ULTRA-SR Challenge: Assessment of Ultrasound Localization and TRacking Algorithms for Super-Resolution Imaging.

With the widespread interest and uptake of super-resolution ultrasound (SRUS) through localization and tracking of microbubbles, also known as ultrasound localization microscopy (ULM), many localization and tracking algorithms have been developed. ULM can image many centimeters into tissue in-vivo and track microvascular flow non-invasively with sub-diffraction resolution. In a significant community effort, we organized a challenge, Ultrasound Localization and TRacking Algorithms for Super-Resolution (ULTRA-SR). The aims of this paper are threefold: to describe the challenge organization, data generation, and winning algorithms; to present the metrics and methods for evaluating challenge entrants; and to report results and findings of the evaluation. Realistic ultrasound datasets containing microvascular flow for different clinical ultrasound frequencies were simulated, using vascular flow physics, acoustic field simulation and nonlinear bubble dynamics simulation. Based on these datasets, 38 submissions from 24 research groups were evaluated against ground truth using an evaluation framework with six metrics, three for localization and three for tracking. In-vivo mouse brain and human lymph node data were also provided, and performance assessed by an expert panel. Winning algorithms are described and discussed. The publicly available data with ground truth and the defined metrics for both localization and tracking present a valuable resource for researchers to benchmark algorithms and software, identify optimized methods/software for their data, and provide insight into the current limits of the field. In conclusion, Ultra-SR challenge has provided benchmarking data and tools as well as direct comparison and insights for a number of the state-of-the art localization and tracking algorithms.

Comment on "So you think you can DAS? A viewpoint on delay-and-sum beamforming" [Ultrasonics 111 (2021) 106309].

It is shown herein that Perrot et al., who reviewed delay-and-sum beamforming for ultrafast ultrasound imaging in [Ultrasonics 111 (2021) 106309], misinterpreted the purpose of dynamic receive apertures. Such apertures widen with the focal length as a function of a given f-number and improve the image quality by suppressing grating lobes. Perrot et al., however, attributed erroneously the image quality improvement to suppression of measurement noise and, in doing so, proposed a suboptimal method to determine an f-number.

Frequency-Dependent F-Number Suppresses Grating Lobes and Improves the Lateral Resolution in Coherent Plane-Wave Compounding.

Ultrafast imaging modes, such as coherent plane-wave compounding (CPWC), increase image uniformity and reduce grating lobe artifacts by dynamic receive apertures. The focal length and the desired aperture width maintain a given ratio, which is called the F -number. Fixed F -numbers, however, exclude useful low-frequency components from the focusing and reduce the lateral resolution. Herein, this reduction is avoided by a frequency-dependent F -number. This F -number derives from the far-field directivity pattern of a focused aperture and can be expressed in closed form. The F -number, at low frequencies, widens the aperture to improve the lateral resolution. The F -number, at high frequencies, narrows the aperture to avoid lobe overlaps and suppress grating lobes. Phantom and in vivo experiments with a Fourier-domain beamforming algorithm validated the proposed F -number in CPWC. The lateral resolution, which was measured by the median lateral full-widths at half-maximum of wires, improved by up to 46.8% and 14.9% in a wire and a tissue phantom, respectively, in comparison to fixed F -numbers. Grating lobe artifacts, which were measured by the median peak signal-to-noise ratios of wires, reduced by up to 9.9 dB in comparison to the full aperture. The proposed F -number thus outperformed F -numbers that were recently derived from the directivity of the array elements.

Ultrasound localization microscopy.

Ultrasound Localization Microscopy (ULM) is an emerging technique that provides impressive super-resolved images of microvasculature, i.e., images with much better resolution than the conventional diffraction-limited ultrasound techniques and is already taking its first steps from preclinical to clinical applications. In comparison to the established perfusion or flow measurement methods, namely contrast-enhanced ultrasound (CEUS) and Doppler techniques, ULM allows imaging and flow measurements even down to the capillary level. As ULM can be realized as a post-processing method, conventional ultrasound systems can be used for. ULM relies on the localization of single microbubbles (MB) of commercial, clinically approved contrast agents. In general, these very small and strong scatterers with typical radii of 1-3 µm are imaged much larger in ultrasound images than they actually are due to the point spread function of the imaging system. However, by applying appropriate methods, these MBs can be localized with sub-pixel precision. Then, by tracking MBs over successive frames of image sequences, not only the morphology of vascular trees but also functional information such as flow velocities or directions can be obtained and visualized. In addition, quantitative parameters can be derived to describe pathological and physiological changes in the microvasculature. In this review, the general concept of ULM and conditions for its applicability to microvessel imaging are explained. Based on this, various aspects of the different processing steps for a concrete implementation are discussed. The trade-off between complete reconstruction of the microvasculature and the necessary measurement time as well as the implementation in 3D are reviewed in more detail, as they are the focus of current research. Through an overview of potential or already realized preclinical and clinical applications - pathologic angiogenesis or degeneration of vessels, physiological angiogenesis, or the general understanding of organ or tissue function - the great potential of ULM is demonstrated.

A Single-Shot Harmonic Imaging Approach Utilizing Deep Learning for Medical Ultrasound.

Tissue Harmonic Imaging (THI) is an invaluable tool in clinical ultrasound owing to its enhanced contrast resolution and reduced reverberation clutter in comparison to fundamental mode imaging. However, harmonic content separation based on high pass filtering suffers from potential contrast degradation or lower axial resolution due to spectral leakage. Whereas nonlinear multi-pulse harmonic imaging schemes, such as amplitude modulation and pulse inversion, suffer from a reduced framerate and comparatively higher motion artifacts due to the necessity of at least two pulse echo acquisitions. To address this problem, we propose a deep-learning-based single-shot harmonic imaging technique capable of generating comparable image quality to pulse amplitude modulation methods, yet at a higher framerate and with fewer motion artifacts. Specifically, an asymmetric convolutional encoder-decoder structure is designed to estimate the combination of the echoes resulting from the half-amplitude transmissions using the echo produced from the full amplitude transmission as input. The echoes were acquired with the checkerboard amplitude modulation technique for training. The model was evaluated across various targets and samples to illustrate generalizability as well as the possibility and impact of transfer learning. Furthermore, for possible interpretability of the network, we investigate if the latent space of the encoder holds information on the nonlinearity parameter of the medium. We demonstrate the ability of the proposed approach to generate harmonic images with a single firing that are comparable to those from a multi-pulse acquisition.

Thermodynamics of an Empty Box.

A gas in a box is perhaps the most important model system studied in thermodynamics and statistical mechanics. Usually, studies focus on the gas, whereas the box merely serves as an idealized confinement. The present article focuses on the box as the central object and develops a thermodynamic theory by treating the geometric degrees of freedom of the box as the degrees of freedom of a thermodynamic system. Applying standard mathematical methods to the thermodynamics of an empty box allows equations with the same structure as those of cosmology and classical and quantum mechanics to be derived. The simple model system of an empty box is shown to have interesting connections to classical mechanics, special relativity, and quantum field theory.

Effects of contrast-enhanced ultrasound treatment on neoadjuvant chemotherapy in breast cancer.

Purpose: Preclinical and clinical data indicate that contrast-enhanced ultrasound can enhance tumor perfusion and vessel permeability, thus, improving chemotherapy accumulation and therapeutic outcome. Therefore, we investigated the effects of high mechanical index (MI) contrast-enhanced Doppler ultrasound (CDUS) on tumor perfusion in breast cancer. Methods: In this prospective study, breast cancer patients were randomly assigned to receive either 18 minutes of high MI CDUS during chemotherapy infusion (n = 6) or chemotherapy alone (n = 5). Tumor perfusion was measured before and after at least six chemotherapy cycles using motion-model ultrasound localization microscopy. Additionally, acute effects of CDUS on vessel perfusion and chemotherapy distribution were evaluated in mice bearing triple-negative breast cancer (TNBC). Results: Morphological and functional vascular characteristics of breast cancer in patients were not significantly influenced by high MI CDUS. However, complete clinical tumor response after neoadjuvant chemotherapy was lower in high MI CDUS-treated (1/6) compared to untreated patients (4/5) and size reduction of high MI CDUS treated tumors tended to be delayed at early chemotherapy cycles. In mice with TNBC high MI CDUS decreased the perfused tumor vessel fraction (p < 0.01) without affecting carboplatin accumulation or distribution. Higher vascular immaturity and lower stromal stabilization may explain the stronger vascular response in murine than human tumors. Conclusion: High MI CDUS had no detectable effect on breast cancer vascularization in patients. In mice, the same high MI CDUS setting did not affect chemotherapy accumulation although strong effects on the tumor vasculature were detected histologically. Thus, sonopermeabilization in human breast cancers might not be effective using high MI CDUS protocols and future applications may rather focus on low MI approaches triggering microbubble oscillations instead of destruction. Furthermore, our results show that there are profound differences in the response of mouse and human tumor vasculature to high MI CDUS, which need to be further explored and considered in clinical translation.

Identification of static nonlinearities by sinusoidal excitation with variable DC offsets.

When identifying nonlinear systems with input-output measurements, a suitable test signal must be selected. Nonlinear systems are almost always in a cascade with linear systems, i.e., a Wiener-Hammerstein type system cascade. A suitable test signal is preferably less influenced by the linear systems and is therefore sinusoidal, if time-varying signals are required for the measurement principle, e.g., for induction or vibration measurements. Then, a sinusoidal excitation with different DC offsets is a suitable signal to analyze a static nonlinear system in a Wiener-Hammerstein type cascade by measuring the cascade output at higher harmonics of the input frequency in a steady state, e.g., by using sensitive lock-in techniques. To calculate the cascade output given the input signal or to reconstruct the static nonlinear system also given the output signal, the transfer function of the DC offset at the nonlinear system input to the higher harmonics at the nonlinear system output is required. Those transfer functions are calculated here with emphasis on the first harmonic component. The reconstruction of a static nonlinear system is demonstrated in a simple simulation scenario by inverse filtering, i.e., deconvolution, with the derived transfer function. It is pointed out that a commonly made small signal assumption to the test signal is bypassed with the deconvolution method, which can lead to more precise measurements in applications due to a higher signal-to-noise ratio at the cascade output.

Ultrasound Imaging.

Ultrasound imaging plays an important role in oncological imaging for more than five decades now. It can be applied in all tissues that are not occluded by bone or gas-filled regions. The quality of ultrasound images benefitted strongly from improved electronics and increased computational power. To the morphological imaging, several functional imaging methods were added: Flow visualization became possible by Doppler techniques and as a recent addition the elastic properties of tissues can be imaged by elastographic methods with transient shear wave imaging. In the beginning of molecular imaging, ultrasound with its contrast based on mechanical tissue properties was an unlikely candidate to play a role. However, with contrast agents consisting of micrometer-sized gas bubbles, which can be imaged with high sensitivity, ligands addressing targets in the vascular wall could be used. Because even single bubbles can be detected, this led to various ultrasound molecular imaging techniques and the ongoing development of clinical molecular contrast media. In this chapter, the basic properties of ultrasonic imaging like its contrast mechanisms and spatiotemporal resolution are discussed. The image formation and its ongoing change from line-oriented scanning to full-volume reconstructions are explained. Then, the ultrasound contrast media and imaging techniques are introduced and emerging new methods like super-resolution vascular imaging demonstrate the ongoing development in this field.

Assessing Vessel Reconstruction in Ultrasound Localization Microscopy by Maximum Likelihood Estimation of a Zero-Inflated Poisson Model.

In clinical applications of super-resolution ultrasound imaging, it is often not possible to achieve a full reconstruction of the microvasculature within a limited measurement time. This makes the comparison of studies and quantitative parameters of vascular morphology and perfusion difficult. Therefore, saturation models were proposed to predict adequate measurement times and estimate the degree of vessel reconstruction. Here, we derive a statistical model for the microbubble counts in super-resolution voxels by a zero-inflated Poisson (ZIP) process. In this model, voxels either belong to vessels with probability Pv and count events with Poisson rate Λ , or they are empty and remain zero. In this model, Pv represents the vessel voxel density in the super-resolution image after infinite measurement time. For the parameters Pv and Λ , we give Cramér-Rao lower bounds (CRLBs) for the estimation variance and derive maximum likelihood estimators (MLEs) in a novel closed-form solution. These can be calculated with knowledge of only the counts at the end of the acquisition time. The estimators are applied to preclinical and clinical data and the MLE outperforms alternative estimators proposed before. The estimated degree of reconstruction lies between 38% and 74% after less than 90 s. Vessel probability Pv ranged from 4% to 20%. The rate parameter Λ was estimated in the range of 0.5-1.3 microbubbles/voxel. For these parameter ranges, the CRLB gives standard deviations of less than 2%, which supports that the parameters can be estimated with good precision already for limited acquisition times.

Super-resolution Ultrasound Imaging.

The majority of exchanges of oxygen and nutrients are performed around vessels smaller than 100 µm, allowing cells to thrive everywhere in the body. Pathologies such as cancer, diabetes and arteriosclerosis can profoundly alter the microvasculature. Unfortunately, medical imaging modalities only provide indirect observation at this scale. Inspired by optical microscopy, ultrasound localization microscopy has bypassed the classic compromise between penetration and resolution in ultrasonic imaging. By localization of individual injected microbubbles and tracking of their displacement with a subwavelength resolution, vascular and velocity maps can be produced at the scale of the micrometer. Super-resolution ultrasound has also been performed through signal fluctuations with the same type of contrast agents, or through switching on and off nano-sized phase-change contrast agents. These techniques are now being applied pre-clinically and clinically for imaging of the microvasculature of the brain, kidney, skin, tumors and lymph nodes.

Modeling and Measurement of the Nonlinear Force on Nanoparticles in Magnetomotive Techniques.

Magnetomotive (MM) ultrasound (US) imaging is the identification of tissue in which magnetic nanoparticle tracers are present by detecting a magnetically induced motion. Although the nanoparticles have a magnetization that depends nonlinearly on the external magnetic field, this has often been neglected, and the presence of resulting higher harmonics in the detected motion has not been reported yet. Here, the magnetization of nanoparticles in gelatin was modeled according to the Langevin theory of superparamagnetism. This nonlinear relationship has a fundamental effect on the resulting force and motion. However, the magnetic field must contain regions with a strong magnetic gradient and a low absolute magnetic field to allow the significant generation of higher harmonics in the force. To validate the model, an MM setup that has a constant magnetic gradient on one axis superimposed by a homogeneous time-varying magnetic field was used. After the magnetic characterization of the nanoparticles and calculations of the expected displacement in the setup, experiments were conducted. A laser Doppler vibrometer was used to quantify the small displacements at higher harmonics. The experimental results followed theoretical predictions. Deviations between model and experiment were attributed to a simplified mechanical modeling and temperature rise during measurements. It is concluded that in MM techniques, the nonlinear magnetization of nanoparticles must generally be considered to reconstruct quantitative parameters, to achieve optimum matching of fields and particles, or to exploit nanoparticle magnetization for tissue characterization. In addition, with the presented experimental setup, the magnetization properties of nanoparticles can be determined by MM techniques alone.

Sonographic visibility of cannulas using convex ultrasound transducers.

The key for safe ultrasound (US)-guided punctures is a good visibility of the cannula. When using convex transducers for deep punctures, the incident angle between US beam and cannula varies along the cannula leading to a complex visibility pattern. Here, we present a method to systematically investigate the visibility throughout the US image. For this, different objective criteria were defined and applied to measurement series with varying puncture angles and depths of the cannula. It is shown that the visibility not only depends on the puncture angle but also on the location of the cannula in the US image when using convex transducers. In some image regions, an unexpected good visibility was observed even for steep puncture angles. The systematic evaluation of the cannula visibility is of fundamental interest to sensitise physicians to the handling of convex transducers and to evaluate new techniques for further improvement.

On the Performance of Time Domain Displacement Estimators for Magnetomotive Ultrasound Imaging.

In magnetomotive (MM) ultrasound (US) imaging, magnetic nanoparticles (NPs) are excited by an external magnetic field and the tracked motion of the surrounding tissue serves as a surrogate parameter for the NP concentration. MMUS procedures exhibit weak displacement contrasts due to small forces on the NPs. Consequently, precise US-based displacement estimation is crucial in terms of a sufficiently high contrast-to-noise ratio (CNR) in MMUS imaging. Conventional MMUS detection of the NPs is based on samplewise evaluation of the phase of the in-phase and quadrature (IQ) data, where a low signal-to-noise ratio (SNR) in the data leads to strong phase noise and, thus, to an increased variance of the displacement estimate. This paper examines the performance of two time-domain displacement estimators (DEs) for MMUS imaging, which differ from conventional MMUS techniques by incorporating data from an axial segment. The normalized cross correlation (NCC) estimator and a recursive Bayesian estimator, incorporating spatial information from neighboring segments, weighted by the local SNR, are adapted for the small MMUS displacement magnitudes. Numerical simulations of MM-induced, time-harmonic bulk and Gaussian-shaped displacement profiles show that the two time-domain estimators yield a reduced estimation error compared to the phase-shift-based estimator. Phantom experiments, using our recently proposed magnetic excitation setup, show a 1.9-fold and 3.4-fold increase of the CNR in the MMUS images for the NCC and Bayes estimator compared to the conventional method, while the amount of required data is reduced by a factor of 100.

Superconducting YBCO Foams as Trapped Field Magnets.

Superconducting foams of YBa2Cu3Oy (YBCO) are proposed as trapped field magnets or supermagnets. The foams with an open-porous structure are light-weight, mechanically strong and can be prepared in large sample sizes. The trapped field distributions were measured using a scanning Hall probe on various sides of an YBCO foam sample after field-cooling in a magnetic field of 0.5 T produced by a square Nd-Fe-B permanent magnet. The maximum trapped field (TF) measured is about 400 G (77 K) at the bottom of the sample. Several details of the TF distribution, the current flow and possible applicatons of such superconducting foam samples in space applications, e.g., as active elements in flux-pinning docking interfaces (FPDI) or as portable strong magnets to collect debris in space, are outlined.

[Perforation as a delayed complication after endoscopic full-thickness resection in a recurrent adenoma of the sigmoid]. / Perforation als Spätkomplikation nach endoskopischer Vollwandresektion eines Rezidivadenoms im Colon sigmoideum.

The endoscopic full-thickness resection (EFTR) is established in ablation of recurrent colorectal adenomas, which cannot be removed by endoscopic resection in cases of fibrosis. The EFTR can be applied with low risk, in one step, with the use of special devices, such as the full-thickness resection device (FTRD®). The main risks described in literature are bleeding and perforations. The mentioned perforations were explained by previous defects of the device system or patient-related predisposed parameters for perforation.We report the case of a 55-year old woman who underwent an endoscopic full-thickness resection with the FTRD® due to a recurrent adenoma with high-grade intraepithelial neoplasm in the sigmoid. After primary uncomplicated development, she presented with a secondary perforation with purulent peritonitis seven days after intervention, so a sigmoid-resection was necessary. There were no signs of defects with the FTRD® system or patient-related predisposed parameters, which prefer a perforation.Our case-report demonstrates the necessity for clinical follow up, after primary uncomplicated endoscopic full-thickness resection, to recognize delayed complications.

Clinical Pilot Application of Super-Resolution US Imaging in Breast Cancer.

Recently, we proved in the first measurements of breast carcinomas the feasibility of super-resolution ultrasound (US) imaging by motion-model ultrasound localization microscopy in a clinical setup. Nevertheless, pronounced in-plane and out-of-plane motions, a nonoptimized microbubble injection scheme, the lower frame rate and the larger slice thickness made the processing more complex than in preclinical investigations. Here, we compare the results of state-of-the-art contrast-enhanced to super-resolution US imaging and systematically analyze the measurements to get indications for the improvement of image acquisition and processing in the future clinical studies. In this regard, the application of a saturation model to the reconstructed vessels is shown to be a valuable tool not only to estimate the measurement times necessary to adequately reconstruct the microvasculature but also for the validation of the measurements. The parameters from this model can also serve to optimize contrast agent concentration and injection protocols. Finally, for the measurements of well-perfused tumors, we observed between 28% and 50% filling for 90-s examination times.

Motion model ultrasound localization microscopy for preclinical and clinical multiparametric tumor characterization.

Super-resolution imaging methods promote tissue characterization beyond the spatial resolution limits of the devices and bridge the gap between histopathological analysis and non-invasive imaging. Here, we introduce motion model ultrasound localization microscopy (mULM) as an easily applicable and robust new tool to morphologically and functionally characterize fine vascular networks in tumors at super-resolution. In tumor-bearing mice and for the first time in patients, we demonstrate that within less than 1 min scan time mULM can be realized using conventional preclinical and clinical ultrasound devices. In this context, next to highly detailed images of tumor microvascularization and the reliable quantification of relative blood volume and perfusion, mULM provides multiple new functional and morphological parameters that discriminate tumors with different vascular phenotypes. Furthermore, our initial patient data indicate that mULM can be applied in a clinical ultrasound setting opening avenues for the multiparametric characterization of tumors and the assessment of therapy response.

Unilateral deep brain stimulation suppresses alpha and beta oscillations in sensorimotor cortices.

Deep brain stimulation (DBS) is an established therapy to treat motor symptoms in movement disorders such as Parkinson's disease (PD). The mechanisms leading to the high therapeutic effectiveness of DBS are poorly understood so far, but modulation of oscillatory activity is likely to play an important role. Thus, investigating the effect of DBS on cortical oscillatory activity can help clarifying the neurophysiological mechanisms of DBS. Here, we aimed at scrutinizing changes of cortical oscillatory activity by DBS at different frequencies using magnetoencephalography (MEG). MEG data from 17 PD patients were acquired during DBS of the subthalamic nucleus (STN) the day after electrode implantation and before implanting the pulse generator. We stimulated the STN unilaterally at two different stimulation frequencies, 130 Hz and 340 Hz using an external stimulator. Data from six patients had to be discarded due to strong artefacts and two other datasets were excluded since these patients were not able to finalize the paradigm. After DBS artefact removal, power spectral density (PSD) values of MEG were calculated for each individual patient and averaged over the group. DBS at both 130 Hz and 340 Hz led to a widespread suppression of cortical alpha/beta band activity (8-22 Hz) specifically over bilateral sensorimotor cortices. No significant differences were observed between the two stimulation frequencies. Our finding of a widespread suppression of cortical alpha/beta band activity is particularly interesting as PD is associated with pathologically increased levels of beta band activity in the basal ganglia-thalamo-cortical circuit. Therefore, suppression of such oscillatory activity might be an essential effect of DBS for relieving motor symptoms in PD and can be achieved at different stimulation frequencies above 100 Hz.

Advanced Ultrasound Technologies for Diagnosis and Therapy.

Ultrasound is among the most rapidly advancing imaging techniques. Functional methods such as elastography have been clinically introduced, and tissue characterization is improved by contrast-enhanced scans. Here, novel superresolution techniques provide unique morphologic and functional insights into tissue vascularization. Functional analyses are complemented by molecular ultrasound imaging, to visualize markers of inflammation and angiogenesis. The full potential of diagnostic ultrasound may become apparent by integrating these multiple imaging features in radiomics approaches. Emerging interest in ultrasound also results from its therapeutic potential. Various applications of tumor ablation with high-intensity focused ultrasound are being clinically evaluated, and its performance strongly benefits from the integration into MRI. Additionally, oscillating microbubbles mediate sonoporation to open biologic barriers, thus improving the delivery of drugs or nucleic acids that are coadministered or coformulated with microbubbles. This article provides an overview of recent developments in diagnostic and therapeutic ultrasound, highlighting multiple innovation tracks and their translational potential.