3D X-ray Histology for the Investigation of Temporal Lobe Epilepsy in a Mouse Model.

The most common form of epilepsy among adults is mesial temporal lobe epilepsy (mTLE), with seizures often originating in the hippocampus due to abnormal electrical activity. The gold standard for the histopathological analysis of mTLE is histology, which is a two-dimensional technique. To fill this gap, we propose complementary three-dimensional (3D) X-ray histology. Herein, we used synchrotron radiation-based phase-contrast microtomography with 1.6 µm-wide voxels for the post mortem visualization of tissue microstructure in an intrahippocampal-kainate mouse model for mTLE. We demonstrated that the 3D X-ray histology of unstained, unsectioned, paraffin-embedded brain hemispheres can identify hippocampal sclerosis through the loss of pyramidal neurons in the first and third regions of the Cornu ammonis as well as granule cell dispersion within the dentate gyrus. Morphology and density changes during epileptogenesis were quantified by segmentations from a deep convolutional neural network. Compared to control mice, the total dentate gyrus volume doubled and the granular layer volume quadrupled 21 days after injecting kainate. Subsequent sectioning of the same mouse brains allowed for benchmarking 3D X-ray histology against well-established histochemical and immunofluorescence stainings. Thus, 3D X-ray histology is a complementary neuroimaging tool to unlock the third dimension for the cellular-resolution histopathological analysis of mTLE.

Zebrafish (Danio rerio) larvae as a predictive model to study gentamicin-induced structural alterations of the kidney.

Nephrotoxicity is an important drug safety aspect to be assessed during drug discovery and development. To study renal toxicity, in vitro cell-based assays are often used. Unfortunately, translating the results of such cell assays to vertebrates including human remains challenging. Therefore, we aim to evaluate whether zebrafish larvae (ZFL) could serve as a vertebrate screening model to detect gentamicin-induced changes of kidney glomeruli and proximal tubules. To validate the model, we compared the results of ZFL with those obtained from kidney biopsies of gentamicin-treated mice. We used transgenic zebrafish lines expressing enhanced green fluorescent proteins in the glomerulus to visualize glomerular damage. Synchrotron radiation-based computed tomography (SRµCT) is a label-free approach providing three-dimensional representations of renal structures with micrometre resolution. Clinically used gentamicin concentrations induce nephrotoxicity and affect glomerular and proximal tubular morphology. Findings were confirmed in mice and ZFL. There was a strong correlation between fluorescent signals in ZFL, SRµCT- derived descriptors of glomerular and proximal tubular morphology and the histological analysis of mouse kidney biopsies. A combination of SRµCT and confocal microscopy provides unprecedented insights into anatomical structures of the zebrafish kidney. Based on our findings, we suggest to use ZFL as a predictive vertebrate screening model to study drug-induced nephrotoxicity and to bridge the gap between cell culture-based test systems and experiments in mammals.

Three-dimensional analysis of aligner gaps and thickness distributions, using hard x-ray tomography with micrometer resolution.

Purpose: The morphology of a polymer aligner, designed according to an orthodontic treatment plan, determines clinical outcomes. A fundamental element of orthodontic tooth movement with aligner treatment is the fit of the aligner's surface to the individual teeth. Gaps between the aligner and teeth do occur because current aligner fabrication is not capable of completely reproducing the complex anatomy of the individual denture. Our study aims at a quantitative three-dimensional assessment of the fit between optically transparent aligners placed on a polymeric model of the upper dental arch for two thermofoil thicknesses at preselected thermoforming temperatures. Approach: Using an intraoral scan of a subject's upper dental arch, eight models were printed using a stereolithographic system. A series of eight NaturAligners® was manufactured with a pressure molding process, using thermofoils with thicknesses of 550 and 750 µ m and preselected process temperatures between 110°C and 210°C. These aligners placed on the corresponding models were imaged by an advanced micro computed tomography system. The aligners and the models were segmented to extract the gaps and aligners' local thicknesses as a function of the processing temperature for the two foil thicknesses. Results: The results indicate that the aligners show a better fit when the foils are processed at higher temperatures. Nevertheless, processing temperatures can be kept below 150°C, as the gain becomes negligible. Thermal processing reduces the average thickness of the aligners to 60% with respect to the planar starting foil. These thickness distributions demonstrate that the aligners are generally thicker on the occlusal surfaces of molars and premolars but thinner around the incisors and buccal as well as on oral surfaces. Conclusions: Hard x-ray tomography with micrometer resolution is a powerful technique employed to localize the gaps between aligners and teeth, and it also enables film thickness measurements after thermoforming. The thicker film on the occlusal surfaces is most welcome because of aligner abrasion during wear. The NaturAligner® surfaces consist of a 25 - µ m -thin cellulose layer, and thus the microplastics released via abrasion of less than this thickness are expected to be substantially less critical than for other commercially available, optically transparent aligners.

Comparative hard x-ray tomography for virtual histology of zebrafish larva, human tooth cementum, and porcine nerve.

Purpose: Synchrotron radiation-based tomography yields microanatomical features in human and animal tissues without physical slicing. Recent advances in instrumentation have made laboratory-based phase tomography feasible. We compared the performance of three cutting-edge laboratory systems benchmarked by synchrotron radiation-based tomography for three specimens. As an additional criterion, the user-friendliness of the three microtomography systems was considered. Approach: The three tomography systems-SkyScan 2214 (Bruker-microCT, Kontich, Belgium), Exciscope prototype (Stockholm, Sweden), and Xradia 620 Versa (Zeiss, Oberkochen, Germany)-were given 36 h to measure three medically relevant specimens, namely, zebrafish larva, archaeological human tooth, and porcine nerve. The obtained datasets were registered to the benchmark synchrotron radiation-based tomography from the same specimens and selected ones to the SkyScan 1275 and phoenix nanotom m® laboratory systems to characterize development over the last decade. Results: Next-generation laboratory-based microtomography almost reached the quality achieved by synchrotron-radiation facilities with respect to spatial and density resolution, as indicated by the visualization of the medically relevant microanatomical features. The SkyScan 2214 system and the Exciscope prototype demonstrated the complementarity of phase information by imaging the eyes of the zebrafish larva. The 3 - µ m thin annual layers in the tooth cementum were identified using Xradia 620 Versa. Conclusions: SkyScan 2214 was the simplest system and was well-suited to visualizing the wealth of anatomical features in the zebrafish larva. Data from the Exciscope prototype with the high photon flux from the liquid metal source showed the spiral nature of the myelin sheaths in the porcine nerve. Xradia 620 Versa, with detector optics as typically installed for synchrotron tomography beamlines, enabled the three-dimensional visualization of the zebrafish larva with comparable quality to the synchrotron data and the annual layers in the tooth cementum.

Virtual histology of an entire mouse brain from formalin fixation to paraffin embedding. Part 2: Volumetric strain fields and local contrast changes.

BACKGROUND: Fixation and embedding of post mortem brain tissue is a pre-requisite for both gold-standard conventional histology and X-ray virtual histology. This process alters the morphology and density of the brain microanatomy. NEW METHOD: To quantify these changes, we employed synchrotron radiation-based hard X-ray tomography with 3 µm voxel length to visualize the same mouse brain after fixation in 4% formalin, immersion in ethanol solutions (50%, 70%, 80%, 90%, and 100%), xylene, and finally after embedding in a paraffin block. The volumetric data were non-rigidly registered to the initial formalin-fixed state to align the microanatomy within the entire mouse brain. RESULTS: Volumetric strain fields were used to characterize local shrinkage, which was found to depend on the anatomical region and distance to external surface. X-ray contrast was altered and enhanced by preparation-induced inter-tissue density changes. The preparation step can be selected to highlight specific anatomical features. For example, fiber tract contrast is amplified in 100% ethanol. COMPARISON WITH EXISTING METHODS: Our method provides volumetric strain fields, unlike approaches based on feature-to-feature or volume measurements. Volumetric strain fields are produced by non-rigid registration, which is less labor-intensive and observer-dependent than volume change measurements based on manual segmentations. X-ray microtomography provides spatial resolution at least an order of magnitude higher than magnetic resonance microscopy, allowing for analysis of morphology and density changes within the brain's microanatomy. CONCLUSION: Our approach belongs to three-dimensional virtual histology with isotropic micrometer spatial resolution and therefore complements atlases based on a combination of magnetic resonance microscopy and optical micrographs of serial histological sections.

Virtual histology of an entire mouse brain from formalin fixation to paraffin embedding. Part 1: Data acquisition, anatomical feature segmentation, tracking global volume and density changes.

BACKGROUND: Micrometer-resolution neuroimaging with gold-standard conventional histology requires tissue fixation and embedding. The exchange of solvents for the creation of sectionable paraffin blocks modifies tissue density and generates non-uniform brain shrinkage. NEW METHOD: We employed synchrotron radiation-based X-ray microtomography for slicing- and label-free virtual histology of the mouse brain at different stages of the standard preparation protocol from formalin fixation via ascending ethanol solutions and xylene to paraffin embedding. Segmentation of anatomical regions allowed us to quantify non-uniform tissue shrinkage. Global and local changes in X-ray absorption gave insight into contrast enhancement for virtual histology. RESULTS: The volume of the entire mouse brain was 60%, 56%, and 40% of that in formalin for, respectively, 100% ethanol, xylene, and paraffin. The volume changes of anatomical regions such as the hippocampus, anterior commissure, and ventricles differ from the global volume change. X-ray absorption of the full brain decreased, while local absorption differences increased, resulting in enhanced contrast for virtual histology. These trends were also observed with laboratory microtomography measurements. COMPARISON WITH EXISTING METHODS: Microtomography provided sub-10 µm spatial resolution with sufficient density resolution to resolve anatomical structures at each step of the embedding protocol. The spatial resolution of conventional computed tomography and magnetic resonance microscopy is an order of magnitude lower and both do not match the contrast of microtomography over the entire embedding protocol. Unlike feature-to-feature or total volume measurements, our approach allows for calculation of volume change based on segmentation. CONCLUSION: We present isotropic micrometer-resolution imaging to quantify morphology and composition changes in a mouse brain during the standard histological preparation. The proposed method can be employed to identify the most appropriate embedding medium for anatomical feature visualization, to reveal the basis for the dramatic X-ray contrast enhancement observed in numerous embedded tissues, and to quantify morphological changes during tissue fixation and embedding.

Ultrasound simulation with deformable and patient-specific scatterer maps.

PURPOSE: Ray-tracing-based simulations model ultrasound (US) interactions with a custom geometric anatomical model, where US texture can be emulated via real-time point-spread function convolutions of a tissue scatterer representation. Such scatterer representations for realistic appearance are difficult to parameterize or model manually and do not respond to volumetric deformations such as those caused with tissue compression by the probe. Herein we utilize brightness mode (B-mode) estimated scatterer maps for ray tracing and propose to enhance the realism of ray-tracing-based simulations by incorporating dynamic speckle patterns that change compliant with tissue deformation. METHODS: In this work, we realistically simulate US texture deformations in the scatterer domain via back-projection of ray segments into a nominal state before sampling during simulation runtime. We estimate scatterer maps from background in vivo images using a pretrained generative adversarial network. RESULTS: We demonstrated our proposed scatterer estimation and runtime background fusion method on simulated transvaginal US scans of detailed surface-based foetal models. We show the viability of modelling deformations in the scatterer domain at interactive frame rates of 28 frames per second. A quantitative and a qualitative evaluations indicated improved realism in comparison to the state of the art. CONCLUSIONS: Transferring a background image in a scatterer representation enables us to capture anatomical content in a physical space, in which deformations can be incorporated physically consistently before convolving with a US point-spread function during simulation runtime. This then uses the same imaging model on both the background and the hand-crafted models leading to a consistent and seamless compounding of contents in the scatterer space.

A comprehensive and volumetric musculoskeletal model for the dynamic simulation of the shoulder function.

We present a volumetric and extensive finite element model of the shoulder usable in the context of inverse control, in which the scapula is left unconstrained on the ribcage. Such a model allows for exploring various shoulder movements, which are essential for making patient-specific decisions. The proposed model consists of 23 volumetric muscles parts modelled using the finite element method. The glenohumeral, acromioclavicular and sternoclavicular joints are modelled with soft ball-socket constraints. The musculoskeletal model can be controlled by a tracking-based algorithm, finding the excitations values in the muscles needed to follow some target points. The moment arms obtained during abduction and rotation are compared with the literature, which includes results from cadaveric data and a fine FE model of the rotator cuff and the deltoid. We simulated the paralysis of serratus anterior, a main reason of scapular winging, and compared it with its physiological counterpart. A deficiency in the range of motion as well as a reduction in upward rotation were observed, which both corroborate clinical observations. This is one of the most comprehensive model of the shoulder, which can be used to study complex pathologies of the shoulder and their impact on functional outcome such as range-of-motion.

An image interpolation approach for acquisition time reduction in navigator-based 4D MRI.

Navigated 2D multi-slice dynamic Magnetic Resonance (MR) imaging enables high contrast 4D MR imaging during free breathing and provides in-vivo observations for treatment planning and guidance. Navigator slices are vital for retrospective stacking of 2D data slices in this method. However, they also prolong the acquisition sessions. Temporal interpolation of navigator slices can be used to reduce the number of navigator acquisitions without degrading specificity in stacking. In this work, we propose a convolutional neural network (CNN) based method for temporal interpolation, with motion field prediction as an intermediate step. The proposed formulation incorporates the prior knowledge that a motion field underlies changes in the image intensities over time. Previous approaches that interpolate directly in the intensity space are prone to produce blurry images or even remove structures in the images. Our method avoids such problems and faithfully preserves the information in the image. Further, an important advantage of our formulation is that it provides an unsupervised estimation of bi-directional motion fields. These motion fields can potentially be used to halve the number of registrations required during 4D reconstruction, thus substantially reducing the reconstruction time. These advantages are achieved while preserving 4D reconstruction quality as compared to that with the true navigators.

ELPHA: Dynamically deformable liver phantom for real-time motion-adaptive radiotherapy treatments.

PURPOSE: Real-time motion-adaptive radiotherapy of intrahepatic tumors needs to account for motion and deformations of the liver and the target location within. Phantoms representative of anatomical deformations are required to investigate and improve dynamic treatments. A deformable phantom capable of testing motion detection and motion mitigation techniques is presented here. METHODS: The dynamically dEformable Liver PHAntom (ELPHA) was designed to fulfill three main constraints: First, a reproducibly deformable anatomy is required. Second, the phantom should provide multimodality imaging contrast for motion detection. Third, a time-resolved dosimetry system to measure temporal effects should be provided. An artificial liver with vasculature was casted from soft silicone mixtures. The silicones allow for deformation and radiographic image contrast, while added cellulose provides ultrasonic contrast. An actuator was used for compressing the liver in the inferior direction according to a prescribed respiratory motion trace. Electromagnetic (EM) transponders integrated in ELPHA help provide ground truth motion traces. They were used to quantify the motion reproducibility of the phantom and to validate motion detection based on ultrasound imaging. A two-dimensional ultrasound probe was used to follow the position of the vessels with a template-matching algorithm. This detected vessel motion was compared to the EM transponder signal by calculating the root-mean-square error (RMSE). ELPHA was then used to investigate the dose deposition of dynamic treatment deliveries. Two dosimetry systems, radio-chromic film and plastic scintillation dosimeters (PSD), were integrated in ELPHA. The PSD allow for time-resolved measurement of the delivered dose, which was compared to a time-resolved dose of the treatment planning system. Film and PSD were used to investigate dose delivery to the deforming phantom without motion compensation and with treatment-couch tracking for motion compensation. RESULTS: ELPHA showed densities of 66 and 45 HU in the liver and the surrounding tissues. A high motion reproducibility with a submillimeter RMSE (<0.32 mm) was measured. The motion of the vasculature detected with ultrasound agreed well with the EM transponder position (RMSE < 1 mm). A time-resolved dosimetry system with a 1 Hz time resolution was achieved with the PSD. The agreement of the planned and measured dose to the PSD decreased with increasing motion amplitude: A dosimetric RMSE of 1.2, 2.1, and 2.7 cGy/s was measured for motion amplitudes of 8, 16, and 24 mm, respectively. With couch tracking as motion compensation, these values decreased to 1.1, 1.4, and 1.4 cGy/s. This is closer to the static situation with 0.7 cGy/s. Film measurements showed that couch tracking was able to compensate for motion with a mean target dose within 5% of the static situation (-5% to +1%), which was higher than in the uncompensated cases (-41% to -1%). CONCLUSIONS: ELPHA is a deformable liver phantom with high motion reproducibility. It was demonstrated to be suitable for the verification of motion detection and motion mitigation modalities. Based on the multimodality image contrast, a high accuracy of ultrasound based motion detection was shown. With the time-resolved dosimetry system, ELPHA is suitable for performance assessment of real-time motion-adaptive radiotherapy, as was shown exemplary with couch tracking.

Evaluation of 2D and 3D ultrasound tracking algorithms and impact on ultrasound-guided liver radiotherapy margins.

PURPOSE: Compensation for respiratory motion is important during abdominal cancer treatments. In this work we report the results of the 2015 MICCAI Challenge on Liver Ultrasound Tracking and extend the 2D results to relate them to clinical relevance in form of reducing treatment margins and hence sparing healthy tissues, while maintaining full duty cycle. METHODS: We describe methodologies for estimating and temporally predicting respiratory liver motion from continuous ultrasound imaging, used during ultrasound-guided radiation therapy. Furthermore, we investigated the trade-off between tracking accuracy and runtime in combination with temporal prediction strategies and their impact on treatment margins. RESULTS: Based on 2D ultrasound sequences from 39 volunteers, a mean tracking accuracy of 0.9 mm was achieved when combining the results from the 4 challenge submissions (1.2 to 3.3 mm). The two submissions for the 3D sequences from 14 volunteers provided mean accuracies of 1.7 and 1.8 mm. In combination with temporal prediction, using the faster (41 vs 228 ms) but less accurate (1.4 vs 0.9 mm) tracking method resulted in substantially reduced treatment margins (70% vs 39%) in contrast to mid-ventilation margins, as it avoided non-linear temporal prediction by keeping the treatment system latency low (150 vs 400 ms). Acceleration of the best tracking method would improve the margin reduction to 75%. CONCLUSIONS: Liver motion estimation and prediction during free-breathing from 2D ultrasound images can substantially reduce the in-plane motion uncertainty and hence treatment margins. Employing an accurate tracking method while avoiding non-linear temporal prediction would be favorable. This approach has the potential to shorten treatment time compared to breath-hold and gated approaches, and increase treatment efficiency and safety.

Reducing Navigators in Free-Breathing Abdominal MRI via Temporal Interpolation Using Convolutional Neural Networks.

Navigated 2-D multi-slice dynamic magnetic resonance imaging (MRI) acquisitions are essential for MR guided therapies. This technique yields time-resolved volumetric images during free-breathing, which are ideal for visualizing and quantifying breathing induced motion. To achieve this, navigated dynamic imaging requires acquiring multiple navigator slices. Reducing the number of navigator slices would allow for acquiring more data slices in the same time, and hence, increasing through-plane resolution or alternatively the overall acquisition time can be reduced while keeping resolution unchanged. To this end, we propose temporal interpolation of navigator slices using convolutional neural networks (CNNs). Our goal is to acquire fewer navigators and replace the missing ones with interpolation. We evaluate the proposed method on abdominal navigated dynamic MRI sequences acquired from 14 subjects. Investigations with several CNN architectures and training loss functions show favorable results for cost and a simple feed-forward network with no skip connections. When compared with interpolation by non-linear registration, the proposed method achieves higher interpolation accuracy on average as quantified in terms of root mean square error and residual motion. Analysis of the differences shows that the better performance is due to more accurate interpolation at peak exhalation and inhalation positions. Furthermore, the CNN-based approach requires substantially lower execution times than that of the registration-based method. At last, experiments on dynamic volume reconstruction reveal minimal differences between reconstructions with acquired and interpolated navigator slices.

Registration of 3D freehand ultrasound to a bone model for orthopedic procedures of the forearm.

PURPOSE: For guidance of orthopedic surgery, the registration of preoperative images and corresponding surgical plans with the surgical setting can be of great value. Ultrasound (US) is an ideal modality for surgical guidance, as it is non-ionizing, real time, easy to use, and requires minimal (magnetic/radiation) safety limitations. By extracting bone surfaces from 3D freehand US and registering these to preoperative bone models, complementary information from these modalities can be fused and presented in the surgical realm. METHODS: A partial bone surface is extracted from US using phase symmetry and a factor graph-based approach. This is registered to the detailed 3D bone model, conventionally generated for preoperative planning, based on a proposed multi-initialization and surface-based scheme robust to partial surfaces. RESULTS: 36 forearm US volumes acquired using a tracked US probe were independently registered to a 3D model of the radius, manually extracted from MRI. Given intraoperative time restrictions, a computationally efficient algorithm was determined based on a comparison of different approaches. For all 36 registrations, a mean (± SD) point-to-point surface distance of [Formula: see text] was obtained from manual gold standard US bone annotations (not used during the registration) to the 3D bone model. CONCLUSIONS: A registration framework based on the bone surface extraction from 3D freehand US and a subsequent fast, automatic surface alignment robust to single-sided view and large false-positive rates from US was shown to achieve registration accuracy feasible for practical orthopedic scenarios and a qualitative outcome indicating good visual image alignment.

Care coordination: Identifying and connecting the most appropriate care to the patients.

Although nurses are increasingly expected to fulfill the role of care coordinator, the knowledge and skills required to be an effective care coordinator are not well understood. The purpose of this study was to describe the knowledge and skills required in care coordination practice using an interpretive phenomenological approach. Fifteen care coordinators from 10 programs were interviewed over a 6-month period. Semi-structured face-to-face interviews were audio recorded, transcribed, and analyzed using interpretive phenomenology. The central theme of care coordination practice was bridging the patient and the healthcare systems. To bridge, care coordinators needed to have knowledge of the patient and healthcare system as well as the skills to identify and negotiate treatments appropriate for the patient. The most salient finding and new to this literature was that care coordinators who used their medical knowledge about available treatment options to discern and negotiate for the most appropriate care to the patient made differences in patient outcomes. Nurses with medical and healthcare system knowledge, combined with the skills to navigate and negotiate with others in an increasingly complex healthcare system, are well situated to be care coordinators and generate optimal outcomes. Further investigations of critical care coordinator competencies are needed to support nurses currently enacting the role of care coordinator and to prepare future nurses to fulfill the role.

Automatic registration of 2D histological sections to 3D microCT volumes: Trabecular bone.

Histomorphometry and microCT are the two dominant imaging techniques to study bone structure and quality to evaluate repair, regeneration, and disease. These two methods are complementary; where histology provides highly resolved tissue properties on a cellular level in 2D, microCT provides spatial information of bone micro-structure in 3D. For this reason, both of these modalities are commonly used in bone studies. As it is not trivial to combine the images of these two modalities, the two methods are typically applied to different specimens within a study. However, we believe that applying both imaging modalities to the same specimen with a suitable fusion strategy may further strengthen the value of each modality. Therefore, we propose a registration method to align 2D histology slices with a 3D microCT volume, without any prior knowledge of the sectioning direction. In a preprocessing step, bone is extracted from both images. Then, we use a strategy for initializing potential locations, and an iterative approach for searching for an ideal fitting plane using Radon-based rigid transforms and feature-based affine alignments. The algorithm was tested and validated with simulated and real data. For the latter, microCT images of trabecular bone with 76 corresponding histological sections acquired from decalcified and calcified specimens were used. The registration resulted in 94.7% acceptable solutions as defined by a registration orientation error of less than 3°. Average registration accuracy of the acceptable results was 0.6°, leading to a target registration error for our method of 106.3µm, computed based on landmarks annotated by an observer. This corresponds roughly to 10pixels in the images; although, the relation to actual visible structures that provide the features to register, is arguably more relevant.

A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation.

BACKGROUND: Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. METHODS: A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. RESULTS: With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. CONCLUSIONS: The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Consistent reconstruction of 4D fetal heart ultrasound images to cope with fetal motion.

PURPOSE: 4D ultrasound imaging of the fetal heart relies on reconstructions from B-mode images. In the presence of fetal motion, current approaches suffer from artifacts, which are unrecoverable for single sweeps. METHODS: We propose to use many sweeps and exploit the resulting redundancy to automatically recover from motion by reconstructing a 4D image which is consistent in phase, space, and time. An interactive visualization framework to view animated ultrasound slices from 4D reconstructions on arbitrary planes was developed using a magnetically tracked mock probe. RESULTS: We first quantified the performance of 10 4D reconstruction formulations on simulated data. Reconstructions of 14 in vivo sequences by a baseline, the current state-of-the-art, and the proposed approach were then visually ranked with respect to temporal quality on orthogonal views. Rankings from 5 observers showed that the proposed 4D reconstruction approach significantly improves temporal image quality in comparison with the baseline. The 4D reconstructions of the baseline and the proposed methods were then inspected interactively for accessibility to clinically important views and rated for their clinical usefulness by an ultrasound specialist in obstetrics and gynecology. The reconstructions by the proposed method were rated as 'very useful' in 71% and were statistically significantly more useful than the baseline reconstructions. CONCLUSIONS: Multi-sweep fetal heart ultrasound acquisitions in combination with consistent 4D image reconstruction improves quality as well as clinical usefulness of the resulting 4D images in the presence of fetal motion.

Robust motion tracking in liver from 2D ultrasound images using supporters.

PURPOSE: Effectiveness of image-guided radiation therapy with precise dose delivery depends highly on accurate target localization, which may involve motion during treatment due to, e.g., breathing and drift. Therefore, it is important to track the motion and adjust the radiation delivery accordingly. Tracking generally requires reliable target appearance and image features, whereas in ultrasound imaging acoustic shadowing and other artifacts may degrade the visibility of a target, leading to substantial tracking errors. To minimize such errors, we propose a method based on so-called supporters, a computer vision tracking technique. This allows us to leverage information from surrounding motion for improving robustness of motion tracking on 2D ultrasound image sequences of the liver. METHODS: Image features, potentially useful for predicting the target positions, are individually tracked, and a supporter model capturing the coupling of motion between these features and the target is learned on-line. This model is then applied to predict the target position, when the target cannot be otherwise tracked reliably. RESULTS: The proposed method was evaluated using the Challenge on Liver Ultrasound Tracking (CLUST)-2015 dataset. Leave-one-out cross-validation was performed on the training set of 24 2D image sequences of each 1-5 min. The method was then applied on the test set (24 2D sequences), where the results were evaluated by the challenge organizers, yielding 1.04 mm mean and 2.26 mm 95%ile tracking error for all targets. We also devised a simulation framework to emulate acoustic shadowing artifacts from the ribs, which showed effective tracking despite the shadows. CONCLUSIONS: Results support the feasibility and demonstrate the advantages of using supporters. The proposed method improves its baseline tracker, which uses optic flow and elliptic vessel models, and yields the state-of-the-art real-time tracking solution for the CLUST challenge.

Isotropic Total Variation Regularization of Displacements in Parametric Image Registration.

Spatial regularization is essential in image registration, which is an ill-posed problem. Regularization can help to avoid both physically implausible displacement fields and local minima during optimization. Tikhonov regularization (squared l2 -norm) is unable to correctly represent non-smooth displacement fields, that can, for example, occur at sliding interfaces in the thorax and abdomen in image time-series during respiration. In this paper, isotropic Total Variation (TV) regularization is used to enable accurate registration near such interfaces. We further develop the TV-regularization for parametric displacement fields and provide an efficient numerical solution scheme using the Alternating Directions Method of Multipliers (ADMM). The proposed method was successfully applied to four clinical databases which capture breathing motion, including CT lung and MR liver images. It provided accurate registration results for the whole volume. A key strength of our proposed method is that it does not depend on organ masks that are conventionally required by many algorithms to avoid errors at sliding interfaces. Furthermore, our method is robust to parameter selection, allowing the use of the same parameters for all tested databases. The average target registration error (TRE) of our method is superior (10% to 40%) to other techniques in the literature. It provides precise motion quantification and sliding detection with sub-pixel accuracy on the publicly available breathing motion databases (mean TREs of 0.95 mm for DIR 4D CT, 0.96 mm for DIR COPDgene, 0.91 mm for POPI databases).