Quantifizierung von Porosität, getrennten Scherwellenfelder der festen und flüssigen Phasen sowie Kopplungsdichte mittels Inversion-Recovery-Magnetresonanzelastographie in porösen Phantomen und In-vivo-Gehirnen

Magnetic resonance elastography (MRE) is an emerging noninvasive technique based on magnetic resonance imaging (MRI) and shear waves that depicts biomechanical properties of biological tissues. In MRE, quantitative parameter maps are usually reconstructed under the assumption of monophasic viscoelastic media. Conversely, the poroelastic model, consisting of a solid porous matrix permeated by a fluid, can better describe the behavior of multiphasic soft tissues, e.g., the brain. However, the assumption of two media and their interactions increases the complexity of the underlying motion equations, impeding their solution without independent information on fluid and solid wavefields and prior porosity quantification. Therefore, the aim of this thesis was threefold: 1) to develop an MRI method for determining porosity; 2) to develop an MRE method for separately encoding shear wave fields of fluid and solid fractions in biphasic tissues; and 3) to estimate coupling density ρ12 and thus experimentally validate the poroelastic model equations. Methods Inversion recovery MRI (IR-MRI) and IR-MRE are introduced for voxel-wise quantification of porosity, shear strain of solid and fluid compartments, and ρ12. Porosity was estimated in fluid phantoms of different relaxation times, fluid-solid tofu phantoms, and in in vivo, in the brains of 21 healthy volunteers. Reference values of phantom porosity were obtained by microscopy and draining the fluid from the matrix. Solid and fluid shear-strain amplitudes and ρ12 were quantified in three tofu phantoms and seven healthy volunteers. Results Phantom porosity measured by IR-MRI agreed well with reference values (R=0.99, P<.01). Average brain tissue porosity was 0.14–0.02 in grey matter and 0.05–0.01 in white matter (P<.001). Fluid shear strain was phase-locked with solid shear strain but had lower amplitudes in both phantoms and brains (P<.05). ρ12 was negative in all materials and biological tissues investigated. Conclusions IR-MRI for the first time allowed noninvasive mapping of in vivo brain porosity and yielded consistent results in tissue-mimicking phantoms. IR-MRI combined with IR-MRE allowed us to separately encode shear strain fields of solid and fluid motion in phantoms and human brain. This led to the quantification of coupling density ρ12, which was negative, as predicted. IR-MRE opens horizons for the development and application of novel imaging markers based on the poroelastic behavior of soft biological tissues. Moreover, quantification of subvoxel multicompartmental interactions provides insight into multiscale mechanical properties, which are potentially relevant for various diagnostic applications.Die Magnetresonanz-Elastographie (MRE) ist eine neuartige Technik, welche die Magnetresonanztomographie (MRT) mit Scherwellen kombiniert, um so die nichtinvasive Darstellung der biomechanischen Gewebeeigenschaften zu ermöglichen. In der MRE werden quantitative Parameterkarten von Weichgewebe unter der Annahme monophasischer, viskoelastischer Materialeigenschaften rekonstruiert. Das in dieser Arbeit verwendete poroelastische Modell hingegen berücksichtigt bei Weichgewebe wie dem Gehirn die Mehrphasigkeit des Gewebe bestehend aus einer festen porösen Matrix und flüssigen Kompartimenten. Deren unabhängige mechanische Eigenschaften und ihre Wechselwirkungen erhöhen die Komplexität der zugrundeliegenden Bewegungsgleichungen in der Poroelastographie, wodurch die Lösung ohne zusätzliche Informationen über die Wellenfelder und vorherige Quantifizierung der Gewebeporosität erschwert wird. Diese Arbeit hatte daher drei Ziele: 1) eine MRT-Methode zur Messung der Gewebeporosität zu entwickeln, 2) eine MRE-Methode zur getrennten Kodierung der Scherwellenfelder von flüssigen und festen Anteilen in biphasischen Geweben zu entwickeln, und 3) die Kopplungsdichte p12 zu bestimmen um so die biphasischen Modellgleichungen experimentell zu validieren. Methoden: Diese Arbeit stellt die Inversion-Recovery-MRT (IR-MRI) sowie die neuartige Inversion-Recovery-MRE (IR-MRE) vor, womit sich die Porosität, die Scherwellenauslenkung der festen und porösen flüssigen Phasen sowie die Kopplungsdichte p12 in Weichgeweben quantifizieren lassen. Porosität wurde in Flüssig-Phantomen unterschiedlicher Relaxationszeiten, Flüssig- Festkörper-Phantomen auf Tofubasis sowie in vivo im Gehirn bei 21 gesunden Probanden ermittelt. Referenzwerte der Porosität wurden in Phantomen durch Mikroskopie sowie Flüssigkeitsdrainage bestimmt. Feste und flüssige Scherauslenkungsamplituden und p12 wurden in drei Tofuphantomen und bei sieben gesunden Probanden quantifiziert. Ergebnisse: Die mittels IR-MRI gemessene Porosität der Phantome stimmte gut mit den Referenzwerten überein (R=0.99, P<.01). Die durchschnittliche Porosität der grauen und weißen Substanz betrug 0.14±0.02 und 0.05±0.01 (P<.001). Die Scherwellenamplituden der flüssigen Anteile und der festen Matrix waren phasengekoppelt, jedoch geringer in den flüssigen Anteilen (P<.05). p12 war in allen untersuchten Materialien und Geweben negativ. Schlussfolgerung: Mittels der IR-MRI konnten erstmals die Porosität von Hirngewebe in vivo nichtinvasiv abgebildet und die Konsistenz der Werte in gewebeähnlichen, porösen Phantomen nachgewiesen werden. Die Kombination von IR-MRI mit IR-MRE ermöglichte die getrennte Kodierung von Scherwellenfeldern fester und flüssiger Phasen und damit die Quantifizierung der Kopplungsdichte p12, welche, wie theoretisch vorhergesagt, negative Werte aufwies. Die IR-MRE eröffnet vielfältige Möglichkeiten zur Entwicklung und Anwendung neuartiger Bildgebungsmarker auf der Grundlage poroelastischer Kenngrößen von Weichgeweben und ermöglicht somit potenziell eine Vielzahl diagnostischer Anwendungen

Viscoelasticity Imaging of Biological Tissues and Single Cells Using Shear Wave Propagation

Changes in biomechanical properties of biological soft tissues are often associated with physiological dysfunctions. Since biological soft tissues are hydrated, viscoelasticity is likely suitable to represent its solid-like behavior using elasticity and fluid-like behavior using viscosity. Shear wave elastography is a non-invasive imaging technology invented for clinical applications that has shown promise to characterize various tissue viscoelasticity. It is based on measuring and analyzing velocities and attenuations of propagated shear waves. In this review, principles and technical developments of shear wave elastography for viscoelasticity characterization from organ to cellular levels are presented, and different imaging modalities used to track shear wave propagation are described. At a macroscopic scale, techniques for inducing shear waves using an external mechanical vibration, an acoustic radiation pressure or a Lorentz force are reviewed along with imaging approaches proposed to track shear wave propagation, namely ultrasound, magnetic resonance, optical, and photoacoustic means. Then, approaches for theoretical modeling and tracking of shear waves are detailed. Following it, some examples of applications to characterize the viscoelasticity of various organs are given. At a microscopic scale, a novel cellular shear wave elastography method using an external vibration and optical microscopy is illustrated. Finally, current limitations and future directions in shear wave elastography are presented

Development of ultrasound to measure deformation of functional spinal units in cervical spine

Neck pain is a pervasive problem in the general population, especially in those working in vibrating environments, e.g. military troops and truck drivers. Previous studies showed neck pain was strongly associated with the degeneration of intervertebral disc, which is commonly caused by repetitive loading in the work place. Currently, there is no existing method to measure the in-vivo displacement and loading condition of cervical spine on the site. Therefore, there is little knowledge about the alternation of cervical spine functionality and biomechanics in dynamic environments. In this thesis, a portable ultrasound system was explored as a tool to measure the vertebral motion and functional spinal unit deformation. It is hypothesized that the time sequences of ultrasound imaging signals can be used to characterize the deformation of cervical spine functional spinal units in response to applied displacements and loading. Specifically, a multi-frame tracking algorithm is developed to measure the dynamic movement of vertebrae, which is validated in ex-vivo models. The planar kinematics of the functional spinal units is derived from a dual ultrasound system, which applies two ultrasound systems to image C-spine anteriorly and posteriorly. The kinematics is reconstructed from the results of the multi-frame movement tracking algorithm and a method to co-register ultrasound vertebrae images to MRI scan. Using the dual ultrasound, it is shown that the dynamic deformation of functional spinal unit is affected by the biomechanics properties of intervertebral disc ex-vivo and different applied loading in activities in-vivo. It is concluded that ultrasound is capable of measuring functional spinal units motion, which allows rapid in-vivo evaluation of C-spine in dynamic environments where X-Ray, CT or MRI cannot be used.2020-02-20T00:00:00

Assessment of Ultrasound Elastography for Orthopedic Applications

Ultrasound imaging is emerging as an attractive alternative modality to standard x-ray and CT methods for bone assessment applications. The high reflectivity at the bone/soft tissue interface that occurs due to high acoustic impedance mismatch presents an important diagnostic opportunity affording the detection of abnormalities at bone surfaces with high accuracy and contrast-to-noise ratios. Furthermore, the mechanical properties of the soft tissue surrounding the bones undergo changes depending on the integrity of the underlying bone, viz. intact, fractured or healing. Unlike other imaging modalities, ultrasound elastography techniques, with their sensitivity to variations in soft tissue stiffness, are able to assist with monitoring bone regrowth. However, there is presently a lack of systematic studies that investigate the performance of diagnostic ultrasound techniques in bone imaging applications. This dissertation aims at understanding the performance limitations of new ultrasound techniques for assessing intact and fractured bones in vitro as well as in vivo. Ultrasound based 2D, 3D and elastography imaging experiments were performed on in vitro and in vivo samples of mammalian as well as non-mammalian bones. Ultrasound measurements of controlled defects were statistically compared with those obtained from the same samples using alternate imaging modalities. The performance of axial strain elastograms and axial shear strain elastograms at the soft tissue/bone interface was also studied in intact and fractured bones, and statistical analysis was carried out using elastographic image quality tools. The results of this study demonstrate that it is feasible to use diagnostic ultrasound imaging techniques to assess bone defects in real time and with high accuracy and precision. The relative strength of the axial strains and the axial shear strains at the bone/soft tissue interface with respect to the background soft tissue reduce in the presence of a fracture. Consequently, the study concluded that a combination of these imaging modalities might provide information regarding the integrity of the underlying bone and also an insight into the severity of the fractures, alignment of bone fragments and the progress of bone healing. In the future, ultrasound imaging techniques might provide a cost-effective, real-time, safe and portable diagnostic tool for bone imaging applications

Assessment of Ultrasound Elastography for Orthopedic Applications

Ultrasound imaging is emerging as an attractive alternative modality to standard x-ray and CT methods for bone assessment applications. The high reflectivity at the bone/soft tissue interface that occurs due to high acoustic impedance mismatch presents an important diagnostic opportunity affording the detection of abnormalities at bone surfaces with high accuracy and contrast-to-noise ratios. Furthermore, the mechanical properties of the soft tissue surrounding the bones undergo changes depending on the integrity of the underlying bone, viz. intact, fractured or healing. Unlike other imaging modalities, ultrasound elastography techniques, with their sensitivity to variations in soft tissue stiffness, are able to assist with monitoring bone regrowth. However, there is presently a lack of systematic studies that investigate the performance of diagnostic ultrasound techniques in bone imaging applications. This dissertation aims at understanding the performance limitations of new ultrasound techniques for assessing intact and fractured bones in vitro as well as in vivo. Ultrasound based 2D, 3D and elastography imaging experiments were performed on in vitro and in vivo samples of mammalian as well as non-mammalian bones. Ultrasound measurements of controlled defects were statistically compared with those obtained from the same samples using alternate imaging modalities. The performance of axial strain elastograms and axial shear strain elastograms at the soft tissue/bone interface was also studied in intact and fractured bones, and statistical analysis was carried out using elastographic image quality tools. The results of this study demonstrate that it is feasible to use diagnostic ultrasound imaging techniques to assess bone defects in real time and with high accuracy and precision. The relative strength of the axial strains and the axial shear strains at the bone/soft tissue interface with respect to the background soft tissue reduce in the presence of a fracture. Consequently, the study concluded that a combination of these imaging modalities might provide information regarding the integrity of the underlying bone and also an insight into the severity of the fractures, alignment of bone fragments and the progress of bone healing. In the future, ultrasound imaging techniques might provide a cost-effective, real-time, safe and portable diagnostic tool for bone imaging applications

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

Optimising the use and assessing the value of intraoperative shear wave elastography in neurosurgery

The clinical outcomes for epilepsy and brain tumour surgery depend on the extent of resection. Neurosurgeons frequently rely on subjective assessment of stiffness and adherence to achieve maximal resection. However, due to similarity in tactile texture and visual appearance of these lesions to normal brain, this can lead to inadequate resection. Magnetic resonance imaging (MRI) has not completely solved this problem for various reasons, including the existence of MRI-negative lesions. Shear wave elastography (SWE) is an ultrasound-based quantitative elasticity imaging technique that provides an objective assessment of stiffness, which has not previously been applied intraoperatively during neurosurgery. This thesis describes the optimisation and assessment of implementing intraoperative SWE in neurosurgery. The aims of the work described in this thesis were to validate SWE measurements; to optimise intraoperative applications by investigating the artefacts of SWE; to evaluate SWE performance in detecting epileptogenic lesions, residual tumour and slippery boundaries; and to determine the histopathological correlation with SWE measurements. Using gelatine phantoms and post-mortem mouse brains, SWE measurements were validated. Through phantom models and ex vivo porcine brains and spinal cords, the factors affecting SWE measurements were established and SWE settings optimised. In addition, novel features of slippery tumour-brain interface were demonstrated in vitro and confirmed intraoperatively. Clinical implementation of SWE in epilepsy (38 patients) and brain tumour surgery (34 patients), demonstrated SWE’s capability in differentiating epileptogenic lesions (p<0.001) and brain tumours (p=0.003) from normal brain. SWE was shown to be superior to MRI in detecting epileptogenic lesions (p=0.001), in particular MRI-negative cases where SWE managed to demonstrate lesions in 4 cases with positive histology. For detecting residual tumour, SWE was shown to be superior to surgeons’ opinion (p=0.001), and similar to MRI (p=1.000) and intraoperative B-mode ultrasound (p=0.727). Histopathologically, there was no correlation with SWE measurements, except for proliferation (p=0.007). In conclusion, this thesis demonstrated potential patient benefit of integrating intraoperative SWE into neurosurgical practice, and therefore, a compelling reason to continue development and optimisation of this technology