Super Resolution Ultrasound Imaging using the Erythrocytes: I: Density Images.

A new approach for vascular super resolution imaging using the erythrocytes as targets (SURE imaging) is described and investigated. SURE imaging does not require fragile contrast agent bubbles, making it possible to use the maximum allowable mechanical index for ultrasound scanning for an increased penetration depth. A synthetic aperture ultrasound sequence was employed with 12 virtual sources using a 10 MHz GE L8-18i-D linear array hockey stick probe. The axial resolution was 1.20λ,(185.0µm) and the lateral resolution was 1.50λ,(231.3µm). Field IIpro simulations were conducted on 12.5 µm radius vessel pairs with varying separations. A vessel pair with a separation of 70 µm could be resolved, indicating a SURE image resolution below half a wavelength. A Verasonics research scanner was used for the in vivo experiments to scan the kidneys of Sprague-Dawley rats for up to 46 s to visualize their microvasculature by processing from 0.1 up to 45 s of data for SURE imaging, and for 46.8 s for super resolution (SR) imaging with a SonoVue contrast agent. Afterward, the renal vasculature was filled with the ex vivo micro-CT contrast agent Microfil, excised, and scanned in a micro-CT scanner at both a 22.6 µm voxel size for 11 hours, and for 20 hours in a 5 µm voxel size for validating the SURE images. Comparing the SURE and micro-CT images revealed that vessels with a diameter of 28 µm, five times smaller than the ultrasound wavelength, could be detected, and the dense grid of microvessels in the full kidney was shown for scan times between 1 to 10 s. The vessel structure in the cortex was also similar for the SURE and SR images. Fourier ring correlation indicated a resolution capability of 29 µm. SURE images are acquired in seconds rather than minutes without any patient preparation or contrast injection, making the method translatable to clinical use.

Super Resolution Ultrasound Imaging Using the Erythrocytes: II: Velocity Images.

Super resolution ultrasound imaging using the erythrocytes (SURE) has recently been introduced. The method uses erythrocytes as targets instead of fragile microbubbles (MBs). The abundance of erythrocyte scatterers makes it possible to acquire SURE data in just a few seconds compared to several minutes in ultrasound localization microscopy (ULM) using MBs. A high number of scatterers can reduce the acquisition time, however, the tracking of uncorrelated and high-density scatterers is quite challenging. This paper hypothesizes that it is possible to detect and track erythrocytes as targets to obtain vascular flow images. A SURE tracking pipeline is used with modules for beamforming, recursive synthetic aperture imaging, motion estimation, echo canceling, peak detection, and recursive nearest neighbor tracker. The SURE tracking pipeline is capable of distinguishing the flow direction and separating tubes of a simulated Field II phantom with 125 to 25 µm wall-to-wall tube distances, as well as a 3D-printed hydrogel micro-flow phantom with 100 to 60 µm wall-to-wall channel distances. The comparison of an in-vivo SURE scan of a Sprague-Dawley rat kidney with ULM and micro-CT scans with voxel sizes of 26.5µm and 5µm demonstrated consistent findings. A microvascular structure composed of 16 vessels exhibited similarities across all imaging modalities. The flow direction and velocity profiles in the SURE scan were found to be concordant with those from ULM.

Super-Resolution Ultrasound Imaging of Renal Vascular Alterations in Zucker Diabetic Fatty Rats during the Development of Diabetic Kidney Disease.

Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels' density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation.

Anatomic and Functional Imaging Using Row-Column Arrays.

Row-column (RC) arrays have the potential to yield full 3-D ultrasound imaging with a greatly reduced number of elements compared to fully populated arrays. They, however, have several challenges due to their special geometry. This review article summarizes the current literature for RC imaging and demonstrates that full anatomic and functional imaging can attain a high quality using synthetic aperture (SA) sequences and modified delay-and-sum beamforming. Resolution can approach the diffraction limit with an isotropic resolution of half a wavelength with low sidelobe levels, and the field of view can be expanded by using convex or lensed RC probes. GPU beamforming allows for three orthogonal planes to be beamformed at 30 Hz, providing near real-time imaging ideal for positioning the probe and improving the operator's workflow. Functional imaging is also attainable using transverse oscillation and dedicated SA sequence for tensor velocity imaging for revealing the full 3-D velocity vector as a function of spatial position and time for both blood velocity and tissue motion estimation. Using RC arrays with commercial contrast agents can reveal super-resolution imaging (SRI) with isotropic resolution below [Formula: see text]. RC arrays can, thus, yield full 3-D imaging at high resolution, contrast, and volumetric rates for both anatomic and functional imaging with the same number of receive channels as current commercial 1-D arrays.

Ultrasound super-resolution imaging with a hierarchical Kalman tracker.

Microbubble (MB) tracking plays an important role in ultrasound super-resolution imaging (SRI) by enabling velocity estimation and improving image quality. This work presents a new hierarchical Kalman (HK) tracker to achieve better performance at scenarios with high concentrations of MBs and high localization uncertainty. The method attempts to follow MBs with different velocity ranges using different Kalman filters. An extended simulation framework for evaluating trackers is also presented and used for comparison of the proposed HK tracker with the nearest-neighbor (NN) and Kalman (K) trackers. The HK tracks were most similar to the ground truth with the highest Jaccard similarity coefficient in 79% of the scenarios and the lowest root-mean-square error in 72% of the scenarios. The HK tracker reconstructed vessels with a more accurate diameter. In a scenario with an uncertainty of 51.2µm in MB localization, a vessel diameter of 250µm was estimated as 257µm by HK tracker, compared with 329µm and 389µm for the K and NN trackers. In the same scenario, the HK tracker estimated MB velocities with a relative bias down to 1.7% and a relative standard deviation down to 8.3%. Finally, the different tracking techniques were applied to in vivo data from rat kidneys, and trends similar to the simulations were observed. Conclusively, the results showed an improvement in tracking performance, when the HK tracker was employed in comparison with the NN and K trackers.

Real-Time Volumetric Synthetic Aperture Software Beamforming of Row-Column Probe Data.

Two delay-and-sum beamformers for 3-D synthetic aperture imaging with row-column addressed arrays are presented. Both beamformers are software implementations for graphics processing unit (GPU) execution with dynamic apodizations and third-order polynomial subsample interpolation. The first beamformer was written in the MATLAB programming language and the second was written in C/C++ with the compute unified device architecture (CUDA) extensions by NVIDIA. Performance was measured as volume rate and sample throughput on three different GPUs: a 1050 Ti, a 1080 Ti, and a TITAN V. The beamformers were evaluated across 112 combinations of output geometry, depth range, transducer array size, number of virtual sources, floating-point precision, and Nyquist rate or in-phase/quadrature beamforming using analytic signals. Real-time imaging defined as more than 30 volumes per second was attained by the CUDA beamformer on the three GPUs for 13, 27, and 43 setups, respectively. The MATLAB beamformer did not attain real-time imaging for any setup. The median, single-precision sample throughput of the CUDA beamformer was 4.9, 20.8, and 33.5 Gsamples/s on the three GPUs, respectively. The throughput of CUDA beamformer was an order of magnitude higher than that of the MATLAB beamformer.

3D printed calibration micro-phantoms for super-resolution ultrasound imaging validation.

This study evaluates the use of 3D printed phantoms for 3D super-resolution ultrasound imaging (SRI) algorithm calibration. The main benefit of the presented method is the ability to do absolute 3D micro-positioning of sub-wavelength sized ultrasound scatterers in a material having a speed of sound comparable to that of tissue. Stereolithography is used for 3D printing soft material calibration micro-phantoms containing eight randomly placed scatterers of nominal size 205 µm × 205 µm × 200 µm. The backscattered pressure spatial distribution is evaluated to show similar distributions from micro-bubbles as the 3D printed scatterers. The printed structures are found through optical validation to expand linearly in all three dimensions by 2.6% after printing. SRI algorithm calibration is demonstrated by imaging a phantom using a λ/2 pitch 3 MHz 62+62 row-column addressed (RCA) ultrasound probe. The printed scatterers will act as point targets, as their dimensions are below the diffraction limit of the ultrasound system used. Two sets of 640 volumes containing the phantom features are imaged, with an intervolume uni-axial movement of the phantom of 12.5 µm, to emulate a flow velocity of 2 mm/s at a frame rate of 160 Hz. The ultrasound signal is passed to a super-resolution pipeline to localise the positions of the scatterers and track them across the 640 volumes. After compensating for the phantom expansion, a scaling of 0.989 is found between the distance between the eight scatterers calculated from the ultrasound data and the designed distances. The standard deviation of the variation in the scatterer positions along each track is used as an estimate of the precision of the super-resolution algorithm, and is expected to be between the two limiting estimates of (σ̃x,σ̃y,σ̃z) = (22.7 µm, 27.6 µm, 9.7 µm) and (σ̃x,σ̃y,σ̃z) = (18.7 µm, 19.3 µm, 8.9 µm). In conclusion, this study demonstrates the use of 3D printed phantoms for determining the accuracy and precision of volumetric super-resolution algorithms.

Tensor Velocity Imaging With Motion Correction.

This article presents a motion compensation procedure that significantly improves the accuracy of synthetic aperture tensor velocity estimates for row-column arrays. The proposed motion compensation scheme reduces motion effects by moving the image coordinates with the velocity field during summation of low-resolution volumes. The velocity field is estimated using a transverse oscillation cross-correlation estimator, and each image coordinate's local tensor velocity is determined by upsampling the field using spline interpolation. The motion compensation procedure is validated using Field II simulations and flow measurements acquired using a 3-MHz row-column addressed probe and the research scanner SARUS. For a peak velocity of 25 cm/s, a pulse repetition frequency of 2 kHz, and a beam-to-flow angle of 60°, the proposed motion compensation procedure was able to reduce the relative bias from -27.0% to -9.4% and the standard deviation from 8.6% to 8.1%. In simulations performed with a pulse repetition frequency of 10 kHz, the proposed method reduces the bias in all cases with beam-to-flow angles of 60° and 75° and peak velocities between 10 and 150 cm/s.

Fast 3-D Velocity Estimation in 4-D Using a 62 + 62 Row-Column Addressed Array.

This article presents an imaging scheme capable of estimating the full 3-D velocity vector field in a volume using row-column addressed arrays (RCAs) at a high volume rate. A 62 + 62 RCA array is employed with an interleaved synthetic aperture sequence. It contains repeated emissions with rows and columns interleaved with B-mode emissions. The sequence contains 80 emissions in total and can provide continuous volumetric data at a volume rate above 125 Hz. A transverse oscillation cross correlation estimator determines all three velocity components. The approach is investigated using Field II simulations and measurements using a specially built 3-MHz 62 + 62 RCA array connected to the SARUS experimental scanner. Both the B-mode and flow sequences have a penetration depth of 14 cm when measured on a tissue-mimicking phantom (0.5-dB/[ [Formula: see text]] attenuation). Simulations of a parabolic flow in a 12-mm-diameter vessel at a depth of 30 mm, beam-to-flow angle of 90°, and xy-rotation of 45° gave a standard deviation (SD) of (3.3, 3.4, 0.4)% and bias of (-3.3, -3.9, -0.1)%, for ( vx , vy , and vz ). Decreasing the beam-to-flow angle to 60° gave an SD of (8.9, 9.1, 0.8)% and bias of (-7.6, -9.5, -7.2)%, showing a slight increase. Measurements were carried out using a similar setup, and pulsing at 2 kHz yielded comparable results at 90° with an SD of (5.8, 5.5, 1.1)% and bias of (1.4, -6.4, 2.4)%. At 60°, the SD was (5.2, 4.7 1.2)% and bias (-4.6, 6.9, -7.4)%. Results from measurements across all tested settings showed a maximum SD of 6.8% and a maximum bias of 15.8% for a peak velocity of 10 cm/s. A tissue-mimicking phantom with a straight vessel was used to introduce clutter, tissue motion, and pulsating flow. The pulsating velocity magnitude was estimated across ten pulse periods and yielded an SD of 10.9%. The method was capable of estimating transverse flow components precisely but underestimated the flow with small beam-to-flow angles. The sequence provided continuous data in both time and space throughout the volume, allowing for retrospective analysis of the flow. Moreover, B-mode planes can be selected retrospectively anywhere in the volume. This shows that tensor velocity imaging (full 3-D volumetric vector flow imaging) can be estimated in 4-D ( x, y, z, and t ) using only 62 channels in receive, making 4-D volumetric imaging implementable on current scanner hardware.

Three-Dimensional Super-Resolution Imaging Using a Row-Column Array.

A 3-D super-resolution (SR) pipeline based on data from a row-column (RC) array is presented. The 3-MHz RC array contains 62 rows and 62 columns with a half wavelength pitch. A synthetic aperture (SA) pulse inversion sequence with 32 positive and 32 negative row emissions is used for acquiring volumetric data using the SARUS research ultrasound scanner. Data received on the 62 columns are beamformed on a GPU for a maximum volume rate of 156 Hz when the pulse repetition frequency is 10 kHz. Simulated and 3-D printed point and flow microphantoms are used for investigating the approach. The flow microphantom contains a 100- [Formula: see text] radius tube injected with the contrast agent SonoVue. The 3-D processing pipeline uses the volumetric envelope data to find the bubble's positions from their interpolated maximum signal and yields a high resolution in all three coordinates. For the point microphantom, the standard deviation on the position is (20.7, 19.8, 9.1) [Formula: see text]. The precision estimated for the flow phantom is below [Formula: see text] in all three coordinates, making it possible to locate structures on the order of a capillary in all three dimensions. The RC imaging sequence's point spread function has a size of 0.58 × 1.05 × 0.31 mm3 ( 1.17λ×2.12λ×0.63λ ), so the possible volume resolution is 28900 times smaller than for SA RC B-mode imaging.