[FG] Magnetic Resonance Physics and MethodologyHead of Research Unit Prof. Dr.Oliver BieriOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 7 foundShow per page10 10 20 50 Development and Application of Rapid Conventional and Unconventional Quantitative Magnetic Resonance Imaging Research Project | 1 Project MembersThe magnetic resonance (MR) signal can be sensitized to a large variety of tissue parameters, as reflected by a vast range of dedicated clinical MR pulse sequences designed to generate contrast even for very subtle tissue alterations with high specificity and sensitivity. Such MR images can be acquired reasonably fast, but their contrast is a non-trivial weighting of various intrinsic and extrinsic parameters and thus not a direct measure for a specific tissue property. As a result, pathological alterations are not identified from a measurable, objective change in tissue properties but rely on a subjective reading of contrast differences on a physically meaningless scale that is affected not only by various random factors but also by instrumentation. Quantification of the MR signal in terms of the underlying biochemical and biophysical tissue parameters is, therefore, generally thought to be the key to MR methodology to push conventional MRI beyond its current limits. It is thus not surprising that the prospect to perform MRI in the tradition of scientific instrumentation has attracted considerable interest in the MR scientific community ever since. Especially, the continuous improvement and progress in scanner hardware and reliability has not only facilitated quantification, but also stimulated the development of a wide variety of methods for the extraction different of biophysical and biochemical parameters. Noteworthy, although quantitative MRI dates back to the early 1970s, its research and development is not only ongoing but performed world-wide with increased interest and effort. Unfortunately, MR-based tissue quantification is typically a very time-consuming process and can be biased by numerous factors. It is thus not surprising that over the years and even for the most fundamental MR tissue parameters, such as tissue relaxation, a whole 'buffet' of MR methods has been proposed to tackle the 'reliable quantification in reasonable time' problem for a successful translation and application in the clinics. Only recently, the extraction of MR tissue quantities has become an even more important paramount goal since artificial intelligence and machine learning has entered the field of MRI relying on the availability of large amounts of standardized and comparable, such as quantitative, MRI data. We have more than a decade of experience in the development and translation of new quantitative MRI methods to the clinical setting. Recent developments, such as spiral readouts and configuration-based imaging methods have shown good prospects and high potential towards a 'reliable quantification in reasonable time' for a wide range of tissue parameters. In this research proposal, we further elaborate and extend our recent methodological achievements in a consequent and innovative manner to develop reliable tissue biomarkers for the detection of widespread pathophysiologic processes, as well as subtle and diffuse tissue alterations with high specificity and sensitivity. Ultrasound guided motion mitigation of proton therapy in the lung Research Project | 3 Project MembersIn comparison to conventional therapy, Pencil Beam Scanned (PBS) proton therapy has the ability to significantly reduce doses to surrounding normal tissue. This is particularly important for treatments of lesions in the thorax, where it is necessary to keep the doses that the volumes of the lungs and heart receive as low as possible. Thus, PBS proton therapy could have significant advantages for the treatment of lung tumours. Indeed, it could eventually be the proton treatment of choice for mobile tumours, due to the relative ease with which it can be adapted for tumour tracking. With tracking, the delivered beams are 'steered' to follow tumour motion ensuring the best combination of target coverage and dose conformation in the presence of motion. Successful tracking, however, requires accurate methods for determining tumour position and motion in real-time. As such, ultrasound (US) and optical surface imaging are interesting modalities, as they are non-invasive and are associated with no additional radiation dose to the patient. Unfortunately, neither can be used to image lung tumours directly. However, US can be used to acquire real-time images of structures in the upper abdomen, such as the diaphragm and liver, whereas surface imaging can track chest and abdominal wall motions, all of which can act as surrogates of lung motion. It is the aim of this project to develop the methods by which ultrasound and/or surface imaging of the upper abdomen can be used to predict three-dimensional motions in the lung with an accuracy of 2-3mm. To achieve such accuracy, we propose to use both ultrasonic monitoring of the diaphragm/liver and surface motions as inputs to a patient specific, statistical model of lung motion. To build this model, simultaneous US and 3D-time resolved MRI (4DMRI) acquisitions will be acquired of volunteers and lung patients using MR compatible ultrasound probes and 4DMRI sequences. In contrast, as surface imaging devices are not MRI compatible, surface motions will be estimated by extracting these indirectly from the 4DMRI data sets. The accuracy of the developed models will be validated using a sophisticated 4D anthropomorphic phantom and through extensive simulations of PBS proton treatments using previously developed approaches based on 4D dose calculations. Should this approach prove successful, it could open the door to highly conformal proton treatments of lung tumours. Moreover, the proposed conceptual approach could be easily transferred to conventional radiotherapy. Development, validation and application of novel strategies for MRI data acquisition, image registration and segmentation of the spinal cord in patients affected by multiple sclerosis. Research Project | 3 Project MembersMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system. Neurodegeneration seems to be the key driver for the accrual of physical and neuropsychological disability and atrophy is one of the hallmarks of neurodegeneration in MS. Spinal cord (SC) atrophy in MS has previously been reported both in cross-sectional and longitudinal studies. Moreover, MS-related physical disability seems to be especially severe when there is spinal cord atrophy. Several MRI-based approaches for measuring SC cross-sectional area and/or volume have been proposed including manual or semi-automatic cross-sectional area measurements and active surface models. However, previous approaches have been hampered by the relatively low-resolution and contrast of the acquired MR images, long measurement times, artifacts as well as the low reproducibility of the segmentation techniques. Moreover, many of the currently applied post-processing techniques require considerable manual interventions leading to high costs and again low interobserver agreement. Such techniques are currently not suitable for application in clinical practice or as outcome measures in therapeutic clinical trials. Moreover, segmentation of the SC into grey and white matter has not been previously achieved using automated methods in MS and hence, so far no clear-cut conclusions on whether volume loss of the spinal cord primarily affects grey or white matter are possible in larger patient populations.We here propose a comprehensive interdisciplinary approach combining MRI sequence development in the setting of cutting-edge 3T MRI infrastructure, development of new techniques for image post-processing and segmentation with the systematic validation and application of such techniques in a large cohort of deeply phenotyped MS patients. This approach will allow studying the relation of SC volume loss to SC lesions and brain lesions, determine the degree and relevance of white versus grey matter loss in the SC, depict key areas of spinal cord involvement and to relate spinal cord changes to other advanced (brain and spinal cord) MRI measures in MS. Finally and most importantly, we will explore the clinical correlations of spinal cord atrophy, specifically spinal cord grey matter atrophy and the suitability to detect changes over time. Once reliable and automated techniques for spinal cord segmentation become available, this will importantly impact the follow-up of MS patients in clinical practice and also provide new potentially more sensitive outcome metrics for clinical trials. The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies. Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps. Micro- and nanoanatomy of human brain tissues Research Project | 6 Project MembersThe human body contains 10^14 cells, which are categorized into 200 to 400 cell types. The human brain accounts for about 2% of the weight of an average person. This is a much larger percentage than in other primates. Despite of its size and complexity one can reasonably assume that it is possible to reveal the individual cells within the human brain and describe its three-dimensional structure on the cellular level. To achieve this goal, we will perform grating-based hard X-ray phase tomography using synchrotron radiation facilities. In addition we will expand the available laboratory system phoenix nanotom® m from GE Healthcare by a grating interferometer. An average human cell contains 10^14 atoms, which are categorized in the 118 elements of the periodic table. Thanks to this clarity, one can reasonably expect that it is possible to reveal the nanostructure of selected pieces of brain tissues. To achieve this, we will perform spatially resolved X-ray scattering experiments at the cSAXS-beamline, Swiss Light Source at the Paul Scherrer Institut. The myelinated axons, for example, which stretch for over 10^8 m if aligned end-to-end, exhibit a quasi-periodical arrangement of the lamellar structure of the myelin sheaths repeating less than every 20 nm. This characteristic periodicity will be used to determine the abundance and the orientation of the myelin fiber bundles in projection images similar to histology and in three-dimensional space applying tomographic reconstruction techniques, which are to be further developed. The interdisciplinary project aims to bridge the gap concerning spatial resolution between the tomography data from clinical modalities (CT and MRI) and histological approaches employed by anatomists and pathologists taking advantage of recent developments in physics: X-ray scattering and phase tomography. Development of fast quantitative diffusion and transverse relaxation time magnetic resonance steady state imaging concepts for living tissues Research Project | 2 Project MembersNo Description available 1 1 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 7 foundShow per page10 10 20 50 Development and Application of Rapid Conventional and Unconventional Quantitative Magnetic Resonance Imaging Research Project | 1 Project MembersThe magnetic resonance (MR) signal can be sensitized to a large variety of tissue parameters, as reflected by a vast range of dedicated clinical MR pulse sequences designed to generate contrast even for very subtle tissue alterations with high specificity and sensitivity. Such MR images can be acquired reasonably fast, but their contrast is a non-trivial weighting of various intrinsic and extrinsic parameters and thus not a direct measure for a specific tissue property. As a result, pathological alterations are not identified from a measurable, objective change in tissue properties but rely on a subjective reading of contrast differences on a physically meaningless scale that is affected not only by various random factors but also by instrumentation. Quantification of the MR signal in terms of the underlying biochemical and biophysical tissue parameters is, therefore, generally thought to be the key to MR methodology to push conventional MRI beyond its current limits. It is thus not surprising that the prospect to perform MRI in the tradition of scientific instrumentation has attracted considerable interest in the MR scientific community ever since. Especially, the continuous improvement and progress in scanner hardware and reliability has not only facilitated quantification, but also stimulated the development of a wide variety of methods for the extraction different of biophysical and biochemical parameters. Noteworthy, although quantitative MRI dates back to the early 1970s, its research and development is not only ongoing but performed world-wide with increased interest and effort. Unfortunately, MR-based tissue quantification is typically a very time-consuming process and can be biased by numerous factors. It is thus not surprising that over the years and even for the most fundamental MR tissue parameters, such as tissue relaxation, a whole 'buffet' of MR methods has been proposed to tackle the 'reliable quantification in reasonable time' problem for a successful translation and application in the clinics. Only recently, the extraction of MR tissue quantities has become an even more important paramount goal since artificial intelligence and machine learning has entered the field of MRI relying on the availability of large amounts of standardized and comparable, such as quantitative, MRI data. We have more than a decade of experience in the development and translation of new quantitative MRI methods to the clinical setting. Recent developments, such as spiral readouts and configuration-based imaging methods have shown good prospects and high potential towards a 'reliable quantification in reasonable time' for a wide range of tissue parameters. In this research proposal, we further elaborate and extend our recent methodological achievements in a consequent and innovative manner to develop reliable tissue biomarkers for the detection of widespread pathophysiologic processes, as well as subtle and diffuse tissue alterations with high specificity and sensitivity. Ultrasound guided motion mitigation of proton therapy in the lung Research Project | 3 Project MembersIn comparison to conventional therapy, Pencil Beam Scanned (PBS) proton therapy has the ability to significantly reduce doses to surrounding normal tissue. This is particularly important for treatments of lesions in the thorax, where it is necessary to keep the doses that the volumes of the lungs and heart receive as low as possible. Thus, PBS proton therapy could have significant advantages for the treatment of lung tumours. Indeed, it could eventually be the proton treatment of choice for mobile tumours, due to the relative ease with which it can be adapted for tumour tracking. With tracking, the delivered beams are 'steered' to follow tumour motion ensuring the best combination of target coverage and dose conformation in the presence of motion. Successful tracking, however, requires accurate methods for determining tumour position and motion in real-time. As such, ultrasound (US) and optical surface imaging are interesting modalities, as they are non-invasive and are associated with no additional radiation dose to the patient. Unfortunately, neither can be used to image lung tumours directly. However, US can be used to acquire real-time images of structures in the upper abdomen, such as the diaphragm and liver, whereas surface imaging can track chest and abdominal wall motions, all of which can act as surrogates of lung motion. It is the aim of this project to develop the methods by which ultrasound and/or surface imaging of the upper abdomen can be used to predict three-dimensional motions in the lung with an accuracy of 2-3mm. To achieve such accuracy, we propose to use both ultrasonic monitoring of the diaphragm/liver and surface motions as inputs to a patient specific, statistical model of lung motion. To build this model, simultaneous US and 3D-time resolved MRI (4DMRI) acquisitions will be acquired of volunteers and lung patients using MR compatible ultrasound probes and 4DMRI sequences. In contrast, as surface imaging devices are not MRI compatible, surface motions will be estimated by extracting these indirectly from the 4DMRI data sets. The accuracy of the developed models will be validated using a sophisticated 4D anthropomorphic phantom and through extensive simulations of PBS proton treatments using previously developed approaches based on 4D dose calculations. Should this approach prove successful, it could open the door to highly conformal proton treatments of lung tumours. Moreover, the proposed conceptual approach could be easily transferred to conventional radiotherapy. Development, validation and application of novel strategies for MRI data acquisition, image registration and segmentation of the spinal cord in patients affected by multiple sclerosis. Research Project | 3 Project MembersMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system. Neurodegeneration seems to be the key driver for the accrual of physical and neuropsychological disability and atrophy is one of the hallmarks of neurodegeneration in MS. Spinal cord (SC) atrophy in MS has previously been reported both in cross-sectional and longitudinal studies. Moreover, MS-related physical disability seems to be especially severe when there is spinal cord atrophy. Several MRI-based approaches for measuring SC cross-sectional area and/or volume have been proposed including manual or semi-automatic cross-sectional area measurements and active surface models. However, previous approaches have been hampered by the relatively low-resolution and contrast of the acquired MR images, long measurement times, artifacts as well as the low reproducibility of the segmentation techniques. Moreover, many of the currently applied post-processing techniques require considerable manual interventions leading to high costs and again low interobserver agreement. Such techniques are currently not suitable for application in clinical practice or as outcome measures in therapeutic clinical trials. Moreover, segmentation of the SC into grey and white matter has not been previously achieved using automated methods in MS and hence, so far no clear-cut conclusions on whether volume loss of the spinal cord primarily affects grey or white matter are possible in larger patient populations.We here propose a comprehensive interdisciplinary approach combining MRI sequence development in the setting of cutting-edge 3T MRI infrastructure, development of new techniques for image post-processing and segmentation with the systematic validation and application of such techniques in a large cohort of deeply phenotyped MS patients. This approach will allow studying the relation of SC volume loss to SC lesions and brain lesions, determine the degree and relevance of white versus grey matter loss in the SC, depict key areas of spinal cord involvement and to relate spinal cord changes to other advanced (brain and spinal cord) MRI measures in MS. Finally and most importantly, we will explore the clinical correlations of spinal cord atrophy, specifically spinal cord grey matter atrophy and the suitability to detect changes over time. Once reliable and automated techniques for spinal cord segmentation become available, this will importantly impact the follow-up of MS patients in clinical practice and also provide new potentially more sensitive outcome metrics for clinical trials. The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies. Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps. Micro- and nanoanatomy of human brain tissues Research Project | 6 Project MembersThe human body contains 10^14 cells, which are categorized into 200 to 400 cell types. The human brain accounts for about 2% of the weight of an average person. This is a much larger percentage than in other primates. Despite of its size and complexity one can reasonably assume that it is possible to reveal the individual cells within the human brain and describe its three-dimensional structure on the cellular level. To achieve this goal, we will perform grating-based hard X-ray phase tomography using synchrotron radiation facilities. In addition we will expand the available laboratory system phoenix nanotom® m from GE Healthcare by a grating interferometer. An average human cell contains 10^14 atoms, which are categorized in the 118 elements of the periodic table. Thanks to this clarity, one can reasonably expect that it is possible to reveal the nanostructure of selected pieces of brain tissues. To achieve this, we will perform spatially resolved X-ray scattering experiments at the cSAXS-beamline, Swiss Light Source at the Paul Scherrer Institut. The myelinated axons, for example, which stretch for over 10^8 m if aligned end-to-end, exhibit a quasi-periodical arrangement of the lamellar structure of the myelin sheaths repeating less than every 20 nm. This characteristic periodicity will be used to determine the abundance and the orientation of the myelin fiber bundles in projection images similar to histology and in three-dimensional space applying tomographic reconstruction techniques, which are to be further developed. The interdisciplinary project aims to bridge the gap concerning spatial resolution between the tomography data from clinical modalities (CT and MRI) and histological approaches employed by anatomists and pathologists taking advantage of recent developments in physics: X-ray scattering and phase tomography. Development of fast quantitative diffusion and transverse relaxation time magnetic resonance steady state imaging concepts for living tissues Research Project | 2 Project MembersNo Description available 1 1
Development and Application of Rapid Conventional and Unconventional Quantitative Magnetic Resonance Imaging Research Project | 1 Project MembersThe magnetic resonance (MR) signal can be sensitized to a large variety of tissue parameters, as reflected by a vast range of dedicated clinical MR pulse sequences designed to generate contrast even for very subtle tissue alterations with high specificity and sensitivity. Such MR images can be acquired reasonably fast, but their contrast is a non-trivial weighting of various intrinsic and extrinsic parameters and thus not a direct measure for a specific tissue property. As a result, pathological alterations are not identified from a measurable, objective change in tissue properties but rely on a subjective reading of contrast differences on a physically meaningless scale that is affected not only by various random factors but also by instrumentation. Quantification of the MR signal in terms of the underlying biochemical and biophysical tissue parameters is, therefore, generally thought to be the key to MR methodology to push conventional MRI beyond its current limits. It is thus not surprising that the prospect to perform MRI in the tradition of scientific instrumentation has attracted considerable interest in the MR scientific community ever since. Especially, the continuous improvement and progress in scanner hardware and reliability has not only facilitated quantification, but also stimulated the development of a wide variety of methods for the extraction different of biophysical and biochemical parameters. Noteworthy, although quantitative MRI dates back to the early 1970s, its research and development is not only ongoing but performed world-wide with increased interest and effort. Unfortunately, MR-based tissue quantification is typically a very time-consuming process and can be biased by numerous factors. It is thus not surprising that over the years and even for the most fundamental MR tissue parameters, such as tissue relaxation, a whole 'buffet' of MR methods has been proposed to tackle the 'reliable quantification in reasonable time' problem for a successful translation and application in the clinics. Only recently, the extraction of MR tissue quantities has become an even more important paramount goal since artificial intelligence and machine learning has entered the field of MRI relying on the availability of large amounts of standardized and comparable, such as quantitative, MRI data. We have more than a decade of experience in the development and translation of new quantitative MRI methods to the clinical setting. Recent developments, such as spiral readouts and configuration-based imaging methods have shown good prospects and high potential towards a 'reliable quantification in reasonable time' for a wide range of tissue parameters. In this research proposal, we further elaborate and extend our recent methodological achievements in a consequent and innovative manner to develop reliable tissue biomarkers for the detection of widespread pathophysiologic processes, as well as subtle and diffuse tissue alterations with high specificity and sensitivity.
Ultrasound guided motion mitigation of proton therapy in the lung Research Project | 3 Project MembersIn comparison to conventional therapy, Pencil Beam Scanned (PBS) proton therapy has the ability to significantly reduce doses to surrounding normal tissue. This is particularly important for treatments of lesions in the thorax, where it is necessary to keep the doses that the volumes of the lungs and heart receive as low as possible. Thus, PBS proton therapy could have significant advantages for the treatment of lung tumours. Indeed, it could eventually be the proton treatment of choice for mobile tumours, due to the relative ease with which it can be adapted for tumour tracking. With tracking, the delivered beams are 'steered' to follow tumour motion ensuring the best combination of target coverage and dose conformation in the presence of motion. Successful tracking, however, requires accurate methods for determining tumour position and motion in real-time. As such, ultrasound (US) and optical surface imaging are interesting modalities, as they are non-invasive and are associated with no additional radiation dose to the patient. Unfortunately, neither can be used to image lung tumours directly. However, US can be used to acquire real-time images of structures in the upper abdomen, such as the diaphragm and liver, whereas surface imaging can track chest and abdominal wall motions, all of which can act as surrogates of lung motion. It is the aim of this project to develop the methods by which ultrasound and/or surface imaging of the upper abdomen can be used to predict three-dimensional motions in the lung with an accuracy of 2-3mm. To achieve such accuracy, we propose to use both ultrasonic monitoring of the diaphragm/liver and surface motions as inputs to a patient specific, statistical model of lung motion. To build this model, simultaneous US and 3D-time resolved MRI (4DMRI) acquisitions will be acquired of volunteers and lung patients using MR compatible ultrasound probes and 4DMRI sequences. In contrast, as surface imaging devices are not MRI compatible, surface motions will be estimated by extracting these indirectly from the 4DMRI data sets. The accuracy of the developed models will be validated using a sophisticated 4D anthropomorphic phantom and through extensive simulations of PBS proton treatments using previously developed approaches based on 4D dose calculations. Should this approach prove successful, it could open the door to highly conformal proton treatments of lung tumours. Moreover, the proposed conceptual approach could be easily transferred to conventional radiotherapy.
Development, validation and application of novel strategies for MRI data acquisition, image registration and segmentation of the spinal cord in patients affected by multiple sclerosis. Research Project | 3 Project MembersMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system. Neurodegeneration seems to be the key driver for the accrual of physical and neuropsychological disability and atrophy is one of the hallmarks of neurodegeneration in MS. Spinal cord (SC) atrophy in MS has previously been reported both in cross-sectional and longitudinal studies. Moreover, MS-related physical disability seems to be especially severe when there is spinal cord atrophy. Several MRI-based approaches for measuring SC cross-sectional area and/or volume have been proposed including manual or semi-automatic cross-sectional area measurements and active surface models. However, previous approaches have been hampered by the relatively low-resolution and contrast of the acquired MR images, long measurement times, artifacts as well as the low reproducibility of the segmentation techniques. Moreover, many of the currently applied post-processing techniques require considerable manual interventions leading to high costs and again low interobserver agreement. Such techniques are currently not suitable for application in clinical practice or as outcome measures in therapeutic clinical trials. Moreover, segmentation of the SC into grey and white matter has not been previously achieved using automated methods in MS and hence, so far no clear-cut conclusions on whether volume loss of the spinal cord primarily affects grey or white matter are possible in larger patient populations.We here propose a comprehensive interdisciplinary approach combining MRI sequence development in the setting of cutting-edge 3T MRI infrastructure, development of new techniques for image post-processing and segmentation with the systematic validation and application of such techniques in a large cohort of deeply phenotyped MS patients. This approach will allow studying the relation of SC volume loss to SC lesions and brain lesions, determine the degree and relevance of white versus grey matter loss in the SC, depict key areas of spinal cord involvement and to relate spinal cord changes to other advanced (brain and spinal cord) MRI measures in MS. Finally and most importantly, we will explore the clinical correlations of spinal cord atrophy, specifically spinal cord grey matter atrophy and the suitability to detect changes over time. Once reliable and automated techniques for spinal cord segmentation become available, this will importantly impact the follow-up of MS patients in clinical practice and also provide new potentially more sensitive outcome metrics for clinical trials.
The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies.
Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps.
Micro- and nanoanatomy of human brain tissues Research Project | 6 Project MembersThe human body contains 10^14 cells, which are categorized into 200 to 400 cell types. The human brain accounts for about 2% of the weight of an average person. This is a much larger percentage than in other primates. Despite of its size and complexity one can reasonably assume that it is possible to reveal the individual cells within the human brain and describe its three-dimensional structure on the cellular level. To achieve this goal, we will perform grating-based hard X-ray phase tomography using synchrotron radiation facilities. In addition we will expand the available laboratory system phoenix nanotom® m from GE Healthcare by a grating interferometer. An average human cell contains 10^14 atoms, which are categorized in the 118 elements of the periodic table. Thanks to this clarity, one can reasonably expect that it is possible to reveal the nanostructure of selected pieces of brain tissues. To achieve this, we will perform spatially resolved X-ray scattering experiments at the cSAXS-beamline, Swiss Light Source at the Paul Scherrer Institut. The myelinated axons, for example, which stretch for over 10^8 m if aligned end-to-end, exhibit a quasi-periodical arrangement of the lamellar structure of the myelin sheaths repeating less than every 20 nm. This characteristic periodicity will be used to determine the abundance and the orientation of the myelin fiber bundles in projection images similar to histology and in three-dimensional space applying tomographic reconstruction techniques, which are to be further developed. The interdisciplinary project aims to bridge the gap concerning spatial resolution between the tomography data from clinical modalities (CT and MRI) and histological approaches employed by anatomists and pathologists taking advantage of recent developments in physics: X-ray scattering and phase tomography.
Development of fast quantitative diffusion and transverse relaxation time magnetic resonance steady state imaging concepts for living tissues Research Project | 2 Project MembersNo Description available
