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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Numerical prediction of frequency dependent 3D maps of mechanical index thresholds in ultrasonic brain therapy.

PURPOSE: Therapeutic ultrasound has been used in the brain for thrombolysis and high intensity focused ultrasound (HIFU) therapy. A low-frequency clinical study of sonothrombolysis, called the transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia (TRUMBI), has revealed an increased incidence of hemorrhage, which may have been caused by cavitation. The goal of this study is to determine if there is a comparable risk of generating cavitation during HIFU brain therapy at different frequencies. METHODS: Two approaches are used to transmit acoustic energy through the skull to the brain: low-frequency ultrasound, with a wavelength that is larger than the skull thickness, and high frequency ultrasound, that is sensitive to aberrations and must use corrective techniques. At high frequency, the mechanical index (MI) is lower, which translates to a higher cavitation threshold. In addition to the nonfocused geometry of the 300 kHz sonothrombolysis treatment device, two types of focused therapeutic transducers were modeled: a low frequency 220 kHz transducer and a 1 MHz transducer that required aberration correction with a time-reversal approach, representing the lowest and highest frequencies currently used. The acoustic field was modeled with a finite difference fullwave acoustic code developed for large scale computations, that is, capable of simulating the entire brain volume. Various MI thresholds and device geometries were considered to determine the regions of the brain that have an increased probability of cavitation events. RESULTS: For an equivalent energy deposition rate, it is shown that at a low frequency there is a significant volume of the brain that is above the MI thresholds. At a high frequency, the volume is over 3 orders of magnitude smaller, and it is entirely confined to a compact focal spot. CONCLUSIONS: The significant frequency dependence of the volumes with an increased probability of cavitation can be attributed to two factors: First, the volume encompassed by the focal region depends on the cube of the frequency. Second, the heat deposition increases with frequency. In conclusion, according to these simulations, the acoustic environment during HIFU brain therapy at 1 MHz is not conducive to a high probability of cavitation in extended regions of the brain.

Attenuation, scattering, and absorption of ultrasound in the skull bone.

PURPOSE: Measured values of ultrasound attenuation in bone represent a combination of different loss mechanisms. As a wave is transmitted from a fluid into bone, reflections occur at the interface. In the bone, mode conversion occurs between longitudinal and shear modes and the mechanical wave is scattered by its complex internal microstructure. Finally, part of the wave energy is absorbed by the bone and converted into heat. Due to the complexity of the wave propagation and the difficulty in performing measurements that are capable of separating the various loss mechanisms, there are currently no estimates of the absorption in bone. The aim of this paper is, thus, to quantify the attenuation, scattering, and thermal absorption in bone. METHODS: An attenuating model of wave propagation in bone is established and used to develop a three-dimensional finite difference time domain numerical algorithm. Hydrophone and optical heterodyne interferometer measurements of the acoustic field as well as a x-ray microtomography of the bone sample are used to drive the simulations and to measure the attenuation. The acoustic measurements are performed concurrently with an infrared camera that can measure the temperature elevation during insonication. A link between the temperature and the absorption via a three-dimensional thermal simulation is then used to quantify the absorption coefficients for longitudinal and shear waves in cortical bone. RESULTS: We demonstrate that only a small part of the attenuation is due to absorption in bone and that the majority of the attenuation is due to reflection, scattering, and mode conversion. In the nine samples of a human used for the study, the absorption time constant for cortical bone was determined to be 1.04 µs ± 28%. This corresponds to a longitudinal absorption of 2.7 dB/cm and a shear absorption of 5.4 dB/cm. The experimentally measured attenuation across the approximately 8 mm thick samples was 13.3 ± 0.97 dB/cm. CONCLUSIONS: This first measurement of ultrasound absorption in bone can be used to estimate the amount of heat deposition based on knowledge of the acoustic field.

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.

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.

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.

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.

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.

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.

Effects of nonlinear ultrasound propagation on high intensity brain therapy.

PURPOSE: As an ultrasound wave propagates nonlinearly, energy is transferred to higher frequencies where it is more strongly attenuated. Compared to soft tissue, the skull has strongly heterogeneous material parameters. The authors characterize with experiments and establish a numerical method that can describe the effects of the skull on the nonlinear components of ultrasonic wave propagation for application to high intensity focused ultrasound (HIFU) therapy in the brain. The impact of nonlinear acoustic propagation on heat deposition and thermal dose delivery is quantified and compared to linear assumptions by coupling an acoustic simulation with a heating model for brain tissue. METHODS: A degassed dessicated human skull was placed in a water tank and insonified at 1 MPa with 7 mm transducer from a custom array designed for HIFU treatment. Two dimensional scans were performed preceding and following propagation through the skull with a calibrated hydrophone. Data from the scan preceding the skull were used as an input to a three dimensional finite difference time domain (FDTD) simulation that calculates the effects of diffraction, density, attenuation with linear dependence on frequency via relaxation mechanisms, and second order nonlinearity. A measured representation of the skull was used to determine the skull's acoustic properties. The validated acoustic model was used to determine the loss due to nonlinear propagation and then coupled to a finite difference simulation of the bioheat equation for two focal configurations at 3 and 7.5 cm from the skull surface. RESULTS: Prior to propagation through the skull, the second harmonic component was 19 dB lower than the fundamental, and the third harmonic component was 37 dB lower. Following the skull, the second harmonic component was 35 dB lower and the third harmonic was 55 dB lower. The simulation is in agreement with the measurements to within 0.5 dB across the considered frequency range and shows good agreement across the two dimensional scan. It is then shown that the volume of treated brain is at least twice as large when assuming nonlinear acoustics. CONCLUSIONS: The authors have established a three dimensional FDTD simulation that accurately models the effects of nonlinearity and attenuation for propagation through the skull. Experimental validation shows good agreement across a broad frequency range and spatial extent. The nonlinear thermal dose was over an order of magnitude larger at the focus than the linear thermal dose and the necrotic volume was larger by at least a factor df 2. These results have particular applications to treatment planning.