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.

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.

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.

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.

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.

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.

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.

Head Impact Telemetry System's Video-based Impact Detection and Location Accuracy.

PURPOSE: This study aimed to quantify the Head Impact Telemetry (HIT) System's impact detection and location measurement accuracy using an impact biomechanics data set paired with video of high school football special teams plays. METHODS: The head impact biomechanics data set and video were collected from 22 high school football players, wearing HIT System instrumented helmets, competing in 218 special teams plays over a single high school football season. We used two separate video analysis approaches. To quantify the impact detection accuracy, we evaluated the video for head impacts independently of the impact data collection triggers collected by the HIT System. Video-observed impacts matched to valid and invalid head impacts by the HIT System algorithm were categorized as true positives, false positives, false negatives, and true negatives. To quantify impact location accuracy, we analyzed video-synchronized head impacts for impact location independent of the HIT System's impact location measurement and quantified the estimated percent agreement of impact location between the HIT System recorded impact location and the impact location observed on video. RESULTS: The HIT System's impact-filtering algorithm had 69% sensitivity, 72% specificity, and 70% accuracy in categorizing true and non-head impact data collection triggers. The HIT System agreed with video-observed impact locations on 64% of the 129 impacts we analyzed (unweighted k = 0.43, 95% confidence interval = 0.31-0.54). CONCLUSION: This work provides data on the HIT System's impact detection and location accuracy during high school football special teams plays using game video analysis that has not been previously published. Based on our data, we believe that the HIT System is useful for estimating population-based impact location distributions for special teams plays.

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.

Superharmonic Ultrasound for Motion-Independent Localization Microscopy: Applications to Microvascular Imaging From Low to High Flow Rates.

Recent advances in high frame rate biomedical ultrasound have led to the development of ultrasound localization microscopy (ULM), a method of imaging microbubble (MB) contrast agents beyond the diffraction limit of conventional coherent imaging techniques. By localizing and tracking the positions of thousands of individual MBs, ultrahigh resolution vascular maps are generated which can be further analyzed to study disease. Isolating bubble echoes from tissue signal is a key requirement for super-resolution imaging which relies on the spatiotemporal separability and localization of the bubble signals. To date, this has been accomplished either during acquisition using contrast imaging sequences or post-beamforming by applying a spatiotemporal filter to the B-mode images. Superharmonic imaging (SHI) is another contrast imaging method that separates bubbles from tissue based on their strongly nonlinear acoustic properties. This approach is highly sensitive, and, unlike spatiotemporal filters, it does not require decorrelation of contrast agent signals. Since this superharmonic method does not rely on bubble velocity, it can detect completely stationary and moving bubbles alike. In this work, we apply SHI to ULM and demonstrate an average improvement in SNR of 10.3-dB in vitro when compared with the standard singular value decomposition filter approach and an increase in SNR at low flow ( [Formula: see text]/frame) from 5 to 16.5 dB. Additionally, we apply this method to imaging a rodent kidney in vivo and measure vessels as small as [Formula: see text] in diameter after motion correction.

The Impact of Acoustic Clutter on Large Array Abdominal Imaging.

Abdominal imaging suffers from a particularly difficult acoustic environment-targets are located deep and overlying tissue layers with varying properties generate acoustic clutter. Increasing array size can overcome the penetration and lateral resolution problems in ideal conditions, but how the impact of clutter scales with increasing array extent is unknown and may limit the benefits in vivo. Previous ex vivo experimental work showed the promise of large arrays but was technically limited to a length of 6.4 cm and to only partial sampling of the array elements. We present an extension of those studies using the Fullwave simulation tool to create a 10 cm ×2 cm matrix array with full lateral element sampling. We used a numerical model of the abdomen based on the maps of tissue acoustical properties and found that propagation through the modeled abdominal layers generated on average 25.4 ns of aberration and 0.74 cm of reverberation clutter across the array extent. Growing the full aperture from 2 to 10 cm improved contrast by 8.6 dB and contrast-to-noise ratio by 22.9% in addition to significantly improving target resolution. Alternative array strategies that may be useful for implementation-mismatched aperture sizes or a swept synthetic aperture-also produced improved quality with growing aperture size. These results motivate the development of larger diagnostic imaging arrays for the purpose of high-resolution imaging in challenging environments.

Super-Resolution Imaging Through the Human Skull.

High-resolution transcranial ultrasound imaging in humans has been a persistent challenge for ultrasound due to the imaging degradation effects from aberration and reverberation. These mechanisms depend strongly on skull morphology and have high variability across individuals. Here, we demonstrate the feasibility of human transcranial super-resolution imaging using a geometrical focusing approach to efficiently concentrate energy at the region of interest, and a phase correction focusing approach that takes the skull morphology into account. It is shown that using the proposed focused super-resolution method, we can image a 208- [Formula: see text] microtube behind a human skull phantom in both an out-of-plane and an in-plane configuration. Individual phase correction profiles for the temporal region of the human skull were calculated and subsequently applied to transmit-receive a custom focused super-resolution imaging sequence through a human skull phantom, targeting the 208- [Formula: see text] diameter microtube at 68.5 mm in depth and at 2.5 MHz. Microbubble contrast agents were diluted to a concentration of 1.6×106 bubbles/mL and perfused through the microtube. It is shown that by correcting for the skull aberration, the RF signal amplitude from the tube improved by a factor of 1.6 in the out-of-plane focused emission case. The lateral registration error of the tube's position, which in the uncorrected case was 990 [Formula: see text], was reduced to as low as 50 [Formula: see text] in the corrected case as measured in the B-mode images. Sensitivity in microbubble detection for the phase-corrected case increased by a factor of 1.48 in the out-of-plane imaging case, while, in the in-plane target case, it improved by a factor of 1.31 while achieving an axial registration correction from an initial 1885- [Formula: see text] error for the uncorrected emission, to a 284- [Formula: see text] error for the corrected counterpart. These findings suggest that super-resolution imaging may be used far more generally as a clinical imaging modality in the brain.

Piecewise parabolic method for propagation of shear shock waves in relaxing soft solids: One-dimensional case.

Shear shock waves can be generated spontaneously deep within the brain during a traumatic injury. This recently observed behavior could be a primary mechanism for the generation of traumatic brain injuries. However, shear shock wave physics and its numerical modeling are relatively unstudied. Existing numerical solvers used in biomechanics are not designed for the extremely large Mach numbers (greater than 1) observed in the brain. Furthermore, soft solids, such as the brain, have a complex nonclassical viscoleastic response, which must be accurately modeled to capture the nonlinear wave behavior. Here, we develop a 1D inviscid velocity-stress-like system to model the propagation of shear shock waves in a homogeneous medium. Then a generalized Maxwell body is used to model a relaxing medium that can describe experimentally determined attenuation laws. Finally, the resulting system is solved numerically with the piecewise parabolic method, a high-order finite volume method. The nonlinear and the relaxing components of this method are validated with theoretical predictions. Comparisons between numerical solutions obtained for the proposed model and the experiments of plane shear shock wave propagation based on high frame-rate ultrasound imaging and tracking are shown to be in excellent agreement.

Adaptive Multifocus Beamforming for Contrast-Enhanced-Super-Resolution Ultrasound Imaging in Deep Tissue.

Contrast-enhanced-super-resolution ultrasound imaging, also referred to as ultrasound localization microscopy, can resolve vessels that are smaller than the diffraction limit and has recently been able to generate super-resolved vascular images of shallow in vivo structures in small animals. To fully translate this technology to the clinic, it is advantageous to be able to detect microbubbles at deeper locations in tissue while maintaining a short acquisition time. Current implementations of this imaging method rely on plane-wave imaging. This method has the advantage of maximizing the frame rate, which is important due to the large amount of frames required for super-resolution processing. However, the wide planar beam used to illuminate the field of view produces poor contrast and low sensitivity bubble detection. Here, we propose an "adaptive multifocus" sequence, a new ultrasound imaging sequence that combines the high frame rate feature of a plane wave with the increased bubble detection sensitivity of a focused beam. This sequence simultaneously sonicates two or more foci with a single emission, hence retaining a high frame rate, yet achieving improved sensitivity to microbubbles. In the limit of one target, the beam reduces to a conventional focused transmission; and for an infinite number of targets, it converges to plane-wave imaging. Numerical simulations, using the full-wave code, are performed to compare the point spread function of the proposed sequence to that generated by the plane-wave emission. Our numerical results predict an improvement of up to 15 dB in the signal-to-noise ratio. Ex vivo experiments of a tissue-embedded microtube phantom are used to generate super-resolved images and to compare the adaptive beamforming approach to plane-wave imaging. These experimental results show that the adaptive multifocus sequence successfully detects 744 microbubble events at 60 mm when they are undetectable by the plane-wave sequence under the same imaging conditions. At a shallower depth of 44 mm, the proposed adaptive multifocus method detects 6.9 times more bubbles than plane-wave imaging (1763 versus 257 bubble events).

Blocked Elements in 1-D and 2-D Arrays-Part I: Detection and Basic Compensation on Simulated and In Vivo Targets.

During a transcostal ultrasound scan, ribs and other highly attenuating and/or reflective tissue structures can block parts of the array. Blocked elements tend to limit the acoustic window and impede visualization of structures of interest. Here, we demonstrate a method to detect blocked elements and we measure the loss of image quality they introduce in simulation and in vivo. We utilize a fullwave simulation tool and a clinical ultrasound scanner to obtain element signals from fully sampled matrix arrays during simulated and in vivo transcostal liver scans, respectively. The elements that were blocked by a rib showed lower average signal amplitude and lower average nearest-neighbor cross correlation than the elements in the remainder of the 2-D aperture. The growing receive-aperture B-mode images created from the element data indicate that the signals on blocked elements are dominated by noise and that turning them OFF has a potential to improve visibility of liver vasculature. Adding blocked elements to the growing receive apertures for five in vivo transcostal acquisitions resulted in average decrease in vessel contrast and contrast to noise ratio of 19% and 10%, respectively.