@article{riley_roeder_zinke_weisend_eidum_pinton_biliroglu_yamaner_oralkan_connolly_2024, title={Activation of primate frontal eye fields with a CMUT phased array system}, volume={402}, ISSN={["1872-678X"]}, DOI={10.1016/j.jneumeth.2023.110009}, abstractNote={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.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.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.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.}, journal={JOURNAL OF NEUROSCIENCE METHODS}, author={Riley, Mitchell R. and Roeder, Brent M. and Zinke, Wolf and Weisend, Michael P. and Eidum, Derek M. and Pinton, Gianmarco F. and Biliroglu, Ali O. and Yamaner, Feisal Y. and Oralkan, Omer and Connolly, Patrick M.}, year={2024}, month={Feb} }
 @article{mccall_chavignon_couture_dayton_pinton_2024, title={Element Position Calibration for Matrix Array Transducers with Multiple Disjoint Piezoelectric Panels}, ISSN={["1096-0910"]}, DOI={10.1177/01617346241227900}, abstractNote={ 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. }, journal={ULTRASONIC IMAGING}, author={McCall, Jacob R. and Chavignon, Arthur and Couture, Olivier and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2024}, month={Feb} }
 @article{mccall_jones_santibanez_latham_zou_dayton_pinton_2024, title={The development of a 1.25 MHz 1024-channel sparse array for human transcranial imaging: <i>in vitro</i> characterization}, volume={35}, ISSN={["1361-6501"]}, DOI={10.1088/1361-6501/ad117f}, abstractNote={Abstract}, number={3}, journal={MEASUREMENT SCIENCE AND TECHNOLOGY}, author={McCall, J. R. and Jones, R. M. and Santibanez, F. and Latham, K. and Zou, J. and Dayton, P. A. and Pinton, G. F.}, year={2024}, month={Mar} }
 @article{mccall_santibanez_belgharbi_pinton_dayton_2023, title={Non-invasive transcranial volumetric ultrasound localization microscopy of the rat brain with continuous, high volume-rate acquisition}, volume={13}, ISSN={["1838-7640"]}, DOI={10.7150/thno.79189}, abstractNote={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.}, number={3}, journal={THERANOSTICS}, author={McCall, Jacob R. and Santibanez, Francisco and Belgharbi, Hatim and Pinton, Gianmarco F. and Dayton, Paul A.}, year={2023}, pages={1235–1246} }
 @article{kapoor_offnick_allen_brown_sachs_gurcan_pinton_d'agostino_bushnell_wolfe_et al._2022, title={Brain topography on adult ultrasound images: Techniques, interpretation, and image library}, ISSN={["1552-6569"]}, DOI={10.1111/jon.13031}, abstractNote={Abstract}, journal={JOURNAL OF NEUROIMAGING}, author={Kapoor, Sahil and Offnick, Austin and Allen, Beddome and Brown, Patrick A. and Sachs, Jeffrey R. and Gurcan, Metin Nafi and Pinton, Gianmarco and D'Agostino, Ralph, Jr. and Bushnell, Cheryl and Wolfe, Stacey and et al.}, year={2022}, month={Aug} }
 @article{mccall_dayton_pinton_2022, title={Characterization of the Ultrasound Localization Microscopy Resolution Limit in the Presence of Image Degradation}, volume={69}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2021.3112074}, abstractNote={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 $\mu \text{m}$ 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.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={McCall, Jacob R. and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2022}, month={Jan}, pages={124–134} }
 @article{mitcham_nevozhay_chen_nguyen_pinton_lai_sokolov_bouchard_2022, title={Effect of perfluorocarbon composition on activation of phase-changing ultrasound contrast agents}, ISSN={["2473-4209"]}, DOI={10.1002/mp.15564}, abstractNote={Abstract}, journal={MEDICAL PHYSICS}, author={Mitcham, Trevor M. and Nevozhay, Dmitry and Chen, Yunyun and Nguyen, Linh D. and Pinton, Gianmarco F. and Lai, Stephen Y. and Sokolov, Konstantin V and Bouchard, Richard R.}, year={2022}, month={Mar} }
 @article{chandrasekaran_santibanez_tripathi_deruiter_bruegge_pinton_2022, title={In situ ultrasound imaging of shear shock waves in the porcine brain}, volume={134}, ISSN={["1873-2380"]}, DOI={10.1016/j.jbiomech.2021.110913}, abstractNote={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.}, journal={JOURNAL OF BIOMECHANICS}, author={Chandrasekaran, Sandhya and Santibanez, Francisco and Tripathi, Bharat B. and DeRuiter, Ryan and Bruegge, Ruth Vorder and Pinton, Gianmarco}, year={2022}, month={Mar} }
 @misc{darmani_bergmann_pauly_caskey_lecea_fomenko_fouragnan_legon_murphy_nandi_et al._2022, title={Non-invasive transcranial ultrasound stimulation for neuromodulation}, volume={135}, ISSN={["1872-8952"]}, DOI={10.1016/j.clinph.2021.12.010}, abstractNote={Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.}, journal={CLINICAL NEUROPHYSIOLOGY}, author={Darmani, G. and Bergmann, T. O. and Pauly, K. Butts and Caskey, C. F. and Lecea, L. and Fomenko, A. and Fouragnan, E. and Legon, W. and Murphy, K. R. and Nandi, T. and et al.}, year={2022}, month={Mar}, pages={51–73} }
 @article{jones_caskey_dayton_oralkan_pinton_2022, title={Transcranial Neuromodulation Array With Imaging Aperture for Simultaneous Multifocus Stimulation in Nonhuman Primates}, volume={69}, ISSN={["1525-8955"]}, url={https://doi.org/10.1109/TUFFC.2021.3108448}, DOI={10.1109/TUFFC.2021.3108448}, abstractNote={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.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, publisher={Institute of Electrical and Electronics Engineers (IEEE)}, author={Jones, Rebecca M. and Caskey, Charles F. and Dayton, Paul A. and Oralkan, Omer and Pinton, Gianmarco F.}, year={2022}, month={Jan}, pages={261–272} }
 @article{xavier_pinton_espindola_2021, title={Comparison of localization methods in super-resolution imaging}, DOI={10.1109/LAUS53676.2021.9639191}, abstractNote={Ultrasound localization microscopy (ULM) produces vascular images with a resolution ten times better than the conventional ultrasound. Generating ULM images requires several steps: injection of the microbubbles (MBs) into the bloodstream, image acquisition, detection, localization, and tracking of MBs. Finally, the accumulation of all MBs positions produces the final image. In this context, the localization step is crucial, and it is still under discussion what is the optimum localization method. In this study, four different MBs localization methods were compared using a simulation along with experimental validation in a microtube phantom. Ultrasound interactions were simulated with the FullWave Solver in a two-dimensional domain. This solver was set to simulate 1000 frames of a plane-wave propagating in a heterogeneous tissue with different diameters of vessels, containing blood and MBs flowing with a parabolic fluid velocity profile. Four methods to localize the MB were compared: Weighted centroid, 2D spline, paraboloid fitting, and onset detection. Four metrics were used to compare the methods; MB distribution error; Full-width-at-half-maximum (FWHM) error; Number of MBs detected per frame; and computational time cost. Paraboloid fitting was the most robust method, regarding different diameters. When compared to the weighted centroid, paraboloid fitting improves the estimates of the localization profile by 56%, and detects near 100% of the MBs, while weighted centroid only detected 25% of them. The precision of the onset detection method depends on the vessel diameter, showing good results only for small vessels. Most importantly, the proposed simulations can be seen as a tool that offers access to the ground truth of many MBs’ localization under relatively realistic physics.}, journal={2021 IEEE UFFC LATIN AMERICA ULTRASONICS SYMPOSIUM (LAUS)}, author={Xavier, Aline and Pinton, Gianmarco and Espindola, David}, year={2021} }
 @article{chandrasekaran_tripathi_espindola_pinton_2021, title={Modeling Ultrasound Propagation in the Moving Brain: Applications to Shear Shock Waves and Traumatic Brain Injury}, volume={68}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2020.3022567}, abstractNote={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 ( $\lambda $ /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.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Chandrasekaran, Sandhya and Tripathi, Bharat B. and Espindola, David and Pinton, Gianmarco F.}, year={2021}, month={Jan}, pages={201–212} }
 @article{zhang_pinton_nightingale_2021, title={ON THE RELATIONSHIP BETWEEN SPATIAL COHERENCE AND IN SITU PRESSURE FOR ABDOMINAL IMAGING}, volume={47}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2021.03.008}, abstractNote={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.}, number={8}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Zhang, Bofeng and Pinton, Gianmarco F. and Nightingale, Kathryn R.}, year={2021}, month={Aug}, pages={2310–2320} }
 @article{zhang_pinton_deng_nightingale_2021, title={QUANTIFYING THE EFFECT OF ABDOMINAL BODY WALL ON IN SITU PEAK RAREFACTION PRESSURE DURING DIAGNOSTIC ULTRASOUND IMAGING}, volume={47}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2021.01.028}, abstractNote={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.}, number={6}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Zhang, Bofeng and Pinton, Gianmarco F. and Deng, Yufeng and Nightingale, Kathryn R.}, year={2021}, month={Jun}, pages={1548–1558} }
 @article{campbell_marshall_luck_pinton_stitzel_boone_guskiewicz_mihalik_2020, title={Head Impact Telemetry System's Video-based Impact Detection and Location Accuracy}, volume={52}, ISSN={["1530-0315"]}, DOI={10.1249/MSS.0000000000002371}, abstractNote={ABSTRACT}, number={10}, journal={MEDICINE AND SCIENCE IN SPORTS AND EXERCISE}, author={Campbell, Kody R. and Marshall, Stephen W. and Luck, Jason F. and Pinton, Gianmarco F. and Stitzel, Joel D. and Boone, Joshua S. and Guskiewicz, Kevin M. and Mihalik, Jason P.}, year={2020}, month={Oct}, pages={2198–2206} }
 @article{espindola_deruiter_santibanez_dayton_pinton_2020, title={Quantitative sub-resolution blood velocity estimation using ultrasound localization microscopy ex-vivo and in-vivo}, volume={6}, ISSN={["2057-1976"]}, DOI={10.1088/2057-1976/ab7f26}, abstractNote={Super-resolution ultrasound imaging relies on the sub-wavelength localization of microbubble contrast agents. By tracking individual microbubbles, the velocity and flow within microvessels can be estimated. It has been shown that the average flow velocity, within a microvessel ranging from tens to hundreds of microns in diameter, can be measured. However, a 2D super-resolution image can only localize bubbles with sub-wavelength resolution in the imaging plane whereas the resolution in the elevation plane is limited by conventional beamwidth physics. Since ultrasound imaging integrates echoes over the elevation dimension, velocity estimates at a single location in the imaging plane include information throughout the imaging slice thickness. This slice thickness is typically a few orders or magnitude larger than the super-resolution limit. It is shown here that in order to estimate the velocity, a spatial integration over the elevation direction must be considered. This operation yields a multiplicative correction factor that compensates for the elevation integration. A correlation-based velocity estimation technique is then presented. Calibrated microtube phantom experiments are used to validate the proposed velocity estimation method and the proposed elevation integration correction factor. It is shown that velocity measurements are in excellent agreement with theoretical predictions within the considered range of flow rates (10 to 90 μl/min) in a microtube with a diameter of 200 μm. Then, the proposed technique is applied to two in-vivo mouse tail experiments imaged with a low frequency human clinical transducer (ATL L7-4) with human clinical concentrations of microbubbles. In the first experiment, a vein was visible with a diameter of 140 μm and a peak flow velocity of 0.8 mm s−1. In the second experiment, a vein was observed in the super-resolved image with a diameter of 120 μm and with maximum local velocity of ≈4.4 mm s−1. It is shown that the parabolic flow profiles within these micro-vessels are resolvable.}, number={3}, journal={BIOMEDICAL PHYSICS & ENGINEERING EXPRESS}, author={Espindola, David and DeRuiter, Ryan M. and Santibanez, Francisco and Dayton, Paul A. and Pinton, Gianmarco}, year={2020}, month={Apr} }
 @misc{christensen-jeffries_couture_dayton_eldar_hynynen_kiessling_o'reilly_pinton_schmitz_tang_et al._2020, title={SUPER-RESOLUTION ULTRASOUND IMAGING}, volume={46}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.11.013}, abstractNote={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.}, number={4}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Christensen-Jeffries, Kirsten and Couture, Olivier and Dayton, Paul A. and Eldar, Yonina C. and Hynynen, Kullervo and Kiessling, Fabian and O'Reilly, Meaghan and Pinton, I. Gianmarco F. and Schmitz, Georg and Tang, Meng-Xing and et al.}, year={2020}, month={Apr}, pages={865–891} }
 @article{soulioti_espindola_dayton_pinton_2020, title={Super-Resolution Imaging Through the Human Skull}, volume={67}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2019.2937733}, abstractNote={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-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> 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-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> diameter microtube at 68.5 mm in depth and at 2.5 MHz. Microbubble contrast agents were diluted to a concentration of <inline-formula> <tex-math notation="LaTeX">$1.6\times 10^{6}$ </tex-math></inline-formula> 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 <inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula>, was reduced to as low as 50 <inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> 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-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> error for the uncorrected emission, to a 284-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> 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.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Soulioti, Danai E. and Espindola, David and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2020}, month={Jan}, pages={25–36} }
 @article{kierski_espindola_newsome_cherin_yin_foster_demore_pinton_dayton_2020, title={Superharmonic Ultrasound for Motion-Independent Localization Microscopy: Applications to Microvascular Imaging From Low to High Flow Rates}, volume={67}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2020.2965767}, abstractNote={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 ( $0.27~\mu \text{m}$ /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 $20~\mu \text{m}$ in diameter after motion correction.}, number={5}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Kierski, Thomas M. and Espindola, David and Newsome, Isabel G. and Cherin, Emmanuel and Yin, Jianhua and Foster, F. Stuart and Demore, Christine E. M. and Pinton, Gianmarco F. and Dayton, Paul A.}, year={2020}, month={May}, pages={957–967} }
 @article{deruiter_markley_rojas_pinton_dayton_2020, title={Transient acoustic vaporization signatures unique to low boiling point phase change contrast agents enable super-resolution ultrasound imaging without spatiotemporal filtering}, volume={10}, ISSN={["2158-3226"]}, DOI={10.1063/5.0029207}, abstractNote={The unique activation signal of phase-change contrast agents (PCCAs or droplets) can be separated from the tissue signal and localized to generate super-resolution (SR) ultrasound (US) images. Lipid-shelled, perfluorocarbon PCCAs can be stochastically vaporized (activated) by a plane wave US transmission thereby enabling them to be used as separable targets for ultrasound localization microscopy. The unique signature of droplet vaporization imaging and the transient inherent nature of this signature increases signal contrast and therefore localization confidence, while the poor resolution of the low-frequency vaporization signal is overcome by the super-resolution result. Furthermore, our proposed PCCA SR technique does not require the use of user-dependent and flow-dependent spatio-temporal filtering via singular-value decomposition. Rather, matched filters selected by Fourier-domain analysis are able to identify and localize PCCA activations. Droplet SR was demonstrated in a crossed-microtube water phantom by localizing the activation signals of octafluoropropane nanodroplets (OFP, C3F8, −37 °C boiling point) to resolve 100 µm diameter fluorinated ethylene propylene tubes, which are ordinarily 35% smaller than the native diffraction-limited resolution of the imaging system utilized.}, number={10}, journal={AIP ADVANCES}, author={DeRuiter, R. M. and Markley, E. N. and Rojas, J. D. and Pinton, G. F. and Dayton, P. A.}, year={2020}, month={Oct} }
 @article{tripathi_espindola_pinton_2019, title={Modeling and simulations of two dimensional propagation of shear shock waves in relaxing soft solids}, volume={395}, ISSN={["1090-2716"]}, DOI={10.1016/j.jcp.2019.06.014}, abstractNote={Soft solids, such as gelatin or soft tissue, have a shear wave speed that is smaller than the compressional wave speed. Recent observations of shear shock wave generation in the brain, which can easily reach a large Mach number regime, suggest that the cubic nonlinear behavior of soft solids could be responsible for traumatic brain injury. However, currently there are no two-dimensional (2D) models describing the propagation of linearly-polarized shear shock waves in relaxing soft solids. These models are required to model the fundamental wave propagation physics like diffraction, focusing etc., and are related to traumatic brain injuries as it can be used to model the skull/brain morphology. In this work, we present a two-dimensional system of first-order equations modeling the propagation of shear shock waves in a relaxing soft solid, and then this system is solved numerically using the piecewise parabolic method, a high-order finite volume method. The numerical solutions are validated in two parts. First, the nonlinear component, which is designed for large Mach numbers, is validated with a step-shock Riemann problem. Then relaxation mechanisms based on a generalized Maxwell body, which model the non-classical attenuation that occurs in soft tissue, are compared to analytical solutions with an error of 5%-10%. The validation of attenuation also includes dispersion due to causality which is determined by the Kramers-Kronig relations. Finally, the full numerical method, which includes nonlinearity, attenuation, and dispersion, is compared to ultrasonic measurements of shear shock wave propagation in tissue-mimicking phantoms. Two experiments were performed based on high frame-rate ultrasound imaging and tracking in a gelatin phantom 1) planar shear shock waves, and 2) focused shear shock wave propagation. The experimental and numerical waveforms closely match, e.g. the RMS amplitude error is between 12.05% and 12.27%. Moreover, the frequency-content of the temporal signal was compared for third and fifth multiples of fundamental harmonic validating the generation of odd-harmonics due to cubic nonlinearity. Furthermore, the numerical tool was able to estimate the nonlinear parameter in the phantom (β=4.4) using a grid-parameter-search. In context of traumatic brain injury, the current method can be used to study the shear shock formation in 2D-sections of human skull, and can also be used for nonlinear parameter estimation in brain.}, journal={JOURNAL OF COMPUTATIONAL PHYSICS}, author={Tripathi, Bharat B. and Espindola, David and Pinton, Gianmarco F.}, year={2019}, month={Oct}, pages={205–222} }
 @article{tripathi_espindola_pinton_2019, title={Piecewise parabolic method for propagation of shear shock waves in relaxing soft solids: One-dimensional case}, volume={35}, ISSN={["2040-7947"]}, DOI={10.1002/cnm.3187}, abstractNote={Abstract}, number={5}, journal={INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING}, author={Tripathi, Bharat B. and Espindola, David and Pinton, Gianmarco F.}, year={2019}, month={May} }
 @article{espindola_lin_soulioti_dayton_pinton_2018, title={Adaptive Multifocus Beamforming for Contrast-Enhanced-Super-Resolution Ultrasound Imaging in Deep Tissue}, volume={65}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2018.2865903}, abstractNote={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).}, number={12}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Espindola, David and Lin, Fanglue and Soulioti, Danai E. and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2018}, month={Dec}, pages={2255–2263} }
 @article{giammarinaro_espindola_coulouvrat_pinton_2018, title={Focusing of Shear Shock Waves}, volume={9}, ISSN={["2331-7019"]}, DOI={10.1103/physrevapplied.9.014011}, abstractNote={Focusing is an ubiquitous mode of transforming waves---even within the human body, as it turns out. Recently, high-frame-rate ultrasound has enabled the observation of shear shock waves in soft solids, such as the brain. The present study uses that technique to further show that shear waves emitted by a cylindrical source into tissue-mimicking gelatin can be focused, and that they form a shock at the focus. This could explain why traumatic brain injuries, such as diffuse axonal injury, occur deep inside the organ, rather than near the skull.}, number={1}, journal={PHYSICAL REVIEW APPLIED}, author={Giammarinaro, Bruno and Espindola, David and Coulouvrat, Francois and Pinton, Gianmarco}, year={2018}, month={Jan} }
 @article{jakovljevic_pinton_dahl_trahey_2017, title={Blocked Elements in 1-D and 2-D Arrays-Part I: Detection and Basic Compensation on Simulated and In Vivo Targets}, volume={64}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2017.2683559}, abstractNote={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.}, number={6}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Jakovljevic, Marko and Pinton, Gianmarco F. and Dahl, Jeremy J. and Trahey, Gregg E.}, year={2017}, month={Jun}, pages={910–921} }
 @article{tripathi_espindola_pinton_2017, title={Piecewise parabolic method for simulating one-dimensional shear shock wave propagation in tissue-mimicking phantoms}, volume={27}, ISSN={["1432-2153"]}, DOI={10.1007/s00193-017-0734-8}, number={6}, journal={SHOCK WAVES}, author={Tripathi, B. B. and Espindola, D. and Pinton, G. F.}, year={2017}, month={Nov}, pages={879–888} }
 @article{espindola_lee_pinton_2017, title={Shear Shock Waves Observed in the Brain}, volume={8}, ISSN={["2331-7019"]}, DOI={10.1103/physrevapplied.8.044024}, abstractNote={The internal deformation of the brain is far more complex than the rigid motion of the skull. An ultrasound imaging technique that we have developed has a combination of penetration, frame-rate, and motion detection accuracy required to directly observe, for the first time, the formation and evolution of shear shock waves in the brain. Experiments at low impacts on the traumatic brain injury scale demonstrate that they are spontaneously generated and propagate within the porcine brain. Compared to the initially smooth impact, the acceleration at the shock front is amplified up to a factor of 8.5. This highly localized increase in acceleration suggests that shear shock waves are a fundamental mechanism for traumatic injuries in soft tissue.}, number={4}, journal={PHYSICAL REVIEW APPLIED}, author={Espindola, David and Lee, Stephen and Pinton, Gianmarco}, year={2017}, month={Oct} }
 @article{pinton_2017, title={Subresolution Displacements in Finite Difference Simulations of Ultrasound Propagation and Imaging}, volume={64}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2016.2638801}, abstractNote={Time domain finite difference simulations are used extensively to simulate wave propagation. They approximate the wave field on a discrete domain with a grid spacing that is typically on the order of a tenth of a wavelength. The smallest displacements that can be modeled by this type of simulation are thus limited to discrete values that are integer multiples of the grid spacing. This paper presents a method to represent continuous and subresolution displacements by varying the impedance of individual elements in a multielement scatterer. It is demonstrated that this method removes the limitations imposed by the discrete grid spacing by generating a continuum of displacements as measured by the backscattered signal. The method is first validated on an ideal perfect correlation case with a single scatterer. It is subsequently applied to a more complex case with a field of scatterers that model an acoustic radiation force-induced displacement used in ultrasound elasticity imaging. A custom finite difference simulation tool is used to simulate propagation from ultrasound imaging pulses in the scatterer field. These simulated transmit–receive events are then beamformed into images, which are tracked with a correlation-based algorithm to determine the displacement. A linear predictive model is developed to analytically describe the relationship between element impedance and backscattered phase shift. The error between model and simulation is  $\lambda / 1364$ , where  $\lambda $  is the acoustical wavelength. An iterative method is also presented that reduces the simulation error to  $\lambda / 5556$  over one iteration. The proposed technique therefore offers a computationally efficient method to model continuous subresolution displacements of a scattering medium in ultrasound imaging. This method has applications that include ultrasound elastography, blood flow, and motion tracking. This method also extends generally to finite difference simulations of wave propagation, such as electromagnetic or seismic waves.}, number={3}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Pinton, Gianmarco F.}, year={2017}, month={Mar}, pages={537–543} }
 @inproceedings{bottenus_pinton_trahey_2016, title={Large coherent apertures: Improvements in deep abdominal imaging and fundamental limits imposed by clutter}, DOI={10.1109/ultsym.2016.7728849}, abstractNote={Reverberation and aberration clutter can significantly degrade the ability to image deep abdominal structures in clinical practice. Despite increased hardware complexity and computing power, modern ultrasound arrays are still commonly limited to a length of several centimeters. We hypothesize that using a larger active aperture will improve image quality even in the presence of clutter. We use a simulated abdominal wall model to study the impact of an extended aperture and analyze both the point spread function and lesion imaging performance over a range of aperture sizes from 1 cm to 10 cm. Simulations demonstrate improved image quality as described by resolution and lesion detectability with growing aperture size up to the full extent of the 10 cm aperture. Although clutter degrades the overall imaging performance, it does not appear to impose a limit on the gains that can be made with increasing array size.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Bottenus, N. and Pinton, G. and Trahey, G.}, year={2016} }
 @article{giammarinaro_coulouvrat_pinton_2016, title={Numerical Simulation of Focused Shock Shear Waves in Soft Solids and a Two-Dimensional Nonlinear Homogeneous Model of the Brain}, volume={138}, ISSN={["1528-8951"]}, DOI={10.1115/1.4032643}, abstractNote={Shear waves that propagate in soft solids, such as the brain, are strongly nonlinear and can develop into shock waves in less than one wavelength. We hypothesize that these shear shock waves could be responsible for certain types of traumatic brain injuries (TBI) and that the spherical geometry of the skull bone could focus shear waves deep in the brain, generating diffuse axonal injuries. Theoretical models and numerical methods that describe nonlinear polarized shear waves in soft solids such as the brain are presented. They include the cubic nonlinearities that are characteristic of soft solids and the specific types of nonclassical attenuation and dispersion observed in soft tissues and the brain. The numerical methods are validated with analytical solutions, where possible, and with self-similar scaling laws where no known solutions exist. Initial conditions based on a human head X-ray microtomography (CT) were used to simulate focused shear shock waves in the brain. Three regimes are investigated with shock wave formation distances of 2.54 m, 0.018 m, and 0.0064 m. We demonstrate that under realistic loading scenarios, with nonlinear properties consistent with measurements in the brain, and when the shock wave propagation distance and focal distance coincide, nonlinear propagation can easily overcome attenuation to generate shear shocks deep inside the brain. Due to these effects, the accelerations in the focal are larger by a factor of 15 compared to acceleration at the skull surface. These results suggest that shock wave focusing could be responsible for diffuse axonal injuries.}, number={4}, journal={JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME}, author={Giammarinaro, B. and Coulouvrat, F. and Pinton, G.}, year={2016}, month={Apr} }
 @inproceedings{pinton_2016, title={Reverberation clutter and sources of image degradation in transcostal imaging}, DOI={10.1109/ultsym.2016.7728711}, abstractNote={The generation of an ultrasound image of human tissue is based on the complex physics of acoustic wave propagation: diffraction, reflection, scattering, frequency dependent attenuation, and nonlinearity. One approach to simulating ultrasound images is to make approximations that can reduce the physics to systems that have a low computational cost. Here a maximalist approach is taken and the full three dimensional wave physics is simulated with finite differences. The objective of this paper is to integrate the Fullwave nonlinear acoustic simulation tool with acoustical maps derived from the National Library of Medicine's Visible Human to generate highly realistic simulations of transcostal imaging. These images and the acoustical field throughout the imaging volume are used to determine the relative importance of nonlinearity, phase aberration, reverberation clutter, and beam shape in image degradation.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Pinton, G.}, year={2016} }
 @article{pinton_2015, title={Three Dimensional Full-wave Nonlinear Acoustic Simulations: Applications to Ultrasound Imaging}, volume={1685}, ISSN={["0094-243X"]}, DOI={10.1063/1.4934438}, abstractNote={Characterization of acoustic waves that propagate nonlinearly in an inhomogeneous medium has significant applications to diagnostic and therapeutic ultrasound. The generation of an ultrasound image of human tissue is based on the complex physics of acoustic wave propagation: diffraction, reflection, scattering, frequency dependent attenuation, and nonlinearity. The nonlinearity of wave propagation is used to the advantage of diagnostic scanners that use the harmonic components of the ultrasonic signal to improve the resolution and penetration of clinical scanners. One approach to simulating ultrasound images is to make approximations that can reduce the physics to systems that have a low computational cost. Here a maximalist approach is taken and the full three dimensional wave physics is simulated with finite differences. This paper demonstrates how finite difference simulations for the nonlinear acoustic wave equation can be used to generate physically realistic two and three dimensional ultrasound imag...}, journal={RECENT DEVELOPMENTS IN NONLINEAR ACOUSTICS}, author={Pinton, Gianmarco}, year={2015} }