Entwicklung der multifrequenten Magnetresonanz-Elastographie zur Quantifizierung der biophysikalischen Eigenschaften von menschlichem Hirngewebe

Magnetic resonance elastography (MRE) is an emerging technique for the quantitative imaging of the biophysical properties of soft tissues in humans. Following its successful clinical application in detecting and characterizing liver fibrosis, the scientific community is investigating the use of viscoelasticity as a biomarker for neurological diseases. Clinical implementation requires a thorough understanding of brain tissue mechanics in conjunction with innovative techniques in new research areas. Therefore, three in vivo studies were conducted to analyze the inherent stiffness dispersion of brain tissue over a wide frequency range, to investigate real-time MRE in monitoring the viscoelastic response of brain tissue during the Valsalva maneuver (VM), and to study mechanical alterations of small lesions in multiple sclerosis (MS). Ultra-low frequency MRE with profile-based wave analysis was developed in 14 healthy subjects to determine large-scale brain stiffness, from pulsation-induced shear waves (1 Hz) to ultra-low frequencies (5 – 10 Hz) to the conventional range (20 – 40 Hz). Furthermore, multifrequency real-time MRE with a frame rate of 5.4 Hz was introduced to analyze stiffness and fluidity changes in response to respiratory challenges and cerebral autoregulation in 17 healthy subjects. 2D and 3D wavenumber-based stiffness reconstruction of the brain was established for conventional MRE in 12 MS patients. MS lesions were analyzed in terms of mechanical contrast with surrounding tissue in relation to white matter (WM) heterogeneity. We found superviscous properties of brain tissue at large scales with a strong stiffness dispersion and a relatively high model-based viscosity of η = 6.6 ± 0.3 Pa∙s. The brain’s viscoelasticity was affected by perfusion changes during VM, which was associated with an increase in brain stiffness of 6.7% ± 4.1% (p<.001), whereas fluidity decreased by -2.1 ± 1.4% (p<.001). In the diseased brain, the analysis of 147 MS lesions revealed 46% of lesions to be softer and 54% of lesions to be stiffer than surrounding tissue. However, due to the heterogeneity of WM stiffness, the results provide no significant evidence for a systematic pattern of mechanical variations in MS. Nevertheless, the results may explain, for the first time, the gap between static ex vivo and dynamic in vivo methods. Fluidity-induced dispersion provides rich information on the structure of tissue compartments. Moreover, viscoelasticity is affected by perfusion during cerebral autoregulation and thus may be sensitive to intracranial pressure modulation. The overall heterogeneity of stiffness obscures changes in MS lesions, and MS may not exhibit sclerosis as a mechanical signature. In summary, this thesis contributes to the field of human brain MRE by presenting new methods developed in studies conducted in new research areas using state-of-the-art technology. The results advance clinical applications and open exciting possibilities for future in vivo studies of human brain tissue.Die Magnetresonanz-Elastographie (MRE) ist ein Verfahren zur quantitativen Darstellung der viskoelastischen Eigenschaften von Weichgewebe. Nach der erfolgreichen klinischen Anwendung in der Leberdiagnostik wird versucht, Viskoelastizität als Biomarker für neurologische Krankheiten zu nutzen. Hierzu bedarf es einer genauen Analyse der Gewebemechanik und innovativen Anwendungsgebieten. Daher, wurden drei Studien durchgeführt, um die Steifigkeitsdispersion von Hirngewebe zu analysieren, das viskoelastische Verhalten während des Valsalva Manövers (VM) abzubilden, und die mechanischen Veränderungen in Läsionen bei Multipler Sklerose (MS) zu untersuchen. Niedrigfrequenz-MRE mit profilbasierter Wellenanalyse wurde in 14 Probanden entwickelt, um die Steifigkeit des Gesamthirns von pulsationsinduzierten Scherwellen (1 Hz) über ultraniedrige Frequenzen (5 – 10 Hz) bis hin zum konventionellen Bereich (20 – 40 Hz) zu bestimmen. Außerdem wurde die multifrequente Echtzeit-MRE mit einer Bildfrequenz von 6.4 Hz eingeführt, um die viskoelastische Antwort des Gehirns auf respiratorische Herausforderungen bei 17 gesunden Probanden zu untersuchen. Neue 2D- und 3D-Wellenzahl-basierte Steifigkeitsrekonstruktionen für das Gehirn wurden in 12 MS Patienten und konventioneller MRE entwickelt. Die Steifigkeitsänderungen in MS-Läsionen wurden mit umliegender weißer Substanz und dessen Heterogenität verglichen. Wir fanden superviskose Eigenschaften des Hirngewebes mit einer starken Dispersion und relativ hohen, modellbasierten Viskosität von η = 6,6 ± 0,3 Pa∙s. Die mechanischen Gewebeeigenschaften wurden durch Perfusionsänderungen während VM beeinflusst und die Hirnsteifigkeit erhöhte sich um 6,7 ± 4,1% (p<.001) wobei sich die Fluidität um -2,1 ± 1,4% (p<.001) verringerte. Die Analyse von 147 MS-Läsionen ergab, dass 54% bzw. 46% der Läsionen steifer bzw. weicher sind als das umgebende Gewebe. Aufgrund der Heterogenität der WM-Steifigkeit konnte jedoch kein Hinweis auf ein systematisches Muster mechanischer Veränderungen in MS-Läsionen gefunden werden. Die Ergebnisse können zum ersten Mal die Lücke zwischen statischen ex vivo und dynamischen in vivo Methoden erklären. Die fluiditätsinduzierte Dispersion liefert interessante Informationen über die zugrundeliegende Gewebestruktur. Darüber hinaus wird die Viskoelastizität durch die Perfusion während der zerebralen Autoregulation beeinflusst und kann daher empfindlich auf intrakranielle Druckschwankungen reagieren. Die allgemeine Heterogenität der Steifigkeit überschattet die Veränderungen in MS-Läsionen, und somit ist Sklerose möglicherweise kein prominentes Merkmal von MS. Zusammenfassend lässt sich festhalten, dass diese Dissertation einen Beitrag zum Gebiet der MRE leistet, indem neue Methoden und Anwendungen in neuen Forschungsgebieten mit modernster Technologie dargestellt werden. Hierdurch wird die klinische Translation gefördert und spannende Möglichkeiten für zukünftige Studien eröffnet

Analysis in magnetic resonance elastography: study and development of image processing techniques

Tese de mestrado em Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012The term “Elastography‖” unifies biomechanics with imaging sciences and was driven by the well-documented effectiveness of palpation as a diagnostic technique for detecting cancer and other diseases. Notoriously, during the last decade Magnetic Resonance Elastography (MRE) has emerged as the most accurate imaging modality to non-invasively assess the rheological properties of tissue. Using a phase-contrast MRI technique together with an external mechanical actuation device, it is possible to detect propagating shear waves inside the human body. Viscoelastic properties can then be extracted by applying inversion methods to the acquired phase data. Due to the richness and significance of the data, and in spite of enduring challenges related to the complexity of the computations involved, MRE attracted strong interest and is now a thriving area of research. The computations necessary to calculate maps of viscoelastic tissue properties are indeed substantial and are generally done on remote computers after completion of experiments. The need for higher flexibility in large scale clinical studies led to the development, in the current project, of an automated toolbox for real time MRE data processing implemented within the scanner environment. The most commonly used direct inversion methods, Algebraic Helmholtz Inversion (AHI) and Local Frequency Estimation, show considerable performance differences under similar initial conditions. Assumptions underlying such algorithms were studied by comparing noise sensitivity and resolution on synthetic, phantom and in vivo brain datasets. Finally, a clinical application of the AHI approach was performed on brain and abdominal data from healthy individuals. The ensuing values of brain viscoelasticity suggest higher stiffness in white matter compared to grey matter. Preliminary results also show a pronounced age-related decrease in brain stiffness and viscosity. The liver, kidney and spleen were assessed with abdominal MRE and the results support a statistically significant higher stiffness in the spleen compared to liver and kidney.A rigidez e viscosidade são das propriedades mecânicas intrínsecas dos tecidos com maior relevância fisiopatológica. Segundo as fontes conhecidas, desde 400 a.C., a palpação tem sido o método mais utilizado como primeira fonte de avaliação médica, de forma a detectar pequenas massas ou tumores em tecidos moles. No entanto, a experiência profissional do médico e a própria localização da massa têm um grande impacto na qualidade do diagnóstico efectuado. Sabendo que o módulo de elasticidade possui uma variabilidade nos tecidos moles superior à de outras propriedades físicas, como a absorção de raios X ou o tempo de relaxamento em ressonância magnética nuclear, e que a ressonância magnética é das técnicas que, até à data, foi capaz de produzir imagens com maior qualidade e resolução espacial, surgiu uma forte motivação para unificar a biomecânica com a imagiologia por ressonância magnética. Deste modo, a Elastografia por Ressonância Magnética (MRE, do inglês “Magnetic Resonance Elastography‖” apareceu em meados dos anos 90 do século passado, permitindo avaliar e medir com um elevado grau de exactidão as propriedades reológicas dos tecidos, de modo não invasivo. Utilizando uma técnica de contraste de fase em MRI, em conjunto com um dispositivo dinâmico de oscilação mecânica, a MRE mostra um potencial muito grande para detectar a propagação de ondas mecânicas no corpo humano, com uma precisão da ordem de grandeza dos mícrons. Posteriormente à aquisição das chamadas “imagens de fase”, o processamento de imagem, através da aplicação de algoritmos de inversão, permite quantificar o comportamento reológico do meio. Esta nova modalidade de diagnóstico deu até hoje lugar a um conjunto de estudos pré-clínicos que permitiram a investigação das condições mecânicas associadas a alterações fisiológicas e patológicas, em tecidos nos quais esta abordagem nunca tinha sido possível. Éntre esses tecidos, é de destacar o caso do cérebro, um órgão onde a palpação ou aplicação de elastrografia convencional, associada a ultrassons, é inviável devido à presença da caixa craniana. Podem-se, assim, enumerar alguns estudos empreendidos com esta técnica até hoje, de inquestionável impacto científico e clínico: a fibrose hepática, o envelhecimento do cérebro, a esclerose múltipla, a hidrocefalia e os tumores cerebrais. Uma das áreas que actualmente atrai maior interesse consiste na correcta quantificação da viscoelasticidade a partir dos dados adquiridos no scanner. Tendo como base premissas diferentes, muitos algoritmos foram propostos para inverter a equação de ondas, calculando parâmetros relevantes a partir da simples propagação das ondas nos tecidos. Os métodos mais intuitivos designam-se por métodos directos, sendo os mais comuns a Inversão Algébrica da equação de Helmholtz (AHI, do inglês “Algebraic Helmholtz Inversion‖” e a Estimação da Frequência Local (LFE, do inglês “Local Frequency Estimation‖”. O primeiro tem por base uma origem matemática, realizando a inversão local em cada ponto da matriz da imagem segundo a equação de Helmholtz. A técnica de LFE, por outro lado, resolve o problema através de métodos de processamento, onde a aplicação de uma cadeia de filtros permite extrair a frequência espacial local das ondas de shear, estando esta relacionada com o módulo da elasticidade através de uma simples relação algébrica. Neste contexto, a tese apresentada prende-se com os métodos de análise de imagem em MRE, nomeadamente tanto no estudo como no desenvolvimento de técnicas que permitem uma avaliação das propriedades dinâmicas do meio, com precisão, exactidão e flexibilidade. Um dos problemas da baixa aplicabilidade da técnica de MRE a grandes estudos clínicos é, de facto, a falta de flexibilidade na obtenção de mapas de elasticidade. O volume de cálculos necessários para a construção desses mapas é muito grande, e por isso esses cálculos são geralmente efectuados em computadores independentes, depois de terminada a etapa da aquisição dos dados. Desta forma, o primeiro projecto consistiu no desenvolvimento de uma toolbox que permitisse o processamento de imagem em tempo real, embutido no proprio scanner. Assim, aquando da aquisição de uma experiência de elastografia, será possível obter não só a disposição espacial e intensidade da propagação das ondas mecânicas, mas também um mapa adicional correspondente à elasticidade do tecido, directamente na sala de controlo. Para este efeito, foi desenvolvido um algoritmo de reconstrução codificado num ambiente compatível com o sistema de computação de scanners da Siemens. Depois de várias fases de avaliação, desenvolvimento, debugging e validação do algoritmo, tanto offline como inline em simuladores, foram realizados testes no próprio scanner em fantomas e no cérebro de um voluntário saudável, utilizando várias frequências de oscilação. Desta forma, pôde-se verificar o sucesso global da toolbox implementada. Ainda assim, será necessária uma fase de optimização no sentido de criar uma toolbox de uso mais familiar e melhorar o algoritmo em si, corrigindo alguns problemas da versão actual. Os dois algoritmos de reconstrução mais utilizados a nível clínico, AHI e LFE, anteriormente apresentados e contextualizados, revelam um desempenho surpreendentemente diferente, sob condições iniciais idênticas e não obstante os princípios físicos subjacentes serem semelhantes. Estas inconsistências reflectem-se numa vasta gama de valores para o módulo de elasticidade verificados na literatura. Por conseguinte, foi efectuado um estudo para testar a qualidade das reconstruções em termos de sensibilidade, resolução espacial e eficácia na reconstrução em fantomas gerados sinteticamente, onde ruído, atenuação, ondas de compressão e padrões de interferência foram adicionados a uma equação de ondas básica. Para avaliar o desempenho dos algoritmos em dados de MRE extraídos do scanner, utilizaram-se jogos de dados obtidos com fantomas de gel sem e com inclusões de elasticidade dissemelhante entre regiões, assim como dados cerebrais de indivíduos saudáveis. Em geral, os resultados demonstram que o método LFE é mais eficaz em condições ideais, mas carece de precisão na análise de imagens sintéticas com artefactos tal como em dados reais. Isto é devido essencialmente a uma filtragem excessiva, assim como ao facto de o algoritmo não considerar a atenuação como uma premissa do modelo. Pelo contrário, os mapas obtidos pelo método AHI são mais nítidos mas são altamente susceptíveis a ruído. Mais se concluiu, que certas metodologias que antecedem a inversão são de extrema importância, destacando-se o processo de filtragem espacial. Finalmente, a medição das propriedades físicas dos fantomas através de reometria convencional permitiu verificar uma disparidade nas duas técnicas, podendo levar à conclusão de que as reconstruções obtidas em MRE são sobrestimadas. No entanto, deve ser efectuada uma análise mais profunda em condições experimentais tão idênticas quanto possível, para que se possam confirmar estes efeitos. O método AHI foi escolhido para estudar o cérebro de nove indivíduos saudáveis com idades compreendidas entre os 19 e os 62 anos. Neste estudo foram identificadas diferenças significativas, tanto na elasticidade como na viscosidade da matéria branca e cinzenta em todos os indivíduos, constatando-se que a última é a menos rígida. Além disso, um modelo linear regressivo foi ajustado aos valores obtidos com o método AHI tendo em conta a idade do sujeito, de forma a verificar tendências relativas esta variável.Resultados preliminares evidenciam uma distribuição linear com um declive negativo indicativo de um decréscimo pronunciado da elasticidade do tecido cerebral com a idade: a percentagem de decréscimo anual previsto foi de 0,75%. Apesar de não ser estatisticamente significativo, foram ainda identificadas pequenas diferenças nas taxas de decréscimo da elasticidade e viscosidade da matéria branca e cinzenta. No entanto, os resultados obtidos fazem parte de um estudo em curso e, como tal, será necessário testar um amostra superior para confirmar os resultados mencionados, assim como métodos mais sofisticados para analisar os dados. Por fim, realizou-se um estudo sobre as propriedades viscoelásticas de tecidos do abdómen. Sendo a sequência utilizada baseada em “Echo Planar Imaging” (EPI), as inomogeneidades do campo magnético e artefactos de ghosting são mais pronunciados na aquisição de imagem em tecidos moles no abdómen. Foi necessário assim, numa primeira fase, optimizar o protocolo de aquisição: o uso de bandas de saturação para suprimir o tecido adiposo, ajustes no “Field of View”, o uso de técnicas de shimming e aquisição de imagem apenas durante apneia expiratória. O dispositivo que permite a distribuição de propagação das ondas nos tecidos também foi explorado, de forma a obter uma propagação uniforme com elevada amplitude ao longo da totalidade do corte. A aquisição de dados de cinco voluntários saudáveis permitiu avaliar três tecidos com níveis de elasticidade distintos: o fígado, os rins e o baço. As principais conclusões retiradas indicam que o fígado e rins apresentam uma elasticidade menor que o baço, sob o modelo linear de tensão-deformação no qual se baseia o método AHI. Ainda assim, todo o processo de optimização está longe de se dar por concluído, pretendendo-se obter uma reprodutibilidade entre experiências com um protocolo de implementação expedito para ser possível aumentar a quantidade de dados e fazer uma análise estatística com um nível de confiança superior. Em conclusão, a técnica de MRE mostra um enorme potencial para detectar alterações na elasticidade dos tecidos através de pequenas deformações periódicas induzidas durante a aquisição de imagem numa ressonância magnética. A tese apresentada aborda pontos importantes relativos à fase do processamento e análise de dados, contribuindo para a evolução da MRE no sentido da aceitação desta técnica em ambiente clínico. Soluções concretas para uma análise rápida a tempo real foram dadas através do desenvolvimento da toolbox. Numa outra perspectiva, foram estudados nesta tese aspectos técnicos relevantes relativos aos algoritmos de inversão, críticos para a obtenção de um processamento profundo e correcto dos dados obtidos. Por fim, os trabalhos desta tese resultaram na identificação e reconhecimento de diferenças entre a viscoelasticidade dos tecidos, medida in vivo, a um nível pré-clínico, deixa em aberto todo um conjunto de ideias para estudos inovadores na área da biomecânica aplicada ao ser humano em conjunção com imagiologia

Cerebral tomoelastography based on multifrequency MR elastography in two and three dimensions

Magnetic resonance elastography (MRE) generates quantitative maps of the mechanical properties of biological soft tissues. However, published values obtained by brain MRE vary largely and lack detail resolution, due to either true biological effects or technical challenges. We here introduce cerebral tomoelastography in two and three dimensions for improved data consistency and detail resolution while considering aging, brain parenchymal fraction (BPF), systolic blood pressure, and body-mass-index. Multifrequency MRE with 2D- and 3D-tomoelastography postprocessing was applied to the brains of 31 volunteers (age range: 22-61 years) for analyzing the coefficient of variation (CV) and effects of biological factors. Eleven volunteers were rescanned after one day and one year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. White matter shear-wave-speed (SWS) was slightly higher in 2D-MRE (1.28±0.02m/s) than 3D-MRE (1.22±0.05m/s, p<0.0001), with less variation after one day in 2D (0.33±0.32%) than in 3D (0.96±0.66%, p=0.004), which was also reflected in a slightly lower CV and higher ICC in 2D (1.84%, 0.97 [0.88-0.99]) than in 3D (3.89%, 0.95 [0.76-0.99]). Remarkably, 3D-MRE was sensitive to a decrease in white matter SWS within only one year, whereas no change in white matter volume was observed during this follow-up period. Across volunteers, stiffness correlated with age and BPF, but not with blood pressure and body-mass-index. Cerebral tomoelastography provides high-resolution viscoelasticity maps with excellent consistency. Brain MRE in 2D shows less variation across volunteers in shorter scan times than 3D-MRE, while 3D-MRE appears to be more sensitive to subtle biological effects such as aging

Standard‐space atlas of the viscoelastic properties of the human brain

Standard anatomical atlases are common in neuroimaging because they facilitate data analyses and comparisons across subjects and studies. The purpose of this study was to develop a standardized human brain atlas based on the physical mechanical properties (i.e., tissue viscoelasticity) of brain tissue using magnetic resonance elastography (MRE). MRE is a phase contrast-based MRI method that quantifies tissue viscoelasticity noninvasively and in vivo thus providing a macroscopic representation of the microstructural constituents of soft biological tissue. The development of standardized brain MRE atlases are therefore beneficial for comparing neural tissue integrity across populations. Data from a large number of healthy, young adults from multiple studies collected using common MRE acquisition and analysis protocols were assembled (N = 134; 78F/ 56 M; 18–35 years). Nonlinear image registration methods were applied to normalize viscoelastic property maps (shear stiffness, μ, and damping ratio, ξ) to the MNI152 standard structural template within the spatial coordinates of the ICBM-152. We find that average MRE brain templates contain emerging and symmetrized anatomical detail. Leveraging the substantial amount of data assembled, we illustrate that subcortical gray matter structures, white matter tracts, and regions of the cerebral cortex exhibit differing mechanical characteristics. Moreover, we report sex differences in viscoelasticity for specific neuroanatomical structures, which has implications for understanding patterns of individual differences in health and disease. These atlases provide reference values for clinical investigations as well as novel biophysical signatures of neuroanatomy. The templates are made openly available (github.com/mechneurolab/mre134) to foster collaboration across research institutions and to support robust cross-center comparisons

A 64-channel personal computer based image reconstruction system and applications in single echo acquisition magnetic resonance elastography and ultra-fast magnetic resonance imaging.

Emerging technologies in parallel magnetic resonance imaging (MRI) with massive receiver arrays have paved the way for ultra-fast imaging at increasingly high frame rates. With the increase in the number of receiver channels used to implement parallel imaging techniques, there is a corresponding increase in the amount of data that needs to be processed, slowing down the process of image reconstruction. To develop a complete reconstruction system which is easy to assemble in a single computer for a real-time rendition of images is a relevant challenge demanding dedicated resources for high speed digital data transfer and computation. We have enhanced a 64 channel parallel receiver system designed for single echo acquisition (SEA) MRI into a real-time imaging system by interfacing it with two commercially available digital signal processor (DSP) boards which are capable of transferring large amounts of digital data via a dedicated bus from two high performance digitizer boards. The resulting system has been used to demodulate raw image data in real-time data and store them at rates of 200 frames per second (fps) and subsequently display the processed data at rates of 26 fps. A further interest in realtime reconstruction techniques is to reduce the data handling issues. Novel ways to minimize the digitized data are presented using reduced sampling rate techniques. The proposed techniques reduce the amount of data generated by a factor of 5 without compromising the SNR and with no additional hardware. Finally, the usability of this tool is demonstrated by investigating fast imaging applications. Of particular interest among them are MR elastography applications. An exploratory study of SEA MRE was done to study the temperature dependency of shear stiffness in an agarose gel and the results correlate well with existing literature. With the ability to make MRE images in a single echo, the SEA MRE technique has an advantage over the conventional MRE techniques

Magnetic Resonance Rheology on Phantoms and Human Brains

In this thesis first systematic measurements on phantoms and human brains using Magnetic Resonance Rheology (MRR) are presented and means to evaluate the acquired data are investigated. MRR is a novel technique designed to image the mechanical properties of human brain tissue by performing a creep relaxation experiment inside a Magnetic Resonance Imaging (MRI) scanner. Using a lifting device inside the head coil the head is basically dropped a distance of approximately 1 mm. The response of the brain tissue to this shock excitation is then measured using motion sensitive phase imaging techniques. Hydrogels with varying stiffness inside PMMA containers with different sizes were used as phantoms emulating the soft brain tissue inside the hard skull to investigate the response to the excitation. Homogeneous phantoms were measured to investigate the response to the shock excitation and to determine the influence of size, stiffness and boundary conditions of the probe. An oscillation in the phase could be observed in response to the excitation and its frequency allowed distinguishing between different phantom configurations. Additionally, different kinds of inhomogeneous phantoms were investigated to evaluate the feasibility to spatially resolve substructures in the mechanical properties of the phantom material. For local structures depicting the phase strain proved to be a useful tool to identify the inclusions. The results from the phantom measurements were transferred to the in vivo measurement of ten healthy volunteers to evaluate the experimental set-up under real conditions. These measurements showed that the brain responses to excitation as expected with a distinct oscillation in each hemisphere. The frequencies extracted showed mostly comparable values over the ten volunteers. In both the phase and the phase strain images similar localized features were visible, some corresponding to anatomical structures like sulci. These result show that in vivo MRR measurements of the human brain are feasible and comparable and though there is room for improvement concerning the reproducibility of the excitation between different measurement sets, MRR appears to be an interesting tool to investigate human brain tissue

Early characterisation of neurodegeneration with high-resolution magnetic resonance elastography

This thesis contributes to recent interest within medical imaging regarding the development and clinical application of magnetic resonance elastography (MRE) to the human brain. MRE is a non-invasive phase-contrast MRI technique for measurement of brain mechanical properties in vivo, shown to reflect the composition and organisation of the complex tissue microstructure. MRE is a promising imaging biomarker for the early characterisation of neurodegeneration due to its exquisite sensitivity to variation among healthy and pathological tissue. Neurodegenerative diseases are debilitating conditions of the human nervous system for which there is currently no cure. Novel biomarkers are required to improve early detection, differential diagnosis and monitoring of disease progression, and could also ultimately improve our understanding of the pathophysiological mechanisms underlying degenerative processes. This thesis begins with a theoretical background of brain MRE and a description of the experimental considerations. A systematic review of the literature is then performed to summarise brain MRE quantitative measurements in healthy participants and to determine the success of MRE to characterise neurological disorders. This review further identified the most promising acquisition and analysis methods within the field. As such, subsequent visits to three brain MRE research centres, within the USA and Germany, enabled the acquisition of exemplar phantom and brain data to assist in discussions to refine an experimental protocol for installation at the Edinburgh Imaging Facility, QMRI (EIF-QMRI). Through collaborations with world-leading brain MRE centres, two high-resolution - yet fundamentally different - MRE pipelines were installed at the EIF-QMRI. Several optimisations were implemented to improve MRE image quality, while the clinical utility of MRE was enhanced by the novel development of a Graphical User Interface (GUI) for the optimised and automatic MRE-toanatomical coregistration and generation of MRE derived output measures. The first experimental study was performed in 6 young and 6 older healthy adults to compare the results from the two MRE pipelines to investigate test-retest agreement of the whole brain and a brain structure of interest: the hippocampal formation. The MRE protocol shown to possess superior reproducibility was subsequently applied in a second experimental study of 12 young and 12 older cognitively healthy adults. Results include finding that the MRE imaging procedure is very well tolerated across the recruited population. Novel findings include significantly softer brains in older adults both across the global cerebrum and in the majority of subcortical grey matter structures including the pallidum, putamen, caudate, and thalamus. Changes in tissue stiffness likely reflect an alteration to the strength in the composition of the tissue network. All MRE effects persist after correcting for brain structure volume suggesting changes in volume alone were not reflective of the detected MRE age differences. Interestingly, no age-related differences to tissue stiffness were found for the amygdala or hippocampus. As for brain viscosity, no group differences were detected for either the brain globally or subcortical structures, suggesting a preservation of the organisation of the tissue network in older age. The third experiment performed in this thesis finds a direct structure-function relationship in older adults between hippocampal viscosity and episodic memory as measured with verbal-paired recall. The source of this association was located to the left hippocampus, thus complementing previous literature suggesting unilateral hippocampal specialisation. Additionally, a more significant relationship was found between left hippocampal viscosity and memory after a new procedure was developed to remove voxels containing cerebrospinal fluid from the MRE analysis. Collectively, these results support the transition of brain MRE into a clinically useful neuroimaging modality that could, in particular, be used in the early characterisation of memory specific disorders such as amnestic Mild Cognitive Impairment and Alzheimer’s disease

Doctor of Philosophy

dissertationImage-based biomechanics, particularly numerical modeling using subject-specific data obtained via imaging, has proven useful for elucidating several biomechanical processes, such as prediction of deformation due to external loads, applicable to both normal function and pathophysiology of various organs. As the field evolves towards applications that stretch the limits of imaging hardware and acquisition time, the information traditionally expected as input for numerical routines often becomes incomplete or ambiguous, and requires specific acquisition and processing strategies to ensure physical accuracy and compatibility with predictive mathematical modeling. These strategies, often derivatives or specializations of traditional mechanics, effectively extend the nominal capability of medical imaging hardware providing subject-specific information coupled with the option of using the results for predictive numerical simulations. This research deals with the development of tools for extracting mechanical measurements from a finite set of imaging data and finite element analysis in the context of constructing structural atlases of the heart, understanding the biomechanics of the venous vasculature, and right ventricular failure. The tools include: (1) application of Hyperelastic Warping image registration to displacement-encoded MRI for reconstructing absolute displacement fields, (2) combination of imaging and a material parameter identification approach to measure morphology, deformation, and mechanical properties of vascular tissue, and (3) extrapolation of diffusion tensor MRI acquired at a single time point for the prediction the structural changes across the cardiac cycle with mechanical simulations. Selected tools were then applied to evaluate structural changes in a reversible animal model for right ventricular failure due to pressure overload

Development of finite element analysis of magnetic resonance elastography to investigate its potential use in abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) is a form of cardiovascular disease whereby a change in the material properties of the vessel wall results in a localised dilation of the abdominal aorta. The primary risk of AAAs is rupture with mortality rates close to 90%. Whilst surgical intervention can be performed to repair AAAs, such procedures are considered high risk. As a result, surgery is only performed upon AAAs that are considered likely to rupture. The current method of prediction is the diameter criterion, with surgical intervention performed if the diameter of the AAA exceeds 5.5cm. Research has demonstrated that this is a weak method of predicting rupture and as such other methodologies are sought. One promising method is patient specific modelling (PSM) which involves the reconstruction of individual patient AAA geometries from imaging datasets, and finite element analysis (FEA) to calculate the stresses acting on the AAA wall, with the peak stress typically used as the predictor. A weakness of this methodology is the lack of patient specific material property values defined in the simulation. A potential technique to address this limitation is magnetic resonance elastography (MRE), an MR-based technique which utilises a phase-contrast sequence to characterise displacements caused by shear waves induced into the tissue by an external mechanical driver. An inversion algorithm is used to calculate local material property values of the tissue from these displacements. The aim of this thesis was to investigate the capability of utilising MRE to obtain material property measurements from AAAs that could be incorporated into PSM. To achieve this an FE method of modelling MRE was developed. The influence of modelling parameters upon the material property measurements made using the direct inversion (DI) algorithm was investigated, with element type and boundary conditions shown to have an effect. The modelling technique was then utilised to demonstrate the influence that the size of an insert had upon shear modulus measurements of that insert using DI in both 2- and 3-dimensions, and the multi-frequency dual elasto-visco algorithm (MDEV), an extension of DI combining information from multiple frequencies. Meanwhile a comparison of the modelling technique against an MRE scan of a phantom showed that whilst measurements made from the two techniques were different at low frequencies, they became similar as the frequency increased. This suggested that such differences were attributable to increased noise in the scanned data. FEA of MRE performed on idealised AAA geometries demonstrated that AAA size, shear viscosity of the thrombus and shear modulus of the AAA wall all influenced the accuracy of MRE measurements in the thrombus. Meanwhile MRE scanning of a small cohort of AAA patients had been undertaken and phase images investigated for signs of wave propagation to investigate the capabilities of the current MRE setup. Phase images were dominated by noise and there was no wave propagation visualised in any of the AAAs. This thesis demonstrates that the current MRE setup is not capable of achieving accurate measurements of material properties of AAA for PSM. Visualisation of wave propagation in AAAs is technically demanding and requires further development. A more fundamental concern however is the size dependence of the inversion algorithm used and the inability to consistently make accurate measurements from AAA geometries