Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.

Shear shock wave injury in vivo: High frame-rate ultrasound observation and histological assessment.

Using high frame-rate ultrasound and ¡1µm sensitive motion tracking we previously showed that shear waves at the surface of ex vivo and in situ brains develop into shear shock waves deep inside the brain, with destructive local accelerations. However post-mortem tissue cannot develop injuries and has different viscoelastodynamic behavior from in vivo tissue. Here we present the ultrasonic measurement of the high-rate shear shock biomechanics in the in vivo porcine brain, and histological assessment of the resulting axonal pathology. A new biomechanical model of brain injury was developed consisting of a perforated mylar surface attached to the brain and vibrated using an electromechanical shaker. Using a custom sequence with 8 interleaved wide beam emissions, brain imaging and motion tracking were performed at 2900 images/s. Shear shock waves were observed for the first time in vivo wherein the shock acceleration was measured to be 2.6 times larger than the surface acceleration ( 95g vs. 36g). Histopathology showed axonal damage in the impacted side of the brain from the brain surface, accompanied by a local shock-front acceleration of >70g. This shows that axonal injury occurs deep in the brain even though the shear excitation was at the brain surface, and the acceleration measurements support the hypothesis that shear shock waves are responsible for deep traumatic brain injuries.

Element Position Calibration for Matrix Array Transducers with Multiple Disjoint Piezoelectric Panels.

Two-dimensional ultrasound transducers enable the acquisition of fully volumetric data that have been demonstrated to provide greater diagnostic information in the clinical setting and are a critical tool for emerging ultrasound methods, such as super-resolution and functional imaging. This technology, however, is not without its limitations. Due to increased fabrication complexity, some matrix probes with disjoint piezoelectric panels may require initial calibration. In this manuscript, two methods for calibrating the element positions of the Vermon 1024-channel 8 MHz matrix transducer are detailed. This calibration is a necessary step for acquiring high resolution B-mode images while minimizing transducer-based image degradation. This calibration is also necessary for eliminating vessel-doubling artifacts in super-resolution images and increasing the overall signal-to-noise ratio (SNR) of the image. Here, we show that the shape of the point spread function (PSF) can be significantly improved and PSF-doubling artifacts can be reduced by up to 10 dB via this simple calibration procedure.

Activation of primate frontal eye fields with a CMUT phased array system.

BACKGROUND: There are pushes toward non-invasive stimulation of neural tissues to prevent issues that arise from invasive brain recordings and stimulation. Transcranial Focused Ultrasound (TFUS) has been examined as a way to stimulate non-invasively, but previous studies have limitations in the application of TFUS. As a result, refinement is needed to improve stimulation results. NEW METHOD: We utilized a custom-built capacitive micromachined ultrasonic transducer (CMUT) that would send ultrasonic waves through skin and skull to targets located in the Frontal Eye Fields (FEF) region triangulated from co-registered MRI and CT scans while a non-human primate subject was performing a discrimination behavioral task. RESULTS: We observed that the stimulation immediately caused changes in the local field potential (LFP) signal that continued until stimulation ended, at which point there was higher voltage upon the cue for the animal to saccade. This co-incided with increases in activity in the alpha band during stimulation. The activity rebounded mid-way through our electrode-shank, indicating a specific point of stimulation along the shank. We observed different LFP signals for different stimulation targets, indicating the ability to"steer" the stimulation through the transducer. We also observed a bias in first saccades towards the opposite direction. CONCLUSIONS: In conclusion, we provide a new approach for non-invasive stimulation during performance of a behavioral task. With the ability to steer stimulation patterns and target using a large amount of transducers, the ability to provide non-invasive stimulation will be greatly improved for future clinical and research applications.

Ultrasound imaging of lung disease and its relationship to histopathology: An experimentally validated simulation approach.

Lung ultrasound (LUS) is a widely used technique in clinical lung assessment, yet the relationship between LUS images and the underlying disease remains poorly understood due in part to the complexity of the wave propagation physics in complex tissue/air structures. Establishing a clear link between visual patterns in ultrasound images and underlying lung anatomy could improve the diagnostic accuracy and clinical deployment of LUS. Reverberation that occurs at the lung interface is complex, resulting in images that require interpretation of the artifacts deep in the lungs. These images are not accurate spatial representations of the anatomy due to the almost total reflectivity and high impedance mismatch between aerated lung and chest wall. Here, we develop an approach based on the first principles of wave propagation physics in highly realistic maps of the human chest wall and lung to unveil a relationship between lung disease, tissue structure, and its resulting effects on ultrasound images. It is shown that Fullwave numerical simulations of ultrasound propagation and histology-derived acoustical maps model the multiple scattering physics at the lung interface and reproduce LUS B-mode images that are comparable to clinical images. However, unlike clinical imaging, the underlying tissue structure model is known and controllable. The amount of fluid and connective tissue components in the lung were gradually modified to model disease progression, and the resulting changes in B-mode images and non-imaging reverberation measures were analyzed to explain the relationship between pathological modifications of lung tissue and observed LUS.

Longitudinal 3-D Visualization of Microvascular Disruption and Perfusion Changes in Mice During the Evolution of Glioblastoma Using Super-Resolution Ultrasound.

Glioblastoma is an aggressive brain cancer with a very poor prognosis in which less than 6% of patients survive more than five-year post-diagnosis. The outcome of this disease for many patients may be improved by early detection. This could provide clinicians with the information needed to take early action for treatment. In this work, we present the utilization of a non-invasive, fully volumetric ultrasonic imaging method to assess microvascular change during the evolution of glioblastoma in mice. Volumetric ultrasound localization microscopy (ULM) was used to observe statistically significant ( ) reduction in the appearance of functional vasculature over the course of three weeks. We also demonstrate evidence suggesting the reduction of vascular flow for vessels peripheral to the tumor. With an 82.5% consistency rate in acquiring high-quality vascular images, we demonstrate the possibility of volumetric ULM as a longitudinal method for microvascular characterization of neurological disease.

Non-invasive transcranial volumetric ultrasound localization microscopy of the rat brain with continuous, high volume-rate acquisition.

Rationale: Structure and function of the microvasculature provides critical information about disease state, can be used to identify local regions of pathology, and has been shown to be an indicator of response to therapy. Improved methods of assessing the microvasculature with non-invasive imaging modalities such as ultrasound will have an impact in biomedical theranostics. Ultrasound localization microscopy (ULM) is a new technology which allows processing of ultrasound data for visualization of microvasculature at a resolution better than allowed by acoustic diffraction with traditional ultrasound systems. Previous application of this modality in brain imaging has required the use of invasive procedures, such as a craniotomy, skull-thinning, or scalp removal, all of which are not feasible for the purpose of longitudinal studies. Methods: The impact of ultrasound localization microscopy is expanded using a 1024 channel matrix array ultrasonic transducer, four synchronized programmable ultrasound systems with customized high-performance hardware and software, and high-performance GPUs for processing. The potential of the imaging hardware and processing approaches are demonstrated in-vivo. Results: Our unique implementation allows asynchronous acquisition and data transfer for uninterrupted data collection at an ultra-high fixed frame rate. Using these methods, the vasculature was imaged using 100,000 volumes continuously at a volume acquisition rate of 500 volumes per second. With ULM, we achieved a resolution of 31 µm, which is a resolution improvement on conventional ultrasound imaging by nearly a factor of ten, in 3-D. This was accomplished while imaging through the intact skull with no scalp removal, which demonstrates the utility of this method for longitudinal studies. Conclusions: The results demonstrate new capabilities to rapidly image and analyze complex vascular networks in 3-D volume space for structural and functional imaging in disease assessment, targeted therapeutic delivery, monitoring response to therapy, and other theranostic applications.

Benchmark problems for transcranial ultrasound simulation: Intercomparison of compressional wave models.

Computational models of acoustic wave propagation are frequently used in transcranial ultrasound therapy, for example, to calculate the intracranial pressure field or to calculate phase delays to correct for skull distortions. To allow intercomparison between the different modeling tools and techniques used by the community, an international working group was convened to formulate a set of numerical benchmarks. Here, these benchmarks are presented, along with intercomparison results. Nine different benchmarks of increasing geometric complexity are defined. These include a single-layer planar bone immersed in water, a multi-layer bone, and a whole skull. Two transducer configurations are considered (a focused bowl and a plane piston operating at 500 kHz), giving a total of 18 permutations of the benchmarks. Eleven different modeling tools are used to compute the benchmark results. The models span a wide range of numerical techniques, including the finite-difference time-domain method, angular spectrum method, pseudospectral method, boundary-element method, and spectral-element method. Good agreement is found between the models, particularly for the position, size, and magnitude of the acoustic focus within the skull. When comparing results for each model with every other model in a cross-comparison, the median values for each benchmark for the difference in focal pressure and position are less than 10% and 1 mm, respectively. The benchmark definitions, model results, and intercomparison codes are freely available to facilitate further comparisons.

Brain topography on adult ultrasound images: Techniques, interpretation, and image library.

BACKGROUND AND PURPOSE: Many studies have explored the possibility of using cranial ultrasound for discerning intracranial pathologies like tumors, hemorrhagic stroke, or subdural hemorrhage in clinical scenarios where computer tomography may not be accessible or feasible. The visualization of intracranial anatomy on B-mode ultrasound is challenging due to the presence of the skull that limits insonation to a few segments on the temporal bone that are thin enough to allow transcranial transmission of sound. Several artifacts are produced by hyperechoic signals inherent in brain and skull anatomy when images are created using temporal windows. METHODS: While the literature has investigated the accuracy of diagnosis of intracranial pathology with ultrasound, we lack a reference source for images acquired on cranial topography on B-mode ultrasound to illustrate the appearance of normal and abnormal structures of the brain and skull. Two investigators underwent hands-on training in Cranial point-of-care ultrasound (c-POCUS) and acquired multiple images from each patient to obtain the most in-depth images of brain to investigate all visible anatomical structures and pathology within 24 hours of any CT/MRI imaging done. RESULTS: Most reproducible structures visible on c-POCUS included bony parts and parenchymal structures. Transcranial and abdominal presets were equivalent in elucidating anatomical structures. Brain pathology like parenchymal hemorrhage, cerebral edema, and hydrocephalus were also visualized. CONCLUSIONS: We present an illustrated anatomical atlas of cranial ultrasound B-mode images acquired in various pathologies in a critical care environment and compare our findings with published literature by performing a scoping review of literature on the subject.

In situ ultrasound imaging of shear shock waves in the porcine brain.

Direct measurement of brain motion at high spatio-temporal resolutions during impacts has been a persistent challenge in brain biomechanics. Using high frame-rate ultrasound and high sensitivity motion tracking, we recently showed shear waves sent to the ex vivo porcine brain developing into shear shock waves with destructive local accelerations inside the brain, which may be a key mechanism behind deep traumatic brain injuries. Here we present the ultrasound observation of shear shock waves in the acoustically challenging environment of the in situ porcine brain during a single-shot impact with sinusoidal and haversine time profiles. The brain was impacted to generate surface amplitudes of 25-33g, and to propagate a 40-50 Hz shear waves into the brain. Simultaneously, images of the moving brain were acquired at 2193 images/s, using a custom sequence with 8 interleaved ultrasound propagation events. For a long field-of-view, wide-beam emissions were designed using time-reversal ultrasound simulations and no compounding was used to avoid motion blurring. For a 40 Hz, 25g sinusoidal impact, a shock-front acceleration of 102g was measured 7.1 mm deep inside the brain. Using a haversine pulse that models a realistic impact more closely, a shock acceleration of 113g was observed 3.0 mm inside the brain, from a 50 Hz, 33g excitation. The experimental velocity, acceleration, and strain-rate waveforms in brain for the monochromatic impact are shown to be in excellent agreement with theoretical predictions from a custom higher-order finite volume method hence demonstrating the capabilities to measure rapid brain motion despite strong acoustical reverberations from the porcine skull.

Effect of perfluorocarbon composition on activation of phase-changing ultrasound contrast agents.

BACKGROUND: While microbubble contrast agents (MCAs) are commonly used in ultrasound (US), they are inherently limited to vascular targets due to their size. Alternatively, phase-changing nanodroplet contrast agents (PNCAs) can be delivered as nanoscale agents (i.e., small enough to extravasate), but when exposed to a US field of sufficient mechanical index (MI), they convert to MCAs, which can be visualized with high contrast using nonlinear US. PURPOSE: To investigate the effect of perfluorocarbon (PFC) core composition and presence of cholesterol in particle coatings on stability and image contrast generated from acoustic activation of PNCAs using high-frequency US suitable for clinical imaging. METHODS: PNCAs with varied core compositions (i.e., mixtures of perfluoropentane [C5] and/or perfluorohexane [C6]) and two coating formulations (i.e., with and without cholesterol) were characterized and investigated for thermal/temporal stability and postactivation, nonlinear US contrast in phantom and in vivo environments. Through hydrophone measurements and nonlinear numerical modeling, MI was estimated for pulse sequences used for PNCA activation. RESULTS: All PNCA compositions were characterized to have similar diameters (249-267 nm) and polydispersity (0.151-0.185) following fabrication. While PNCAs with majority C5 core composition showed higher levels of spontaneous signal (i.e., not due to US activation) in phantoms than C6-majority PNCAs, all compositions were stable during imaging experiments. When activating PNCAs with a 12.3-MHz US pulse (MI = 1.1), C6-core particles with cholesterol-free coatings (i.e., CF-C6-100 particles) generated a median contrast of 3.1, which was significantly higher (p < 0.001) than other formulations. Further, CF-C6-100 particles were activated in a murine model, generating US contrast ≥ $ \ge $ 3.4. CONCLUSION: C6-core PNCAs can provide high-contrast US imaging with minimal nonspecific activation in phantom and in vivo environments.

Transcranial Neuromodulation Array With Imaging Aperture for Simultaneous Multifocus Stimulation in Nonhuman Primates.

Even simple behaviors arise from the simultaneous activation of multiple regions in the brain. Thus, the ability to simultaneously stimulate multiple regions within a brain circuit should allow for better modulation of function. However, performing simultaneous multifocus ultrasound neuromodulation introduces challenges to transducer design. Using 3-D Fullwave simulations, we have designed an ultrasound neuromodulation array for nonhuman primates that: 1) can simultaneously focus on multiple targets and 2) include an imaging aperture for additional functional imaging. This design is based on a spherical array, with 128 15-mm elements distributed in a spherical helix pattern. It is shown that clustering the elements tightly around the 65-mm imaging aperture located at the top of the array improves targeting at shallow depths, near the skull surface. Spherical arrays have good focusing capabilities through the skull at the center of the array, but focusing on off-center locations is more challenging due to the natural geometric configuration and the angle of incidence with the skull. In order to mitigate this, the 64 elements closest to the aperture were rotated toward and focusing on a shallow target, and the 64 elements farthest from the aperture were rotated toward and focusing on a deeper target. Data illustrated that this array produced focusing on the somatosensory cortex with a gain of 4.38 and to the thalamus with a gain of 3.82. To improve upon this, the array placement was optimized based on phase aberration simulations, allowing for the elements with the largest impact on the gain at each focal point to be found. This optimization resulted in an array design that can focus on the somatosensory cortex with a gain of 5.19 and the thalamus with a gain of 4.45. Simulations were also performed to evaluate the ability of the array to focus on 28 additional brain regions, showing that off-center target regions can be stimulated, but those closer to the skull will require corrective steps to deliver the same amount of energy to those locations. This simulation and design process can be adapted to an individual monkey or human skull morphologies and specific target locations within individuals by using orientable 3-D printing of the transducer case and by electronic phase aberration correction.

Characterization of the Ultrasound Localization Microscopy Resolution Limit in the Presence of Image Degradation.

Ultrasound localization microscopy (ULM) has been able to overcome the diffraction limit of ultrasound imaging. The resolution limit of ULM has been previously modeled using the Cramér-Rao lower bound (CRLB). While this model has been validated in a homogeneous medium, it estimates a resolution limit, which has not yet been achieved in vivo. In this work, we investigated the effects of three sources of image degradation on the resolution limit of ULM. The Fullwave simulation tool was used to simulate acquisitions of transabdominal contrast-enhanced data at depth. The effects of reverberation clutter, trailing clutter, and phase aberration were studied. The resolution limit, in the presence of reverberation clutter alone, was empirically measured to be up to 39 times worse in the axial dimension and up to 2.1 times worse in the lateral dimension than the limit predicted by the CRLB. While reverberation clutter had an isotropic impact on the resolution, trailing clutter had a constant impact on both dimensions across all signal-to-trailing-clutter ratios (STCR). Phase aberration had a significant impact on the resolution limit over the studied analysis ranges. Phase aberration alone degraded the resolution limit up to 70 and 160 [Formula: see text] in the lateral and axial dimensions, respectively. These results illustrate the importance of phase aberration correction and clutter filtering in ULM postprocessing. The analysis results were demonstrated through the simulation of the ULM process applied to a cross-tube model that was degraded by each of the three aforementioned sources of degradation.

A Rapid Prototyping Method for Sub-MHz Single-Element Piezoelectric Transducers by Using 3D-Printed Components.

We present a rapid prototyping method for sub-megahertz single-element piezoelectric transducers by using 3D-printed components. In most of the early research phases of applying new sonication ideas, the prototyping quickness is prioritized over the final packaging quality, since the quickness of preliminary demonstration is crucial for promptly determining specific aims and feasible research approaches. We aim to develop a rapid prototyping method for functional ultrasonic transducers to overcome the current long lead time (>a few weeks). Here, we used 3D-printed external housing parts considering a single matching layer and either air backing or epoxy-composite backing (acoustic impedance > 5 MRayl). By molding a single matching layer on the top surface of a piezoceramic in a 3D-printed housing, an entire packaging time was significantly reduced (<26 h) compared to the conventional methods with grinding, stacking, and bonding. We demonstrated this prototyping method for 590-kHz single-element, rectangular-aperture transducers for moderate pressure amplitudes (mechanical index > 1) at focus with temporal pulse controllability (maximum amplitude by <5-cycle burst). We adopted an air-backing design (Type A) for efficient pressure outputs, and bandwidth improvement was tested by a tungsten-composite-backing (Type B) design. The acoustic characterization results showed that the type A prototype provided 3.3 kPa/Vpp far-field transmitting sensitivity with 25.3% fractional bandwidth whereas the type B transducer showed 2.1 kPa/Vpp transmitting sensitivity with 43.3% fractional bandwidth. As this method provided discernable quickness and cost efficiency, this detailed rapid prototyping guideline can be useful for early-phase sonication projects, such as multi-element therapeutic ultrasound array and micro/nanomedicine testing benchtop device prototyping.

Acoustic Molecular Imaging Beyond the Diffraction Limit In Vivo.

Ultrasound molecular imaging (USMI) is a technique used to noninvasively estimate the distribution of molecular markers in vivo by imaging microbubble contrast agents (MCAs) that have been modified to target receptors of interest on the vascular endothelium. USMI is especially relevant for preclinical and clinical cancer research and has been used to predict tumor malignancy and response to treatment. In the last decade, methods that improve the resolution of contrast-enhanced ultrasound by an order of magnitude and allow researchers to noninvasively image individual capillaries have emerged. However, these approaches do not translate directly to molecular imaging. In this work, we demonstrate super-resolution visualization of biomarker expression in vivo using superharmonic ultrasound imaging (SpHI) with dual-frequency transducers, targeted contrast agents, and localization microscopy processing. We validate and optimize the proposed method in vitro using concurrent optical and ultrasound microscopy and a microvessel phantom. With the same technique, we perform a proof-of-concept experiment in vivo in a rat fibrosarcoma model and create maps of biomarker expression co-registered with images of microvasculature. From these images, we measure a resolution of 23 µm, a nearly fivefold improvement in resolution compared to previous diffraction-limited molecular imaging studies.

Diagnostic ultrasound imaging of the lung: A simulation approach based on propagation and reverberation in the human body.

Although ultrasound cannot penetrate a tissue/air interface, it images the lung with high diagnostic accuracy. Lung ultrasound imaging relies on the interpretation of "artifacts," which arise from the complex reverberation physics occurring at the lung surface but appear deep inside the lung. This physics is more complex and less understood than conventional B-mode imaging in which the signal directly reflected by the target is used to generate an image. Here, to establish a more direct relationship between the underlying acoustics and lung imaging, simulations are used. The simulations model ultrasound propagation and reverberation in the human abdomen and at the tissue/air interfaces of the lung in a way that allows for direct measurements of acoustic pressure inside the human body and various anatomical structures, something that is not feasible clinically or experimentally. It is shown that the B-mode images beamformed from these acoustical simulations reproduce primary clinical features that are used in diagnostic lung imaging, i.e., A-lines and B-lines, with a clear relationship to known underlying anatomical structures. Both the oblique and parasagittal views are successfully modeled with the latter producing the characteristic "bat sign," arising from the ribs and intercostal part of the pleura. These simulations also establish a quantitative link between the percentage of fluid in exudative regions and the appearance of B-lines, suggesting that the B-mode may be used as a quantitative imaging modality.

On the Relationship between Spatial Coherence and In Situ Pressure for Abdominal Imaging.

Tissue harmonic signal quality has been shown to improve with elevated acoustic pressure. The peak rarefaction pressure (PRP) for a given transmit, however, is limited by the Food and Drug Administration guidelines for mechanical index. We have previously demonstrated that the mechanical index overestimates in situ PRP for tightly focused beams in vivo, due primarily to phase aberration. In this study, we evaluate two spatial coherence-based image quality metrics-short-lag spatial coherence and harmonic short-lag spatial coherence-as proxy estimates for phase aberration and assess their correlation with in situ PRP in simulations and experiments when imaging through abdominal body walls. We demonstrate strong correlation between both spatial coherence-based metrics and in situ PRP (R2 = 0.77 for harmonic short-lag spatial coherence, R2 = 0.67 for short-lag spatial coherence), an observation that could be leveraged in the future for patient-specific selection of acoustic output.

Quantifying the Effect of Abdominal Body Wall on In Situ Peak Rarefaction Pressure During Diagnostic Ultrasound Imaging.

In this study, 3-D non-linear ultrasound simulations and experimental measurements were used to estimate the range of in situ pressures that can occur during transcutaneous abdominal imaging and to identify the sources of error when estimating in situ peak rarefaction pressures (PRPs) using linear derating, as specified by the mechanical index (MI) guideline. Using simulations, it was found that, for a large transmit aperture (F/1.5), MI consistently over-estimated in situ PRP by 20%-48% primarily owing to phase aberration. For a medium transmit aperture (F/3), the MI accurately estimated the in situ PRP to within 8%. For a small transmit aperture (F/5), MI consistently underestimated the in situ PRP by 32%-50%, with peak locations occurring 1-2 cm before the focal depth, often within the body wall itself. The large variability across body wall samples and focal configurations demonstrates the limitations of the simplified linear derating scheme. The results suggest that patient-specific in situ PRP estimation would allow for increases in transmit pressures, particularly for tightly focused beams, to improve diagnostic image quality while ensuring patient safety.

Modeling Ultrasound Propagation in the Moving Brain: Applications to Shear Shock Waves and Traumatic Brain Injury.

Traumatic brain injury (TBI) studies on the living human brain are experimentally infeasible due to ethical reasons and the elastic properties of the brain degrade rapidly postmortem. We present a simulation approach that models ultrasound propagation in the human brain, while it is moving due to the complex shear shock wave deformation from a traumatic impact. Finite difference simulations can model ultrasound propagation in complex media such as human tissue. Recently, we have shown that the fullwave finite difference approach can also be used to represent displacements that are much smaller than the grid size, such as the motion encountered in shear wave propagation from ultrasound elastography. However, this subresolution displacement model, called impedance flow, was only implemented and validated for acoustical media composed of randomly distributed scatterers. Herein, we propose a generalization of the impedance flow method that describes the continuous subresolution motion of structured acoustical maps, and in particular of acoustical maps of the human brain. It is shown that the average error in simulating subresolution displacements using impedance flow is small when compared to the acoustical wavelength ( λ /1702). The method is then applied to acoustical maps of the human brain with a motion that is imposed by the propagation of a shear shock wave. This motion is determined numerically with a custom piecewise parabolic method that is calibrated to ex vivo observations of shear shocks in the porcine brain. Then the fullwave simulation tool is used to model transmit-receive imaging sequences based on an L7-4 imaging transducer. The simulated radio frequency data are beamformed using a conventional delay-and-sum method and a normalized cross-correlation method designed for shock wave tracking is used to determine the tissue motion. This overall process is an in silico reproduction of the experiments that were previously performed to observe shear shock waves in fresh porcine brain. It is shown that the proposed generalized impedance flow method accurately captures the shear wave motion in terms of the wave profile, shock front characteristics, odd harmonic spectrum generation, and acceleration at the shear shock front. We expect that this approach will lead to improvements in image sequence design that takes into account the aberration and multiple reflections from the brain and in the design of tracking algorithms that can more accurately capture the complex brain motion that occurs during a traumatic impact. These methods of modeling ultrasound propagation in moving media can also be applied to other displacements, such as those generated by shear wave elastography or blood flow.

Rapid quantitative imaging of high intensity ultrasonic pressure fields.

High intensity focused ultrasound (FUS) is a noninvasive technique for treatment of tissues that can lie deep within the body. There is a need for methods to rapidly and quantitatively map FUS pressure beams for quality assurance and accelerate development of FUS systems and techniques. However, conventional ultrasound pressure beam mapping instruments, including hydrophones and optical techniques, are slow, not portable, and expensive, and most cannot map beams at actual therapeutic pressure levels. Here, a rapid projection imaging method to quantitatively map FUS pressure beams based on continuous-wave background-oriented schlieren (CW-BOS) imaging is reported. The method requires only a water tank, a background pattern, and a camera and uses a multi-layer deep neural network to reconstruct two-dimensional root-mean-square (RMS) projected pressure maps that resolve the ultrasound propagation dimension and one lateral dimension. In this work, the method was applied to collect beam maps over a 3 × 1 cm2 field-of-view with 0.425 mm resolution for focal pressures up to 9 MPa. Results at two frequencies and comparisons to hydrophone measurements show that CW-BOS imaging produces high-resolution quantitative RMS projected FUS pressure maps in under 10 s, the technique is linear and robust to beam rotations and translations, and it can map aberrated beams.