Three-Dimensional Shear Wave Elastography Using Acoustic Radiation Force and a 2-D Row-Column Addressing (RCA) Array.

Acoustic radiation force (ARF)-based shear wave elastography (SWE) is a clinically available ultrasound imaging mode that noninvasively and quantitatively measures tissue stiffness. Current implementations of ARF-SWE are largely limited to 2-D imaging, which does not provide a robust estimation of heterogeneous tissue mechanical properties. Existing 3-D ARF-SWE solutions that are clinically available are based on wobbler probes, which cannot provide true 3-D shear wave motion detection. Although 3-D ARF-SWE based on 2-D matrix arrays have been previously demonstrated, they do not provide a practical solution because of the need for a high channel-count ultrasound system (e.g., 1024-channel) to provide adequate volume rates and the delicate circuitries (e.g., multiplexers) that are vulnerable to the long-duration "push" pulses. To address these issues, here we propose a new 3-D ARF-SWE method based on the 2-D row-column addressing (RCA) array which has a much lower element count (e.g., 256), provides an ultrafast imaging volume rate (e.g., 2000 Hz), and can withstand the push pulses. In this study, we combined the comb-push shear elastography (CUSE) technique with 2-D RCA for enhanced SWE imaging field-of-view (FOV). In vitro phantom studies demonstrated that the proposed method had robust 3-D SWE performance in both homogenous and inclusion phantoms. An in vivo study on a breast cancer patient showed that the proposed method could reconstruct 3-D elasticity maps of the breast lesion, which was validated using a commercial ultrasound scanner. These results demonstrate strong potential for the proposed method to provide a viable and practical solution for clinical 3-D ARF-SWE.

Ultrasound-targeted microbubble destruction mediates PDE5i/NO integration for cavernosum remodeling and penile rehabilitation.

Erectile dysfunction (ED) caused by cavernous nerve injury (CNI) is refractory to heal mainly ascribed to the adverse remodeling of the penis induced by ineffectual microvascular perfusion, fibrosis, and neurotrophins scarcity in cavernosum. Phosphodiesterase type V inhibitors (PDE5i) have been regarded as an alternative candidate drug for avoiding penile neuropathy. However, the therapeutic efficacy is severely limited due to poor accumulation under systemic medication and endogenous nitric oxide (NO) deficiency in cavernosum. Herein, an innovative liposomal microbubble (MB) loaded with both Sildenafil (one of PDE5i) and NO was designed. Ultrasound-targeted MB destruction (UTMD)-mediated efficient release and integration erectogenic agents into corpus cavernosum with high biosafety. On a bilateral CNI rat model, the multifunctional MB-cooperated UTMD improved microvascular perfusion in penis, simultaneously, alleviated hypoxia and oxidative stress, indicating successful activation of NO-cyclic guanosine monophosphate pathway. Also, evaluation of the endothelial/muscular composition, intracavernosal pressure, and neural integrity in the penis proved that coordinated intervention reversed the abnormal structural remodeling and promoted the recovery of functional erection. Our work demonstrates that MB loading Sildenafil and NO combined with UTMD hold great promise to "awaken" the efficacy of PDE5i in neurogenic ED, which provided a superior option for ensuring penile rehabilitation.

Joint localization and classification of breast masses on ultrasound images using an auxiliary attention-based framework.

Multi-task learning (MTL) methods have been extensively employed for joint localization and classification of breast lesions on ultrasound images to assist in cancer diagnosis and personalized treatment. One typical paradigm in MTL is a shared trunk network architecture. However, such a model design may suffer information-sharing conflicts and only achieve suboptimal performance for individual tasks. Additionally, the model relies on fully-supervised learning methodologies, imposing heavy burdens on data annotation. In this study, we propose a novel joint localization and classification model based on attention mechanisms and a sequential semi-supervised learning strategy to address these challenges. Our proposed framework offers three primary advantages. First, a lesion-aware network with multiple attention modules is designed to improve model performance on lesion localization. An attention-based classifier explicitly establishes correlations between the two tasks, alleviating information-sharing conflicts while leveraging location information to assist in classification. Second, a two-stage sequential semi-supervised learning strategy is designed for model training to achieve optimal performance on both tasks and substantially reduces the need for data annotation. Third, the asymmetric and modular model architecture allows for the flexible interchangeability of individual components, rendering the model adaptable to various applications. Experimental results from two different breast ultrasound image datasets under varied conditions have demonstrated the effectiveness of the proposed method. Furthermore, we conduct comprehensive investigations into the impacts of various factors on model performance, gaining in-depth insights into the mechanism of our proposed framework. The code is available at https://github.com/comp-imaging-sci/lanet-bus.git.

High-Volume-Rate 3-D Ultrasound Imaging Using Fast-Tilting and Redirecting Reflectors.

Three-dimensional ultrasound imaging has many advantages over 2-D imaging such as more comprehensive tissue evaluation and less operator dependence. However, developing a low-cost and accessible 3-D ultrasound solution with high volume rate and imaging quality remains a challenging task. Recently, we proposed a 3-D ultrasound imaging technique: fast acoustic steering via tilting electromechanical reflectors (FASTER), which uses a fast-tilting acoustic reflector to steer ultrafast plane waves elevationally to achieve high-volume-rate 3-D imaging with conventional 1-D transducers. However, the initial FASTER implementation requires a water tank for acoustic wave conduction and cannot be conveniently used for regular handheld scanning. To address these limitations, here, we developed a novel ultrasound probe clip-on device that encloses a fast-tilting reflector, a redirecting reflector, and an acoustic wave conduction medium. The new FASTER 3-D imaging device can be easily attached to or removed from clinical ultrasound transducers, allowing rapid transformation from 2-D to 3-D imaging. In vitro B-mode studies demonstrated that the proposed method provided comparable imaging quality to conventional, mechanical-translation-based 3-D imaging while offering a much faster volume rate (e.g., 300 versus  âˆ¼  10 Hz). We also demonstrated 3-D power Doppler (PD) and 3-D super-resolution ultrasound localization microscopy (ULM) with the FASTER device. An in vivo imaging study showed that the FASTER device could clearly visualize the 3-D anatomy of the basilic vein. These results suggest that the newly developed redirecting reflector and the clip-on device could overcome key hurdles for future clinical translation of the FASTER 3-D imaging technology.

High Volume Rate 3-D Ultrasound Imaging Using Fast-Tilting and Redirecting Reflectors.

3-D ultrasound imaging has many advantages over 2-D imaging such as more comprehensive tissue evaluation and less operator dependence. Although many 3-D ultrasound imaging techniques have been developed in the last several decades, a low-cost and accessible solution with high imaging volume rate and imaging quality remains elusive. Recently we proposed a new, high volume rate 3-D ultrasound imaging technique: Fast Acoustic Steering via Tilting Electromechanical Reflectors (FASTER), which uses a water-immersible and fast-tilting acoustic reflector to steer ultrafast plane waves in the elevational direction to achieve high volume rate 3-D ultrasound imaging with conventional 1-D array transducers. However, the initial implementation of FASTER imaging only involves a single fast-tilting acoustic reflector, which is inconvenient to use because the probe cannot be held in the regular upright position. Also, conventional FASTER imaging can only be performed inside a water tank because of the necessity of using water for acoustic conduction. To address these limitations of conventional FASTER, here we developed a novel ultrasound probe clip-on device that encloses a fast-tilting reflector, a redirecting reflector, and an acoustic wave conduction medium. The new FASTER 3-D imaging device can be easily attached to or removed from clinical ultrasound transducers, allowing rapid transformation from 2-D to 3-D ultrasound imaging. In vitro B-mode imaging studies demonstrated that the proposed method provided comparable imaging quality (e.g., spatial resolution and contrast-to-noise ratio) to conventional, mechanical-translation-based 3-D imaging while providing a much faster 3-D volume rate (e.g., 300 Hz vs ∻10 Hz). In addition to B-mode imaging, we also demonstrated 3-D power Doppler imaging and 3-D super-resolution ultrasound localization microscopy with the newly developed FASTER device. An in vivo imaging study showed that the FASTER device could clearly visualize the 3-D anatomy of the basilic vein of a healthy volunteer, and customized beamforming was implemented to accommodate the speed of sound difference between the acoustic medium and the imaging object (e.g., soft tissue). These results suggest that the newly developed redirecting reflector and the clip-on device could overcome key hurdles for future clinical translation of the FASTER 3-D imaging technology.

High-fidelity deep functional photoacoustic tomography enhanced by virtual point sources.

Photoacoustic tomography (PAT), a hybrid imaging modality that acoustically detects the optical absorption contrast, is a promising technology for imaging hemodynamic functions in deep tissues far beyond the traditional optical microscopy. However, the most clinically compatible PAT often suffers from the poor image fidelity, mostly due to the limited detection view of the linear ultrasound transducer array. PAT can be improved by employing highly-absorbing contrast agents such as droplets and nanoparticles, which, however, have low clinical translation potential due to safety concerns and regulatory hurdles imposed by these agents. In this work, we have developed a new methodology that can fundamentally improve PAT's image fidelity without hampering any of its functional capability or clinical translation potential. By using clinically-approved microbubbles as virtual point sources that strongly and isotropically scatter the local pressure waves generated by surrounding hemoglobin, we can overcome the limited-detection-view problem and achieve high-fidelity functional PAT in deep tissues, a technology referred to as virtual-point-source PAT (VPS-PAT). We have thoroughly investigated the working principle of VPS-PAT by numerical simulations and in vitro phantom experiments, clearly showing the signal origin of VPSs and the resultant superior image fidelity over traditional PAT. We have also demonstrated in vivo applications of VPT-PAT for functional small-animal studies with physiological challenges. We expect that VPS-PAT can find broad applications in biomedical research and accelerated translation to clinical impact.

Ultrasensitive US Microvessel Imaging of Hepatic Microcirculation in the Cirrhotic Rat Liver.

Background Liver microcirculation dysfunction plays a vital role in the occurrence and development of liver diseases, and thus, there is a clinical need for in vivo, noninvasive, and quantitative evaluation of liver microcirculation. Purpose To evaluate the feasibility of ultrasensitive US microvessel imaging (UMI) in the visualization and quantification of hepatic microvessels in healthy and cirrhotic rats. Materials and Methods In vivo studies were performed to image hepatic microvasculature by means of laparotomy in Sprague-Dawley rats (five cirrhotic and five control rats). In vivo conventional power Doppler US and ex vivo micro-CT were performed for comparison. UMI-based quantifications of perfusion, tortuosity, and integrity of microvessels were compared between the control and cirrhotic groups by using the Wilcoxon test. Spearman correlations between quantification parameters and pathologic fibrosis, perfusion function, and hepatic hypoxia were evaluated. Results UMI helped detect minute vessels below the liver capsule, as compared with conventional power Doppler US and micro-CT. With use of UMI, lower perfusion indicated by vessel density (median, 22% [IQR, 20%-28%] vs 41% [IQR, 37%-46%]; P = .008) and fractional moving blood volume (FMBV) (median, 6.4% [IQR, 4.8%-8.6%] vs 13% [IQR, 12%-14%]; P = .008) and higher tortuosity indicated by the sum of angles metric (SOAM) (median, 3.0 [IQR, 2.9-3.0] vs 2.7 [IQR, 2.6-2.9]; P = .008) were demonstrated in the cirrhotic rat group compared with the control group. Vessel density (r = 0.85, P = .003), FMBV (r = 0.86, P = .002), and median SOAM (r = -0.83, P = .003) showed strong correlations with pathologically derived vessel density labeled with dextran. Vessel density (r = -0.81, P = .005) and median SOAM (r = 0.87, P = .001) also showed strong correlations with hepatic tissue hypoxia. Conclusion Contrast-free ultrasensitive US microvessel imaging provided noninvasive in vivo imaging and quantification of hepatic microvessels in cirrhotic rat liver. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Fetzer in this issue.

Molecular response of keloids to ionizing radiation: targeting FOXO1 radiosensitizes keloids.

PURPOSE: Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies. MATERIALS AND METHODS: Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes. RESULTS: We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation. CONCLUSION: Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids.

Improved Ultrasound Attenuation Estimation with Non-uniform Structure Detection and Removal.

Accurate detection of liver steatosis is important for liver disease management. Ultrasound attenuation coefficient estimation (ACE) has great potential in quantifying liver fat content. The ACE methods commonly assume uniform tissue characteristics. However, in vivo tissues typically contain non-uniform structures, which may bias the attenuation estimation and lead to large standard deviations. Here we propose a series of non-uniform structure detection and removal (NSDR) methods to reduce the impact from non-uniform structures during ACE analysis. The effectiveness of NSDR was validated through phantom and in vivo studies. In a pilot clinical study, ACE with NSDR provided more robust in vivo performance as compared with ACE without NSDR, indicating its potential for in vivo applications.

Adaptive and Robust Vessel Quantification in Contrast-Free Ultrafast Ultrasound Microvessel Imaging.

The morphological features of vasculature in diseased tissue differ significantly from those in normal tissue. Therefore, vasculature quantification is crucial for disease diagnosis and staging. Ultrasound microvessel imaging (UMI) with ultrafast ultrasound acquisitions has been determined to have potential in clinical applications given its superior sensitivity in blood flow detection. However, the presence of spatial-dependent noise caused by a low imaging signal-to-noise ratio and incoherent clutter artifacts caused by moving hyperechoic scatterers degrades the performance of UMI and the reliability of vascular quantification. To tackle these issues, we proposed an improved UMI technique along with an adaptive vessel segmentation workflow for robust vessel identification and vascular feature quantification. A previously proposed sub-aperture cross-correlation technique and a normalized cross-correlation technique were applied to equalize the spatially dependent noise level and suppress the incoherent clutter artifact. A square operator and non-local means filter were then used to better separate the blood flow signal from residual background noise. On the de-noised ultrasound microvessel image, an automatic and adaptive vessel segmentation method was developed based on the different spatial patterns of blood flow signal and background noise. The proposed workflow was applied to a CIRS phantom, to a Doppler flow phantom and to an inflammatory bowel, kidney and liver, to validate its feasibility. Results revealed that automatic adaptive, and robust vessel identification performance can be achieved using the proposed method without the subjectivity caused by radiologists/operators.

Curvelet Transform-Based Sparsity Promoting Algorithm for Fast Ultrasound Localization Microscopy.

Ultrasound localization microscopy (ULM) based on microbubble (MB) localization was recently introduced to overcome the resolution limit of conventional ultrasound. However, ULM is currently challenged by the requirement for long data acquisition times to accumulate adequate MB events to fully reconstruct vasculature. In this study, we present a curvelet transform-based sparsity promoting (CTSP) algorithm that improves ULM imaging speed by recovering missing MB localization signal from data with very short acquisition times. CTSP was first validated in a simulated microvessel model, followed by the chicken embryo chorioallantoic membrane (CAM), and finally, in the mouse brain. In the simulated microvessel study, CTSP robustly recovered the vessel model to achieve an 86.94% vessel filling percentage from a corrupted image with only 4.78% of the true vessel pixels. In the chicken embryo CAM study, CTSP effectively recovered the missing MB signal within the vasculature, leading to marked improvement in ULM imaging quality with a very short data acquisition. Taking the optical image as reference, the vessel filling percentage increased from 2.7% to 42.2% using 50ms of data acquisition after applying CTSP. CTSP used 80% less time to achieve the same 90% maximum saturation level as compared with conventional MB localization. We also applied CTSP on the microvessel flow speed maps and found that CTSP was able to use only 1.6s of microbubble data to recover flow speed images that have similar qualities as those constructed using 33.6s of data. In the mouse brain study, CTSP was able to reconstruct the majority of the cerebral vasculature using 1-2s of data acquisition. Additionally, CTSP only needed 3.2s of microbubble data to generate flow velocity maps that are comparable to those using 129.6s of data. These results suggest that CTSP can facilitate fast and robust ULM imaging especially under the circumstances of inadequate microbubble localizations.

Reverberation clutter signal suppression in ultrasound attenuation estimation using wavelet-based robust principal component analysis.

Objective. Ultrasound attenuation coefficient estimation (ACE) has diagnostic potential for clinical applications such as quantifying fat content in the liver. Previously, we have proposed a system-independent ACE technique based on spectral normalization of different frequencies, called the reference frequency method (RFM). This technique does not require a well-calibrated reference phantom for normalization. However, this method may be vulnerable to severe reverberation clutter introduced by the body wall. The clutter superimposed on liver echoes may bias the estimation.Approach. We proposed to use robust principal component analysis, combined with wavelet-based sparsity promotion, to suppress the severe reverberation clutters. The capability to mitigate the reverberation clutters was validated through phantom andin vivostudies.Main Results. In the phantom studies with added reverberation clutters, higher normalized cross-correlation and smaller mean absolute errors were attained as compared to RFM results without the proposed method, demonstrating the capability to reconstruct tissue signals from reverberations. In a pilot patient study, the correlation between ACE and proton density fat fraction (PDFF), a measurement of liver fat by MRI as a reference standard, was investigated. The proposed method showed an improvement of the correlation (coefficient of determination,R = 0.82) as compared with the counterpart without the proposed method (R = 0.69).Significance: The proposed method showed the feasibility of suppressing the reverberation clutters, providing an important basis for the development of a robust ACE with large reverberation clutters.

Three-Dimensional Shear Wave Elastography Using a 2D Row Column Addressing (RCA) Array.

Objective. To develop a 3D shear wave elastography (SWE) technique using a 2D row column addressing (RCA) array, with either external vibration or acoustic radiation force (ARF) as the shear wave source. Impact Statement. The proposed method paves the way for clinical translation of 3D SWE based on the 2D RCA, providing a low-cost and high volume rate solution that is compatible with existing clinical systems. Introduction. SWE is an established ultrasound imaging modality that provides a direct and quantitative assessment of tissue stiffness, which is significant for a wide range of clinical applications including cancer and liver fibrosis. SWE requires high frame rate imaging for robust shear wave tracking. Due to the technical challenges associated with high volume rate imaging in 3D, current SWE techniques are typically confined to 2D. Advancing SWE from 2D to 3D is significant because of the heterogeneous nature of tissue, which demands 3D imaging for accurate and comprehensive evaluation. Methods. A 3D SWE method using a RCA array was developed with a volume rate up to 2000 Hz. The performance of the proposed method was systematically evaluated on tissue-mimicking elasticity phantoms and in an in vivo case study. Results. 3D shear wave motion induced by either external vibration or ARF was successfully detected with the proposed method. Robust 3D shear wave speed maps were reconstructed for phantoms and in vivo. Conclusion. The high volume rate 3D imaging provided by the 2D RCA array provides a robust and practical solution for 3D SWE with a clear pathway for future clinical translation.

Super-Resolution Ultrasound Localization Microscopy for Visualization of the Ocular Blood Flow.

OBJECTIVE: The ocular vascular system plays an important role in preserving the visual function. Alterations in either anatomy or hemodynamics of the eye may have adverse effects on vision. Thus, an imaging approach that can monitor alterations of ocular blood flow of the deep eye vasculature ranging from capillary-level vessels to large supporting vessels would be advantageous for detection of early stage retinal and optic nerve diseases. METHODS: We propose a super-resolution ultrasound localization microscopy (ULM) technique that can assess both the microvessel and flow velocity of the deep eye with high resolution. Ultrafast plane wave imaging was acquired using an L22-14v linear array on a high frequency Verasonics Vantage system. A robust microbubble localization and tracking technique was applied to reconstruct ULM images. The experiment was first performed on pre-designed flow phantoms in vitro and then tested on a New Zealand white rabbit eye in vivo calibrated to various intraocular pressures (IOP) - 10 mmHg, 30 mmHg and 50 mmHg. RESULTS: We demonstrated that retinal/choroidal vessels, central retinal artery, posterior ciliary artery, and vortex vein were all visible at high resolution. In addition, reduction of vascular density and flow velocity were observed with elevated IOPs. CONCLUSION: These results indicate that super-resolution ULM is able to image the deep ocular tissue while maintaining high resolution that is comparable with optical coherence tomography angiography. SIGNIFICANCE: Capability to detect subtle changes of blood flow may be clinically important in detecting and monitoring eye diseases such as glaucoma.

Quantitative Shear Wave Speed Assessment for Muscles With the Diagnosis of Taut Bands and/or Myofascial Trigger Points Using Probe Oscillation Shear Wave Elastography: A Pilot Study.

OBJECTIVE: To use probe oscillation shear wave elastography (PROSE) with two vibration sources to generate two shear waves in the imaging plane to quantitatively assess the shear wave speeds (SWSs) of muscles with and without the diagnosis of taut bands (TB) and/or myofascial trigger points (MTrPs). METHODS: Thirty-three patients were scanned with the PROSE technique. Shear waves were generated through continuous vibration of the ultrasound probe, while the shear wave motions were detected using the same probe. SWSs for the sides with and without TBs and/or MTrPs were computed and compared. The pressure pain thresholds (PPTs) were measured as an indicator of maximum pain tolerance of patients. The statistical differences between the SWSs with and without TBs and/or MTrPs with different PPT values were analyzed using the nonparametric Wilcoxon rank-sum test. RESULTS: The mean SWSs for the sides with TBs and/or MTrPs are faster than that of the contralateral side without TBs and/or MTrPs. A significant difference was observed between mean SWSs with and without TBs and/or MTrPs without any information of PPT, with rank-sum test P < .005. Additionally, with the information of PPT, a significant difference was observed between mean SWSs for the sides with and without TBs and/or MTrPs, for PPT values between 0 and 50 N/cm2 (P < .005), but for PPT values between 50 and 90 N/cm2 , it was difficult to differentiate mean SWSs with and without TBs and/or MTrPs. CONCLUSION: Our preliminary results show that SWSs measured from patients had a significant difference between the mean SWSs with and without TBs and/or MTrPs.

Three-Dimensional Ultrasound Localization Microscopy with Bipartite Graph-Based Microbubble Pairing and Kalman-Filtering-Based Tracking on a 256-Channel Verasonics Ultrasound System with a 32 × 32 Matrix Array.

Three-dimensional (3D) ultrasound localization microscopy (ULM) using a 2-D matrix probe and microbubbles (MBs) has been recently proposed to visualize microvasculature beyond the ultrasound diffraction limit in three spatial dimensions. However, 3D ULM suffers from several limitations: (1) high system complexity due to numerous channel counts, (2) complex MB flow dynamics in 3D, and (3) extremely long acquisition time. To reduce the system complexity while maintaining high image quality, we used a sub-aperture process to reduce received channel counts. To address the second issue, a 3D bipartite graph-based method with Kalman filtering-based tracking was used in this study for MB tracking. An MB separation approach was incorporated to separate high concentration MB data into multiple, sparser MB datasets, allowing better MB localization and tracking for a limited acquisition time. The proposed method was first validated in a flow channel phantom, showing improved spatial resolutions compared with the contrasted enhanced power Doppler image. Then the proposed method was evaluated with an in vivo chicken embryo brain dataset. Results showed that the reconstructed 3D super-resolution image achieved a spatial resolution of around 52 µm (smaller than the wavelength of around 200 µm). Microvessels that cannot be resolved clearly using localization only, can be well identified with the tailored 3D pairing and tracking algorithms. To sum up, the feasibility of the 3D ULM is shown, indicating the great possibility in clinical applications.

Novel Uses of Ultrasound to Assess Kidney Mechanical Properties.

Ultrasound is a key imaging tool for evaluating the kidney. Over the last two decades, methods to measure the mechanical properties of soft tissues have been developed and used in clinical practice, although use in the kidney has not been as widespread as for other applications. The mechanical properties of the kidney are determined by the structure and composition of the renal parenchyma and perfusion characteristics. Because pathologic processes change these factors, the mechanical properties change and can be used for diagnostic purposes and for monitoring treatment or disease progression. Ultrasound-based elastography methods for evaluating the mechanical properties of the kidney use focused ultrasound beams to perturb the kidney and then high frame-rate ultrasound methods are used to measure the resulting motion. The motion is analyzed to estimate the mechanical properties. This review will describe the principles of these methods and discuss several seminal studies related to characterizing the kidney. Additionally, an overview of the clinical use of elastography methods in native and kidney allografts will be provided. Perspectives on future developments and uses of elastography technology along with other complementary ultrasound imaging modalities will be provided.

In vivo Visualization of Pig Vagus Nerve "Vagotopy" Using Ultrasound.

Background: Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal. Objective: Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein. However, it lacks sufficient resolution to provide details about the vagus fascicular organization, or detail about smaller neural structures such as the recurrent and superior laryngeal branch responsible for therapy limiting side effects. Here, we characterize the use of ultrasound with the transducer placed in the surgical pocket to improve resolution without adding significant additional risk to the surgical procedure in the pig model. Methods: Ultrasound images were obtained from a point of known functional organization at the nodose ganglia to the point of placement of stimulating electrodes within the surgical window. Naïve volunteers with minimal training were then asked to use these ultrasound videos to trace afferent groupings of fascicles from the nodose to their location within the surgical window where a stimulating cuff would normally be placed. Volunteers were asked to select a location for epineural electrode placement away from the fascicles containing efferent motor nerves responsible for therapy limiting side effects. 2-D and 3-D reconstructions of the ultrasound were directly compared to post-mortem histology in the same animals. Results: High-resolution ultrasound from the surgical pocket enabled 2-D and 3-D reconstruction of the cervical vagus and surrounding structures that accurately depicted the functional vagotopy of the pig vagus nerve as confirmed via histology. Although resolution was not sufficient to match specific fascicles between ultrasound and histology 1 to 1, it was sufficient to trace fascicle groupings from a point of known functional organization at the nodose ganglia to their locations within the surgical window at stimulating electrode placement. Naïve volunteers were able place an electrode proximal to the sensory afferent grouping of fascicles and away from the motor nerve efferent grouping of fascicles in each subject (n = 3). Conclusion: The surgical pocket itself provides a unique opportunity to obtain higher resolution ultrasound images of neural targets responsible for intended therapeutic effect and limiting off-target effects. We demonstrate the increase in resolution is sufficient to aid patient-specific electrode placement to optimize outcomes. This simple technique could be easily adopted for multiple neuromodulation targets to better understand how patient specific anatomy impacts functional outcomes.

Photoacoustic computed tomography of mechanical HIFU-induced vascular injury.

Mechanical high-intensity focused ultrasound (HIFU) has been used for cancer treatment and drug delivery. Existing monitoring methods for mechanical HIFU therapies such as MRI and ultrasound imaging often suffer from high cost, poor spatial-temporal resolution, and/or low sensitivity to tissue's hemodynamic changes. Evaluating vascular injury during mechanical HIFU treatment, therefore, remains challenging. Photoacoustic computed tomography (PACT) is a promising tool to meet this need. Intrinsically sensitive to optical absorption, PACT provides high-resolution imaging of blood vessels using hemoglobin as the endogenous contrast. In this study, we have developed an integrated HIFU-PACT system for detecting vascular rupture in mechanical HIFU treatment. We have demonstrated singular value decomposition for enhancing hemorrhage detection. We have validated the HIFU-PACT performance on phantoms and in vivo animal tumor models. We expect that PACT-HIFU will find practical applications in oncology research using small animal models.