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- Our research activities
- High-resolution multifrequency MRE at high field strengths
- Longitudinal in vivo MRE study on mouse model of hepatocellular carcinoma (HCC)
- MRE in inflammatory neurological diseases
- Ultrasound time-harmonic elastography for the assessment of glomerulonephritis
- Time-harmonic ultrasound elastography of the brain
- MRE in the mouse brain
- Designing of a realistic tissue mimicking-elastography phantom
- Rapid multi-frequency steady-state MR elastography for quantification of short-term alterations of viscoelasticity in biological soft tissue
- Compression sensitive elastography
Our research activities
- development of MRI sequences
- construction of mechanical devices for elastography
- signal processing and numerical methods for the solution of inverse problems
- viscoelastic modeling
- pressure and elasticity in porous media
- time-harmonic ultrasound elastography
- micro MRE of tissue samples and animal models
- abdominal MRE
- cardiac MRE
- cerebral MRE
- MRE of skeletal muscle
- MRE of the lung
- elastography for the diagnosis of:
- cardiac relaxation abnormalities
- liver fibrosis
- neurodegenerative processes
- tumors
High-resolution multifrequency MRE at high field strengths
Gergely Bertalan, Jürgen Braun, Ingolf Sack
Rheological constants measured on different length scales provide insight into the biomechanical properties of the tissue. However, it is largely unknown to which extend biomechanical properties are scale-invariant and if tissue mechanical parameters can be compared when acquired at different scales. State-of-the-art measurement modalities for investigating tissue mechanical properties at different scales such as scanning force microscopy, tensile tests or macro indentation are limited by being surface based and do often not provide measurements in a wider dynamic range. In contrast, MRE can quantify the mechanical properties of biological tissues in volume samples at different mechanical excitation frequencies.
State-of-the-art MRE measures mechanical properties on the millimeter and sub-millimeter scale. In this project, we try to develop MRE for investigations of small tissue samples at high harmonic stimulation frequencies with high spatial resolution to bridge the gap between macroscopic MRE measurements and micromechanical test methods.
Longitudinal in vivo MRE study on mouse model of hepatocellular carcinoma (HCC)
Karolina Garczynska, Jing Guo
Tumor progression, reorganization and migration of cancer cells cause changes in the extracellular matrix (ECM) and stromal cells, the so called tumor surrounding environment (TSE).
In the first part of the project, we plan to study longitudinally hepatocellular carcinoma (HCC), one of the most aggressive and prevalent tumor types, in an orthotropic, syngeneic mouse model. Using in vivo MRE , we will investigate the mechanical properties of both HCC and its TSE during tumorigenesis. We will also compare our in vivo findings with ex vivo histopathological analysis which could link mechanical property variation with micro-structural alternation.
In the second part of our project, we will treat our HCC bearing mice with novel fusion proteins and monitor the mechanical and biological treatment response with in vivo MRE and ex vivo analysis, respectively. Treatment response of fusion proteins will also be compared with that of conventional chemotherapy.
The aims of this project are to establish an elastographic model of cancerous liver considering also the contribution of ECM in TSE and to develop smart drugs for cancer treatment.
MRE in inflammatory neurological diseases
Helge Herthum, Ingolf Sack
High-Resolution magnetic resonance elastography (MRE) allows the investigation of spatially localized inflammatory processes in various organs and as well in the brain [1] [2]. This project aims at understanding the underlying mechanical-structural changes accompanying progressive inflammatory disease like multiple sclerosis. Viscoelastic properties of brain tissue can serve as a quantitative marker for monitoring disease progress and give new insights into pathologic features of multiple sclerosis (MS) [3]. Since magnetic resonance imaging (MRI) has emerged as the most important tool for MS diagnosis, MRE can be integrated easily in the clinical workflow and yields important additional information [3]. The sensitivity of MRE to focal demyelinated plaques within the CNS needs to be investigated further to enable the reliable differentiation between active and late chronic lesions inside the brain parenchyma.
The project is supported by the German Research Foundation.
Dittmann, F., et al., In Vivo Wideband Multifrequency MR Elastography of the Human Brain and Liver. Magnetic Resonance in Medicine, 2016. 76(4): p. 1116-1126.
Streitberger, K.J., et al., Brain Viscoelasticity Alteration in Chronic-Progressive Multiple Sclerosis. Plos One, 2012. 7(1).
Fehlner, A., et al., Higher-Resolution MR Elastography Reveals Early Mechanical Signatures of Neuroinflammation in Patients with Clinically Isolated Syndrome. Journal of Magnetic Resonance Imaging, 2016. 44(1): p. 51-58.
Ultrasound time-harmonic elastography for the assessment of glomerulonephritis
Markus Großmann, Ingolf Sack, Stephan Rodrigo Marticorena Garcia
The kidney function is of vital importance for the human metabolism, blood circulation and endocrine system. Glomerulonephritides comprises a group of immunologic renal diseases that can result in structural damage and functional failure due to inflammatory processes in the kidney. Unfortunately, currently available noninvasive tests are barely capable to detect early stage kidney disease and invasive renal biopsies are unsuitable for screening purposes. Since chronic kidney damage is irreversible there is a notable interest for noninvasive diagnostic tools to identify early stage candidates and might open new perspectives for treating early disease stages.
The objective of this project is to adapt the ultrasound time-harmonic elastography (THE) for native kidneys to acquire full field-of-view maps of renal stiffness and to apply the THE as a noninvasive medical imaging for the detection of structural changes in glomerulonephritis.
In our study we enroll healthy volunteers and patients with biopsy-proven glomerulonephritis and stage 1 to 4 chronic kidney disease. We obtain full field-of-view maps of renal shear wave speed (SWS) to assess renal tissue stiffness. SWS will be analyzed separately in kidney substructures such as renal parenchyma, cortex and medulla to be correlated with clinical data, conventional ultrasound measurements and resistive indices (RI).
Time-harmonic ultrasound elastography of the brain
Bernhard Kreft, Heiko Tzschätzsch, Judith Bergs, Jürgen Braun, Ingolf Sack
Cerebral stiffness (CS) is related to many structural and physiological changes in the brain. Magnetic resonance elastography (MRE) is feasible to measure CS with high spatial resolution. However, MRE suffers from poor temporal resolution. Time-harmonic ultrasound elastography (THE) in contrast provides measurements within one second and can be used to measure fast alterations in CS due to changes of intracranial pressure (ICP).
Shear waves of multiple frequencies are generated in the brain with a special patient bed modified with a vibration unit. Radiofrequency data is acquired with a research ultrasound scanner in one second. The shear wave speed (SWS), representing the tissue stiffness, is calculated with the k-MDEV-algorithm and compounded to an elastogram.
Cerebral THE shows to be sensitive to structural changes due to ageing as well as to ICP changes induced by the Valsalva maneuver. Therefore, THE has the potential to measure ICP non-invasively for the first time and can be of great use in many neurological applications.
Publications
Tzschatzsch, H., et al. (2018). „In vivo time-harmonic ultrasound elastography of the human brain detects acute cerebral stiffness changes induced by intracranial pressure variations.“ Sci Rep 8(1): 17888.
MRE in the mouse brain
Anna Morr, Rafaela Vieira da Silva, Gergerly Bertalan, Barbara Steiner, Carmen Infante Duarte, Ingolf Sack
Alterations and pathological changes in the brain can lead to changes of its viscoelastic properties, which are detectable by magnetic resonance elastography (MRE). In these projects, we study changes in viscoelasticity due to different processes such as inflammation and neurogenesis. In our previous work, we already showed changes in viscoelasticity in pathologies of different mouse models such as Alzheimer’s disease [1], Parkinson [2] and Multiples Sclerosis (EAE mouse model) [3]. We now aim to explore the correlation of viscoelastic changes in the EAE model with biological alterations in the tissue, mainly with changes of the extracellular matrix (ECM) of the brain, as inflammation and damage of the central nervous system (CNS) affect the ECM. Our preliminary data suggest that MRE can detect alterations of the CNS matrix composition during disease. Therefore, the specific objective of this SFB-1340 sponsored project is to explore inflammation-related ECM alterations as targets for in vivo imaging of tissue pathology in the course of autoimmune neuroinflammatory disorders such as Multiples Sclerosis and its EAE model. Additionally, these findings shall be further correlated and explored by ex-vivo test methods such as the surface tensiometer. Furthermore, we are interested how neurogenesis, elicited through voluntary physical exercise, affects the viscoelastic properties of the brain and correlates with biological changes as ECM alterations. Taken together, these projects shed light on processes that affect the stiffness of the brain. These alterations will be correlated with biochemical and histological findings to explore MRE as an in vivo technique to assess disease courses and biological processes in the brain.
- Munder, T., et al., MR elastography detection of early viscoelastic response of the murine hippocampus to amyloid beta accumulation and neuronal cell loss due to Alzheimer’s disease. J Magn Reson Imaging, 2018. 47(1): p. 105-114.
- Klein, C., et al., Enhanced adult neurogenesis increases brain stiffness: in vivo magnetic resonance elastography in a mouse model of dopamine depletion. PLoS One, 2014. 9(3): p. e92582.
- Magnetic resonace elastography reveals altered brain viscoelasticity in experimental autoimmune encephalomyelitis Riek et al 2012.
Designing of a realistic tissue mimicking-elastography phantom
Anna Morr, Heiko Tzschätzsch, Felix Schrank, Helge Herthum, Jürgen Braun, Ingolf Sack
Viscoelastic properties of commercially available tissue-mimicking elastography phantoms are different from those of human soft tissue. Therefore, we aim to design an elastography phantom which viscoelastic properties over a wide frequency range are similar to in vivo human liver. Polyacrylamide serves as the base of thesephantoms and varying the concentration of the contents can influence its viscoelastic properties. To determine the shear wave speed and shear wave damping of this new phantom, different techniques as rheometry, tabletop magnetic resonance elastography (MRE) and human MRE are used.
Rapid multi-frequency steady-state MR elastography for quantification of short-term alterations of viscoelasticity in biological soft tissue
Felix Schrank, Carsten Warmuth, Lars-Arne Schaafs, Thomas Elgeti, Ingolf Sack
While MR elastography (MRE) is an established imaging modality for mapping viscoelastic properties of the human liver and brain [1], there is a growing need to apply MRE in situations when the organ moves or viscoelasticity rapidly changes. One of our research interests is to quantify short-term alterations of viscoelasticity of soft tissue as a response to muscle function, perfusion, or cardiac work. Such MRE applications require rapid wave field encoding with precise synchronization of imaging sequence and wave dynamics.
To address these challenges, we developed a cardiac-gated steady-state gradient echo MRI sequence with segmented spiral k-space acquisition, respiratory navigation, and stroboscopic wave field sampling. We applied this method on the human brain to show for the first time how cerebral arterial pulsation influences brain viscoelasticity. Intriguingly, we showed that the brain becomes softer and more viscous during cerebral systole, possibly due to an effect of CAP-induced arterial expansion (see Fig.1) [2]. We are further developing cardiac MRE to quantify the temporal variation of myocardial stiffness over the heart cycle. Preliminary results in healthy volunteers show a periodic stiffening and softening of the left ventricular wall during systole and diastole, reflecting the mechanical work performed by the beating heart (see Fig.2) [3].
References
Hirsch, S., Sack, I., & Braun, J. (2017). Magnetic resonance elastography: physical background and medical applications. John Wiley & Sons.
Schrank, F., Warmuth, C., Tzschätzsch, H., Kreft, B., Hirsch, S., Braun, J., Elgeti, T., Sack, I. (2019). Cardiac-gated steady-state multifrequency magnetic resonance elastography of the brain: Effect of cerebral arterial pulsation on brain viscoelasticity. Journal of Cerebral Blood Flow & Metabolism. www.ncbi.nlm.nih.gov/pubmed/31142226.
Schrank, F., Warmuth, C., Schaafs, L., Tzschätzsch, H., Elgeti, T., Braun, J., Sack, I. (2019). C Multi-frequency magnetic resonance elastography with spiral readout, respiratory navigator and stroboscopic wave sampling for cardiac stiffness mapping with high spatial and temporal resolution, digital poster #3975.
Compression sensitive elastography
Ledia Lilaj, Thomas Fischer, Jing Guo, Jürgen Braun, Ingolf Sack, Sebastian Hirsch
Background: Many diseases are associated with imbalanced fluid pressure regulation mechanisms. For example, normal pressure hydrocephalus or hepatic hypertension impose permanent or transient parenchymal pressure alterations, which are hard to detect by conventional imaging methods. MRE, sensitive to mechanical constants of living tissue, may offer a way for the early and noninvasive detection of such pressure-related diseases.
Problem: Being composed of about 75% water, biological tissue is normally regarded incompressible. Classical MRE quantifies the shear elasticity of biological tissue, which is independent of the bulk modulus and compressibility of the tissue. Considering biological tissue as a bi-phasic medium composed of incompressible parenchyma permeated by fluid-filled pores provides the link between compressibility and tissue pressure in biological soft matter. Restrictions to the fluid motion due to fast dynamics (e.g. in ultrasound) or by confined boundary conditions yield a compression modulus of soft biological tissue in the range of gigapascals (about thousand times higher than the shear modulus).
Proposed solution: 3D displacement fields as usually induced in MRE consist of both shear and compression wave fields. We measure the compression wave field utilizing an adapted fast MR imaging sequence and apply the divergence operator to the field. The irrotational field displays pure compression, which is not zero in living biological tissue due to the aforementioned poroelastic properties [1,2].
In human lung, we observed significantly higher strain amplitudes in inspiration than in expiration, reflecting the influence of the intrapulmonary air volume on the mechanics of lung parenchyma [3]. Moreover, induced volumetric strain was quantified in the human brain. Volunteers were asked to sustain contraction of the abdominal muscles during the first experiment, thus hindering venous outflow of blood from the brain and hence increasing intra-cranial fluid pressure. This state was compared to the physiologically normal, relaxed state. Strain amplitudes in the high-pressure state were clearly elevated. Similarly, the influence of cardiac pulsation on brain mechanics was analyzed by means of ECG-gated data acquisition [4].
Since MRI measures a combined signal of the two soft tissue compartment, we developed a method that combines inversion recovery MR imaging (IR-MRI) and a biphasic MR signal model to measure, independently from MRE, the contribution of each phase to the total signal and their volume ratio. Therefore, porosity, which is defined as the volume of the fluid phase divided by the entire volume of the medium, is quantified in each voxel leading to porosity maps of the tissue. This method was validated in tissue-mimicking phantoms and applied to in-vivo healthy brain [5, 6].
Further studies will be performed in the context of different pathologies to assess the diagnostic potential of pressure-sensitive MRE with the additional knowledge of porosity as a characteristic parameter of the poroelastic model.
References
1. Hirsch, S., Sack, I. & Braun, J. Magnetic Resonance Elastography: Physical Background And Medical Applications. John Wiley & Sons 131-144 (2017). DOI:10.1002/9783527696017
2. Sack, I. & Schaeffter, T. Quantification of Biophysical Parameters in Medical Imaging. Quantification of Biophysical Parameters in Medical Imaging. Springer 71-88 (2018). DOI:10.1007/978-3-319-65924-4
3. Hirsch, S., Posnansky, O., Papazoglou, S. & Elgeti, T. Measurement of Vibration-Induced Volumetric Strain in the Human Lung. Magn. Reson. Med. 69:667–674 (2013). DOI: 10.1002/mrm.24294
4. Hirsch, S., Klatt, D., Freimann, F., Scheel, M., Braun, J. & Sack, I. In vivo measurement of volumetric strain in the human brain induced by arterial pulsation and harmonic waves. Magn. Reson. Med. 70:671–683 (2013). DOI:10.1002/mrm.24499
5. Lilaj, L., Braun, J., Fischer, T., Sack I. & Hirsch, S. Inversion-recovery MRI based biphasic analysis of porous media: simulations, phantom experiments and in vivo brain study [abstract]. ISMRM 2019, Montreal, Canada. Abstract nr 4977.
6. Lilaj, L., Braun, J., Fischer, T., Sack I. & Hirsch, S. Inversion Recovery Magnetic Resonance Poro-Elastography for Encoding Solid and Fluid Motion in Biphasic Media [abstract]. WCB 2018, Dublin, Ireland. Abstract nr 00652.