao [16] e a prostata. Relativamente ao uso de DTI para o estudo da prostata, esta tecnica tem sido utilizada para estudar este orgao em condicoes normais [17] e para definir metricas que permitam distinguir tecido saudavel de tumoral [18]. Ademais, estudos tem avaliado os feixes neuro-vasculares da prostata antes e apos a cirurgia e correlacionado com a disfunção eretil pos-prostatectomia radical [7]. Para alem de um estudo que investigou o esfincter uretral feminino usando DTI [19], que se tenha conhecimento, existe apenas um estudo que conseguiu utilizar DTI para estudo da microarquitectura do esfincter masculino em sujeitos jovens e sem patologia [3]. Assim, o principal objetivo da presente tese de mestrado e investigar variacoes derivadas da idade no complexo do esfincter uretral, que compreende os esfincteres proximais e distais e a uretra membranosa – correspondente ao segmento da uretra que se estende desde o apice da prostata ate ao bulbo peniano. No sentido de estudar o efeito da presenca de uma condicao da prostata, incluindo cancro da prostata e hiperplasia benigna da prostata (HBP), a variacao das metricas de DTI do esfincter para o grupo de pacientes diagnosticados foi tambem avaliada. Como objetivo secundario, que teve importancia na etapa de processamento dos dados de DTI, foi investigado se a correcao de movimento durante a aquisicao e correcao de correntes de Foucault afetava significativamente as metricas de DTI em estudo, para cada uma das estruturas. Para tal, os esfincteres proximal e distal, bem como a uretra membranosa, foram reconstruidos para 95 individuos usando o algoritmo deterministico de tractografia no software DSIStudio [4]. Previamente foram definidas manualmente um conjunto de regioes de interesse nos mapas coloridos de FA para os esfincteres proximal e distal, e na imagem anatomica em T2 para a uretra membranosa. Para a tractografia, foram otimizados alguns parametros segundo uma abordagem de tentativa e erro, que acabou por estabelecer um valor limite de anisotropia fracional de 0.15, e um limite angular de 75o e 45o, respetivamente para os esfincteres e para a uretra. As metricas de DTI foram extraidas para cada uma das estruturas reconstruidas, incluindo o comprimento e densidade das fibras, FA, AD, MD e RD e parametros adicionais do histograma para cada metrica de DTI, ou seja, desvio padrao, mediana, media aparada, desvio absoluto mediano, minimo, maximo, amplitude, assimetria, curtose, erro padrao e os percentis 5, 25, 75 e 95. A influencia do movimento e da presenca de correntes de Foucault nas métricas de DTI extraidas foram investigadas. Regressoes lineares e correlacoes de Pearson ou Spearman foram realizadas entre a idade e cada uma das metricas de DTI. Alem disso, uma analise de variância (ANOVA) – ou o equivalente teste nao parametrico de Kruskal-Wallis –, foram realizados para comparar metricas de DTI entre quatro faixas etarias (de 50 a 59, 60 a 69, 70 a 79 e 80 a 89 anos). Para um subconjunto dos 69 individuos com diagnostico confirmado de cancro de prostata, HBP ou da ausencia de qualquer um dos dois, o teste ANOVA foi usado para comparar entre grupos de doenca. Adicionalmente, testes t-student – ou o teste nao parametrico de Wilcoxon – foram utilizados para comparar a presenca vs. ausencia de cancro. Para resultados estatisticamente significativos do teste ANOVA, foram posteriormente empregues testes t-student para investigar entre que grupos se encontrava a diferenca. Nao foram encontradas diferencas estatisticamente significativas nas metricas de DTI com e sem correcao de movimento e correntes de Foucault, logo, os dados de DTI sem correcao foram utilizados para a analise subsequente. Neste estudo, verificou-se que as distribuicoes de MD e RD variaram significativamente com a idade. Em particular, individuos mais velhos evidenciaram menor curtose da RD no esfincter proximal, menor valor maximo de MD no esfincter distal e maior desvio absoluto mediano de MD na uretra membranosa. Por outro lado, sao necessarias investigacoes adicionais para entender se a presenca de uma condicao da prostata pode afetar as metricas de DTI dos esfincteres e da uretra membranosa. Tal acontece, pois os resultados obtidos neste estudo para a presenca de doença estao limitados pela heterogeneidade da amostra em termos das diferentes condicoes que cada individuo pode apresentar. Julga-se que este estudo foi o primeiro a identificar variacoes com a idade nas metricas de DTI do esfincter. Alem disso, definiu a inclusao de uma sequencia de DTI a ressonancia magnética multiparametrica da pratica clinica da Fundacao Champalimaud. Por se tratar de um estudo prospetivo, foi possivel definir os parametros de aquisicao – nomeadamente o valor de b (em s/mm2), o numero de direcoes da aplicacao do gradiente, o numero de cortes adquiridos e a extensao da aquisicao - otimospara a visualizacao das estruturas do complexo uretral masculino, com o melhor compromisso entre duracao da aquisicao (em minutos) e a resolucao espacial (em milimetros). Esta nova sequencia so comecou a ser incluida na clinica desde Janeiro 2019, o que representa cerca de 14 pacientes operados, dos 45 diagnosticados com cancro da prostata. Assim que for possivel aumentar a amostra de pacientes operados com um intervalo de tempo pos-cirurgico de 3 a 6 meses, sera possivel utilizar os resultados dos testes de incontinencia, os dados de DTI do esfincter corrigidos da idade e as medidas do comprimento da uretra em T2, para prever o tempo de recuperacao de continencia pos-cirurgica. No futuro, esperamos poder extrair os biomarcadores de DTI para o complexo do esfincter uretral de cada paciente e usa-los como um preditor da taxa de incontinencia pos-cirurgica. No entanto, e importante que este modelo tenha em conta alteracoes nas metricas de DTI do complexo uretral masculino que são influenciadas pelo envelhecimento. Esse modelo preditivo pode orientar os pacientes na escolha informada da melhor opcao de tratamento personalizado para tratar o tumor da prostata e, simultaneamente, proporcionar uma qualidade de vida satisfatoria

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

Segmentierung medizinischer Bilddaten und bildgestützte intraoperative Navigation

Die Entwicklung von Algorithmen zur automatischen oder semi-automatischen Verarbeitung von medizinischen Bilddaten hat in den letzten Jahren mehr und mehr an Bedeutung gewonnen. Das liegt zum einen an den immer besser werdenden medizinischen Aufnahmemodalitäten, die den menschlichen Körper immer feiner virtuell abbilden können. Zum anderen liegt dies an der verbesserten Computerhardware, die eine algorithmische Verarbeitung der teilweise im Gigabyte-Bereich liegenden Datenmengen in einer vernünftigen Zeit erlaubt. Das Ziel dieser Habilitationsschrift ist die Entwicklung und Evaluation von Algorithmen für die medizinische Bildverarbeitung. Insgesamt besteht die Habilitationsschrift aus einer Reihe von Publikationen, die in drei übergreifende Themenbereiche gegliedert sind: -Segmentierung medizinischer Bilddaten anhand von vorlagenbasierten Algorithmen -Experimentelle Evaluation quelloffener Segmentierungsmethoden unter medizinischen Einsatzbedingungen -Navigation zur Unterstützung intraoperativer Therapien Im Bereich Segmentierung medizinischer Bilddaten anhand von vorlagenbasierten Algorithmen wurden verschiedene graphbasierte Algorithmen in 2D und 3D entwickelt, die einen gerichteten Graphen mittels einer Vorlage aufbauen. Dazu gehört die Bildung eines Algorithmus zur Segmentierung von Wirbeln in 2D und 3D. In 2D wird eine rechteckige und in 3D eine würfelförmige Vorlage genutzt, um den Graphen aufzubauen und das Segmentierungsergebnis zu berechnen. Außerdem wird eine graphbasierte Segmentierung von Prostatadrüsen durch eine Kugelvorlage zur automatischen Bestimmung der Grenzen zwischen Prostatadrüsen und umliegenden Organen vorgestellt. Auf den vorlagenbasierten Algorithmen aufbauend, wurde ein interaktiver Segmentierungsalgorithmus, der einem Benutzer in Echtzeit das Segmentierungsergebnis anzeigt, konzipiert und implementiert. Der Algorithmus nutzt zur Segmentierung die verschiedenen Vorlagen, benötigt allerdings nur einen Saatpunkt des Benutzers. In einem weiteren Ansatz kann der Benutzer die Segmentierung interaktiv durch zusätzliche Saatpunkte verfeinern. Dadurch wird es möglich, eine semi-automatische Segmentierung auch in schwierigen Fällen zu einem zufriedenstellenden Ergebnis zu führen. Im Bereich Evaluation quelloffener Segmentierungsmethoden unter medizinischen Einsatzbedingungen wurden verschiedene frei verfügbare Segmentierungsalgorithmen anhand von Patientendaten aus der klinischen Routine getestet. Dazu gehörte die Evaluierung der semi-automatischen Segmentierung von Hirntumoren, zum Beispiel Hypophysenadenomen und Glioblastomen, mit der frei verfügbaren Open Source-Plattform 3D Slicer. Dadurch konnte gezeigt werden, wie eine rein manuelle Schicht-für-Schicht-Vermessung des Tumorvolumens in der Praxis unterstützt und beschleunigt werden kann. Weiterhin wurde die Segmentierung von Sprachbahnen in medizinischen Aufnahmen von Hirntumorpatienten auf verschiedenen Plattformen evaluiert. Im Bereich Navigation zur Unterstützung intraoperativer Therapien wurden Softwaremodule zum Begleiten von intra-operativen Eingriffen in verschiedenen Phasen einer Behandlung (Therapieplanung, Durchführung, Kontrolle) entwickelt. Dazu gehört die erstmalige Integration des OpenIGTLink-Netzwerkprotokolls in die medizinische Prototyping-Plattform MeVisLab, die anhand eines NDI-Navigationssystems evaluiert wurde. Außerdem wurde hier ebenfalls zum ersten Mal die Konzeption und Implementierung eines medizinischen Software-Prototypen zur Unterstützung der intraoperativen gynäkologischen Brachytherapie vorgestellt. Der Software-Prototyp enthielt auch ein Modul zur erweiterten Visualisierung bei der MR-gestützten interstitiellen gynäkologischen Brachytherapie, welches unter anderem die Registrierung eines gynäkologischen Brachytherapie-Instruments in einen intraoperativen Datensatz einer Patientin ermöglichte. Die einzelnen Module führten zur Vorstellung eines umfassenden bildgestützten Systems für die gynäkologische Brachytherapie in einem multimodalen Operationssaal. Dieses System deckt die prä-, intra- und postoperative Behandlungsphase bei einer interstitiellen gynäkologischen Brachytherapie ab

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'

Quantitative MRI correlates of hippocampal and neocortical pathology in intractable temporal lobe epilepsy

Intractable or drug-resistant epilepsy occurs in over 30% of epilepsy patients, with many of these patients undergoing surgical excision of the affected brain region to achieve seizure control. Advances in MRI have the potential to improve surgical treatment of epilepsy through improved identification and delineation of lesions. However, validation is currently needed to investigate histopathological correlates of these new imaging techniques. The purpose of this work is to investigate histopathological correlates of quantitative relaxometry and DTI from hippocampal and neocortical specimens of intractable TLE patients. To achieve this goal I developed and evaluated a pipeline for histology to in-vivo MRI image registration, which finds dense spatial correspondence between both modalities. This protocol was divided in two steps whereby sparsely sectioned histology from temporal lobe specimens was first registered to the intermediate ex-vivo MRI which is then registered to the in-vivo MRI, completing a pipeline for histology to in-vivo MRI registration. When correlating relaxometry and DTI with neuronal density and morphology in the temporal lobe neocortex, I found T1 to be a predictor of neuronal density in the neocortical GM and demonstrated that employing multi-parametric MRI (combining T1 and FA together) provided a significantly better fit than each parameter alone in predicting density of neurons. This work was the first to relate in-vivo T1 and FA values to the proportion of neurons in GM. When investigating these quantitative multimodal parameters with histological features within the hippocampal subfields, I demonstrated that MD correlates with neuronal density and size, and can act as a marker for neuron integrity within the hippocampus. More importantly, this work was the first to highlight the potential of subfield relaxometry and diffusion parameters (mainly T2 and MD) as well as volumetry in predicting the extent of cell loss per subfield pre-operatively, with a precision so far unachievable. These results suggest that high-resolution quantitative MRI sequences could impact clinical practice for pre-operative evaluation and prediction of surgical outcomes of intractable epilepsy

Enhancing microstructural specificity in diffusion MRI analysis

Enclosed within a protective bony shell, the human brain poses a significant challenge for direct physical examination. Therefore, non-invasive methods, such as Magnetic Resonance Imaging (MRI), have become very important tools for exploring the brain’s structure and functionality. Nevertheless, these indirect techniques are not without their limitations, notably a lack of specificity. Although they are sensitive to microstructural variations, their capacity to link changes in signals to meaningful biophysical processes is limited. Microstructural modelling has risen to address this problem, offering a means to correlate these otherwise abstract measurements with meaningful biophysical parameters. However, as the complexity of these models, either in terms of geometry or physical properties, improves, so does the number of free parameters required, posing a substantial challenge for reliable parameter estimation. This thesis seeks to address two substantial issues within the field of microstructural modelling of diffusion MRI data. Firstly, it proposes a novel approach to identify the microstructural parameter alterations that can explain observed differences in diffusion MRI between diseased and control group. This approach enables the application of highly specific models without the associated concerns about parameter estimation. Secondly, it advocates for the development of a tool that extracts fibre-specific features from diffusion MRI data in a manner that promotes comparability across different subjects, facilitated by the use of hierarchical Bayesian models. By offering these approaches to analyze diffusion MRI data, this research aims to circumventing the constraints imposed by existing microstructural modeling techniques, thus improve the precision of brain structure diagnosis and comprehension

Advanced MRI methods for probing disease severity and functional decline in multiple sclerosis

Multiple sclerosis (MS) is a chronic and severe disease of the central nervous system characterized by complex pathology including inflammatory demyelination and neurodegeneration. MS impacts >2.8 million people worldwide, with most starting with a relapsing-remitting form (RRMS) in young adulthood, and many of them worsening to a secondary-progressive course (SPMS) despite treatment. So, there is a clear need for improved disease characterization. MRI is an ideal tool for non-invasive assessment of MS pathology, but there is still no established measure of disease activity and functional consequences. This project aims to overcome the challenge by developing novel imaging measures based on brain diffusion MRI and phase congruency texture analysis of conventional MRI. Through advanced modeling and analysis of clinically feasible brain MRI, this thesis investigates whether and how the derived measures differentiate MS pathology types and disease severity and predict functional outcomes in MS. The overall process has led to important technical innovations in several aspects. These include: innovative modeling of simple diffusion acquisitions to generate high angular resolution diffusion imaging (HARDI) measures; new optimization and harmonization techniques for diffusion MRI; innovative neural network models to create new diffusion data for comprehensive HARDI modeling; and novel methods and a graphic user interface for optimizing phase congruency analyses. Assisted by different machine learning methods, collective findings show that advanced measures from both diffusion MRI and phase congruency are highly sensitive to subtle differences in MS pathology, which differentiate disease severity between RRMS and SPMS through multi-dimensional analyses including chronic active lesions, and predict functional outcomes especially in physical and neurocognitive domains. These results are clinically translational and the new measures and techniques can help improve the evaluation and management of both MS and similar diseases