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Background and ObjectivesThe choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD.MethodsIn this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters.ResultsWe studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78–8.1; p = 0.018).DiscussionThis study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis.

The multipurpose X-ray beamline of the Munich Compact Light Source, a compact synchrotron radiation facility based on an inverse Compton X-ray source, is presented including its design and instrumentation. Its wide range of capabilities is discussed based on application examples ranging from spectroscopic as well as phase-contrast X-ray imaging and tomography to X-ray absorption spectroscopy or micro-beam radiation therapy research., Inverse Compton scattering provides means to generate low-divergence partially coherent quasi-monochromatic, i.e. synchrotron-like, X-ray radiation on a laboratory scale. This enables the transfer of synchrotron techniques into university or industrial environments. Here, the Munich Compact Light Source is presented, which is such a compact synchrotron radiation facility based on an inverse Compton X-ray source (ICS). The recent improvements of the ICS are reported first and then the various experimental techniques which are most suited to the ICS installed at the Technical University of Munich are reviewed. For the latter, a multipurpose X-ray application beamline with two end-stations was designed. The beamline’s design and geometry are presented in detail including the different set-ups as well as the available detector options. Application examples of the classes of experiments that can be performed are summarized afterwards. Among them are dynamic in vivo respiratory imaging, propagation-based phase-contrast imaging, grating-based phase-contrast imaging, X-ray microtomography, K-edge subtraction imaging and X-ray spectroscopy. Finally, plans to upgrade the beamline in order to enhance its capabilities are discussed.

X-ray grating interferometry is a powerful emerging tool in biomedical imaging, providing access to three complementary image modalities. In addition to the conventional attenuation modality, interferometry provides a phase modality, which visualizes soft tissue structures, and a dark-field modality, which relates to the number and size of sub-resolution scattering objects. A particularly strong dark-field signal originates from the alveoli or air sacs in the lung. Dark-field lung radiographs in animal models have already shown increased sensitivity in diagnosing lung diseases, such as lung cancer or emphysema, compared to conventional X-ray chest radiography. However, to date, X-ray dark-field lung imaging has either averaged information over several breaths or has been captured during a breath hold. In this paper, we demonstrate the first time-resolved dark-field imaging of a breath cycle in a mechanically ventilated mouse, in vivo , which was obtained using a grating interferometer. We achieved a time resolution of 0.1 s, visualizing the changes in the dark-field, phase, and attenuation images during inhalation and exhalation. These measurements show that the dark-field signal depends on the air volume and, hence, the alveolar dimensions of the lung. Conducting this type of scan with animal disease models would help to locate the optimum breath point for single-image diagnostic dark-field imaging and could indicate if the changes in the dark-field signal during breath provide a diagnostically useful complementary measure.

Pencil beam scanned (PBS) proton therapy of lung tumours is hampered by respiratory motion and the motion-induced density changes along the beam path. In this simulation study, we aim to investigate the effectiveness of proton beam tracking for lung tumours both under ideal conditions and in conjunction with a respiratory motion model guided by real-time ultrasound imaging of the liver. Multiple-breathing-cycle 4DMRIs of the thorax and abdominal 2D ultrasound images were acquired simultaneously for five volunteers. Deformation vector fields extracted from the 4DMRI, referred to as ground truth motion, were used to generate 4DCT(MRI) data sets of two lung cancer patients, resulting in 10 data sets with variable motion patterns. Given the 4DCT(MRI) and the corresponding ultrasound images as surrogate data, a patient-specific motion model was built. The model consists of an autoregressive model and Gaussian process regression for the temporal and spatial prediction, respectively. Two-field PBS plans were optimised on the reference CTs, and 4D dose calculations (4DDC) were used to simulate dose delivery for (a) unmitigated motion, (b) ideal 2D and 3D tracking (both beam adaption and 4DDC based on ground truth motion), and (c) realistic 2D and 3D tracking (beam adaption based on motion predictions, 4DDC on ground truth motion). Model-guided tracking retrieved clinically acceptable target dose homogeneity, as seen in a substantial reduction of the D5%–D95% compared to the non-mitigated simulation. Tracking in 2D and 3D resulted in a similar improvement of the dose homogeneity, as did ideal and realistic tracking simulations. In some cases, however, the tracked deliveries resulted in a shift towards higher or lower dose levels, leading to unacceptable target over- or under-coverage. The presented motion modelling framework was shown to be an accurate motion prediction tool for the use in proton beam tracking. Tracking alone, however, may not always effectively mitigate motion effects, making it necessary to combine it with other techniques such as rescanning.

Motion mitigation strategies are crucial for scanned particle therapy of mobile tumours in order to prevent geometrical target miss and interplay effects. We developed a patient-specific respiratory motion model based on simultaneously acquired time-resolved volumetric MRI and 2D abdominal ultrasound images. We present its effects on 4D pencil beam scanned treatment planning and simulated dose distributions. Given an ultrasound image of the liver and the diaphragm, principal component analysis and Gaussian process regression were applied to infer dense motion information of the lungs. 4D dose calculations for scanned proton therapy were performed using the estimated and the corresponding ground truth respiratory motion; the differences were compared by dose difference volume metrics. We performed this simulation study on 10 combined CT and 4DMRI data sets where the motion characteristics were extracted from 5 healthy volunteers and fused with the anatomical CT data of two lung cancer patients. Median geometrical estimation errors below 2 mm for all data sets and maximum dose differences of [Formula: see text] = 43.2% and [Formula: see text] = 16.3% were found. Moreover, it was shown that abdominal ultrasound imaging allows to monitor organ drift. This study demonstrated the feasibility of the proposed ultrasound-based motion modelling approach for its application in scanned proton therapy of lung tumours.

The versatile X-ray beamline at the Munich Compact Light Source is described. Its design and instrumentation were optimized to accommodate techniques exploiting the unique characteristics of inverse Compton Sources for which application examples are presented.

Bright synchrotron x-ray sources enable imaging with short exposure times, and hence in a high-speed image sequence. These x-ray movies can capture not only sample structure, but also how the sample changes with time, how it functions. The use of a synchrotron x-ray source also provides high spatial coherence, which facilitates the capture of not only a conventional attenuation-based x-ray image, but also phase-contrast and dark-field signals. These signals are strongest from air/tissue interfaces, which means that they are particularly useful for examining the respiratory system. We have performed a range of x-ray imaging studies that look at lung function, airway surface function, inhaled and instilled treatment delivery, and treatment effect in live small animal models [Morgan, 2019]. These have utilized a range of optical set-ups and phase-contrast imaging methods in order to be sensitive to the relevant sample features, and be compatible with high-speed imaging. For example, we have used a grating interferometer to measure how the airsacs in the lung inflate during inhalation, via changes in the dark-field signal [Gradl, 2018], a single-exposure, single-grid set-up to capture changes in the liquid lining of the airways [Morgan, 2015] and propagation-based phase contrast to image clearance of inhaled debris [Donnelley, 2019]. Studies have also utilized a range of analysis methods to extract how the sample features change within a time-sequence of two-dimensional projections or three-dimensional volumes. While these imaging studies began in large-scale synchrotron facilities, we have recently performed these kinds of studies at an inverse-Compton-based compact synchrotron, the Munich Compact Light Source (MuCLS) [Gradl, 2018b]. 1. Morgan, Kaye, et al., “Methods for dynamic synchrotron X-ray imaging of live animals.”, under review 01/2019. 2. Gradl, R., et al. "Dynamic in vivo chest x-ray dark-field imaging in mice." IEEE Transactions on Medical Imaging (2018). 3. Morgan, Kaye S., et al. "In vivo X-ray imaging reveals improved airway surface hydration after a therapy designed for cystic fibrosis." American Journal of Respiratory and Critical Care Medicine 190.4 (2014): 469-472. 4. Donnelley, Martin, et al. "Live-pig-airway surface imaging and whole-pig CT at the Australian Synchrotron Imaging and Medical Beamline." Journal of Synchrotron Radiation 26.1 (2019). 5. Gradl, Regine, et al. "In vivo Dynamic Phase-Contrast X-ray Imaging using a Compact Light Source." Scientific Reports 8.1 (2018b): 6788.

Although the mortality rate of breast cancer has been reduced with the introduction of screening mammography, many women undergo unnecessary subsequent examinations due to inconclusive diagnoses. Therefore, spatial resolution and soft tissue contrast must meet very high standards. The former is necessary in order to be able to detect and distinguish closely spaced microcalcifications from each other. Thus, a high spatial resolution is demanded. Superposition of anatomical structures especially within dense breasts in conjunction with the inherently low soft tissue contrast of absorption images compromises image quality. This can be overcome by phase-contrast imaging. In this study, we analyze the spatial resolution of grating-based multimodal mammography dose-dependently using a mammographic phantom and one freshly dissected mastectomy specimen at an inverse Compton X-ray source. Here, the main focus was on estimating the spatial resolution with the sample in the beam path and discussing benefits and drawbacks of the method used as well as the estimation of the mean glandular dose. Finally, the possibility of improving the spatial resolution is investigated by comparison of the monochromatic grating-based mammography with the standard one. In almost all cases, the spatial resolution is higher in our proposed approach while the dose can be significantly reduced. Additionally, phase-contrast imaging helps to improve the detection of tumor lesions

Inverse Compton scattering of infrared photons from relativistic electrons generates brilliant quasi-monochromatic X-rays with an electron accelerator with dimensions of only a few meters, e.g. at the storage ring based inverse Compton scattering X-ray source employed at the Munich Compact Light Source. Availability of synchrotron light in a laboratory comes along with broader access to synchrotron techniques, especially in - but not limited to - clinical imaging and pre-clinical biomedical applications. We have been exploring the latter in daily user operation since commissioning of the MuCLS. So far, the focus has been on dynamic in vivo small-animal respiratory imaging, grating-based phase-contrast imaging, e.g. for quantitative material decomposition, and spectroscopic imaging, e.g. for angiography.

Nature Communications 10(1), 2494 (2019). doi:10.1038/s41467-019-10537-x, Modern transmission X-ray microscopy techniques provide very high resolution at low and medium X-ray energies, but suffer from a limited field-of-view. If sub-micrometre resolution is desired, their field-of-view is typically limited to less than one millimetre. Although the field-of-view increases through combining multiple images from adjacent regions of the specimen, so does the required data acquisition time. Here, we present a method for fast full-field super-resolution transmission microscopy by structured illumination of the specimen. This technique is well-suited even for hard X-ray energies above 30 keV, where efficient optics are hard to obtain. Accordingly, investigation of optically thick specimen becomes possible with our method combining a wide field-of-view spanning multiple millimetres, or even centimetres, with sub-micron resolution and hard X-ray energies., Published by Nature Publishing Group UK, [London]

We present a generalization of the convolution-based variational image registration approach, in which different regularizers can be implemented by conveniently exchanging the convolution kernel, even if it is nonseparable or nonstationary. Nonseparable kernels pose a challenge because they cannot be efficiently implemented by separate 1D convolutions. We propose to use a low-rank tensor decomposition to efficiently approximate nonseparable convolution. Nonstationary kernels pose an even greater challenge because the convolution kernel depends on, and needs to be evaluated for, every point in the image. We propose to pre-compute the local kernels and efficiently store them in memory using the Tucker tensor decomposition model. In our experiments we use the nonseparable exponential kernel and a nonstationary landmark kernel. The exponential kernel replicates desirable properties of elastic image registration, while the landmark kernel incorporates local prior knowledge about corresponding points in the images. We examine the trade-off between the computational resources needed and the approximation accuracy of the tensor decomposition methods. Furthermore, we obtain very smooth displacement fields even in the presence of large landmark displacements.

Through the development of specific magnetic resonance sequences, it is possible to measure the physiological properties of the lung parenchyma, e.g., ventilation. Automatic segmentation of pathologies in such ventilation maps is essential for the clinical application. The generation of labeled ground truth data is costly, time-consuming and requires much experience in the field of lung anatomy and physiology. In this paper, we present a weakly supervised learning strategy for the segmentation of defected lung areas in those ventilation maps. As a weak label, we use the Lung Clearance Index (LCI) which is measured by a Multiple Breath Washout test. The LCI is a single global measure for the ventilation inhomogeneities of the whole lung. We designed a network and a training procedure in order to infer a pixel-wise segmentation from the global LCI value. Our network is composed of two autoencoder sub-networks for the extraction of global and local features respectively. Furthermore, we use self-supervised regularization to prevent the network from learning non-meaningful segmentations. The performance of our method is evaluated by a rating of the created defect segmentations by 5 human experts, where over \(60\%\) of the segmentation results are rated with very good or perfect.

Monitoring subtle choroidal thickness changes in the human eye delivers insight into the pathogenesis of various ocular diseases such as myopia and helps planning their treatment. However, a thorough evaluation of detection-performance is challenging as a ground truth for comparison is not available. Alternatively, an artificial ground truth can be generated by averaging the manual expert segmentations. This makes the ground truth very sensitive to ambiguities due to different interpretations by the experts. In order to circumvent this limitation, we present a novel validation approach that operates independently from a ground truth and is uniquely based on the common agreement between algorithm and experts. Utilizing an appropriate index, we compare the joint agreement of several raters with the algorithm and validate it against manual expert segmentation. To illustrate this, we conduct an observational study and evaluate the results obtained using our previously published registration-based method. In addition, we present an adapted state-of-the-art evaluation method, where a paired t-test is carried out after leaving out the results of one expert at the time. Automated and manual detection were performed on a dataset of 90 OCT 3D-volume stack pairs of healthy subjects between 8 and 18 years of age from Asian urban regions with a high prevalence of myopia.

Thanks to recent advancements of specific acquisition methods and post-processing, proton Magnetic Resonance Imaging became an alternative imaging modality for detecting and monitoring chronic pulmonary disorders. Currently, ventilation maps of the lung are calculated from time-resolved image series which are acquired under free breathing. Each series consists of 140 coronal 2D images containing several breathing cycles. To cover the majority of the lung, such a series is acquired at several coronal slice-positions. A reduction of the number of images per slice enable an increase in the number of slice-positions per patient and therefore a more detailed analysis of the lung function without adding more stress to the patient. In this paper, we present a new method in order to reduce the number of images for one coronal slice while preserving the quality of the ventilation maps. As the input is a time-dependent signal, we designed our model based on Gated Recurrent Units. The results show that our method is able to compute ventilation maps with a high quality using only 40 images. Furthermore, our method shows strong robustness regarding changes in the breathing cycles during the acquisition.

Motion management strategies are crucial for radiotherapy of mobile tumours in order to ensure proper target coverage, save organs at risk and prevent interplay effects. We present a feasibility study for an inter-fractional, patient-specific motion model targeted at active beam scanning proton therapy. The model is designed to predict dense lung motion information from 2D abdominal ultrasound images. In a pretreatment phase, simultaneous ultrasound and magnetic resonance imaging are used to build a regression model. During dose delivery, abdominal ultrasound imaging serves as a surrogate for lung motion prediction. We investigated the performance of the motion model on five volunteer datasets. In two cases, the ultrasound probe was replaced after the volunteer has stood up between two imaging sessions. The overall mean prediction error is 2.9 mm and 3.4 mm after repositioning and therefore within a clinically acceptable range. These results suggest that the ultrasound-based regression model is a promising approach for inter-fractional motion management in radiotherapy.

Dentin is a mineralized material making up most of the tooth bulk. A system of microtubules, so called dentinal tubules, transverses it radially from the pulp chamber to the outside. This highly oriented structure leads to anisotropic mechanical properties directly connected to the tubules orientation and density: the ultimate tensile strength as well as the fracture toughness and the shear strength are largest perpendicular to dentinal tubules. Consequently, the fatigue strength depends on the direction of dentinal tubules, too. However, none of the existing techniques used to investigate teeth provide access to orientation and density of dentinal tubules for an entire specimen in a non-destructive way. In this paper, we measure a third molar human tooth both with conventional micro-CT and X-ray tensor tomography (XTT). While the achievable resolution in micro-CT is too low to directly resolve the dentinal tubules, we provide strong evidence that the direction and density of dentinal tubules can be indirectly measured by XTT, which exploits small-angle X-ray scattering to retrieve a 3D map of scattering tensors. We show that the mean directions of scattering structures correlate to the orientation of dentinal tubules and that the mean effective scattering strength provides an estimation of the relative density of dentinal tubules. Thus, this method could be applied to investigate the connection between tubule orientation and fatigue or tensile properties of teeth for a full sample without cutting one, non-representative peace of tooth out of the full sample.

While large-scale synchrotron sources provide a highly brilliant monochromatic X-ray beam, these X-ray sources are expensive in terms of installation and maintenance, and require large amounts of space due to the size of storage rings for GeV electrons. On the other hand, laboratory X-ray tube sources can easily be implemented in laboratories or hospitals with comparatively little cost, but their performance features a lower brilliance and a polychromatic spectrum creates problems with beam hardening artifacts for imaging experiments. Over the last decade, compact synchrotron sources based on inverse Compton scattering have evolved as one of the most promising types of laboratory-scale X-ray sources: they provide a performance and brilliance that lie in between those of large-scale synchrotron sources and X-ray tube sources, with significantly reduced financial and spatial requirements. These sources produce X-rays through the collision of relativistic electrons with infrared laser photons. In this study, an analysis of the performance, such as X-ray flux, source size and spectra, of the first commercially sold compact light source, the Munich Compact Light Source, is presented.

When used in combination with raster scanning, small-angle X-ray scattering (SAXS) has proven to be a valuable imaging technique of the nanoscale, for example of bone, teeth and brain matter. Although two-dimensional projection imaging has been used to characterize various materials successfully, its three-dimensional extension, SAXS computed tomography, poses substantial challenges, which have yet to be overcome. Previous work using SAXS computed tomography was unable to preserve oriented SAXS signals during reconstruction. Here we present a solution to this problem and obtain a complete SAXS computed tomography, which preserves oriented scattering information. By introducing virtual tomography axes, we take advantage of the two-dimensional SAXS information recorded on an area detector and use it to reconstruct the full three-dimensional scattering distribution in reciprocal space for each voxel of the three-dimensional object in real space. The presented method could be of interest for a combined six-dimensional real and reciprocal space characterization of mesoscopic materials with hierarchically structured features with length scales ranging from a few nanometres to a few millimetres--for example, biomaterials such as bone or teeth, or functional materials such as fuel-cell or battery components.