Contrast-enhanced ultrasound imaging using capacitive micromachined ultrasonic transducers.

Capacitive micromachined ultrasonic transducers (CMUTs) have a nonlinear relationship between the applied voltage and the emitted signal, which is detrimental to conventional contrast enhanced ultrasound (CEUS) techniques. Instead, a three-pulse amplitude modulation (AM) sequence has been proposed, which is not adversely affected by the nonlinearly emitted harmonics. In this paper, this is shown theoretically, and the performance of the sequence is verified using a 4.8 MHz linear capacitive micromachined ultrasonic transducer (CMUT) array, and a comparable lead zirconate titanate (PZT) array, across 6-60 V applied alternating current (AC) voltage. CEUS images of the contrast agent SonoVue flowing through a 3D printed hydrogel phantom showed an average enhancement in contrast-to-tissue ratio (CTR) between B-mode and CEUS images of 49.9 and 37.4 dB for the PZT array and CMUT, respectively. Furthermore, hydrophone recordings of the emitted signals showed that the nonlinear emissions from the CMUT did not significantly degrade the cancellation in the compounded AM signal, leaving an average of 2% of the emitted power between 26 and 60 V of AC. Thus, it is demonstrated that CMUTs are capable of CEUS imaging independent of the applied excitation voltage when using a three-pulse AM sequence.

Accurate prediction of transmission through a lensed row-column addressed array.

Using a diverging lens on a row-column array (RCA) can increase the size of its volumetric image and thus significantly improve its clinical value. Here, a ray tracing method is presented to predict the position of the transmitted wave so that it can be used to make beamformed images. The usable transmitted field-of-view (FOV) is evaluated for a lensed 128 + 128 element RCA by comparing the theoretic prediction of the emitted wavefront position with three-dimensional (3D) finite element simulation of the emitted field. The FOV of the array is found to be 122° ± 2° in the direction orthogonal to the emitting elements and 28.5°-51.2°, depending on depth and element position, for the direction lying along the element. Moreover, the proposed ray tracing method is compared with a simpler thin lens model, and it is shown that the improved accuracy of the proposed method can increase the usable transmitted FOV up to 25.1°.

Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicopathological parameters.

Enhancer of zeste homolog 2 (EZH2) plays an important role in tumor development and progression by interacting with histone and nonhistone proteins. In the current study, we analyzed prevalence and prognostic impact of EZH2 in prostate cancer. EZH2 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12400 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence and molecular subtypes defined by ERG status as well as genomic deletions of 3p, 5q, 6q and PTEN. EZH2 immunostaining was detectable in 56.6% of 10168 interpretable cancers and considered strong in 1.1%, moderate in 12.2% and weak in 43.3% of cases. High EZH2 expression was strongly associated with high Gleason grade (P < 0.0001), advanced pathological tumor stage (P < 0.0001), positive nodal status (P < 0.0001), elevated preoperative PSA level (P = 0.0066), early PSA recurrence (P < 0.0001) and increased cell proliferation P < 0.0001). High-level EZH2 staining was also associated with TMPRSS2:ERG rearrangement and ERG expression in prostate cancers (P < 0.0001) and was linked to deletions of PTEN, 6q15, 5q21 and 3p13 (P < 0.0001 each) particularly in ERG-negative cancers. The prognostic impact of EZH2 was independent of established pre- and postoperatively assessed clinicopathological parameters. EZH2 has strong prognostic impact in prostate cancer and might contribute to the development of a fraction of genetically instable and particularly aggressive prostate cancers. EZH2 analysis might therefore be of clinical value for risk stratification of prostate cancer.

Modal radiation patterns of baffled circular plates and membranes.

The far field velocity potential and radiation pattern of baffled circular plates and membranes are found analytically using the full set of modal velocity profiles derived from the corresponding equation of motion. The derivation is valid for a plate or membrane subjected to an external excitation force, which is used as a sound receiver in any medium or as a sound transmitter in a gaseous medium. A general, concise expression is given for the radiation pattern of any mode of the membrane and the plate with arbitrary boundary conditions. Specific solutions are given for the four special cases of a plate with clamped, simply supported, and free edge boundary conditions as well as for the membrane. For all non-axisymmetric modes, the velocity potential along the axis of the radiator is found to be strictly zero. In the long wavelength limit, the radiation pattern of all axisymmetric modes approaches that of a monopole, while the non-axisymmetric modes exhibit multipole behavior. Numerical results are also given, demonstrating the implications of having non-axisymmetric excitation using both a point excitation with varying eccentricity and a homogeneous excitation acting on half of the circular radiator.

Variations in deep-sea methane seepage linked to millennial-scale changes in bottom water temperatures ~ 50-6 ka, NW Svalbard margin.

During the last glaciation, the northern hemisphere experienced profound millennial-scale changes (termed Dansgaard-Oeschger (DO) events) in atmospheric and oceanic temperatures. In the North Atlantic, the fluctuations resulted in extremely unstable bottom water conditions with bottom water temperatures (BWT) varying up to > 5 °C. We have studied these changes in a core from 1,300 m water depth at Vestnesa Ridge, northwestern Svalbard margin to investigate a possible connection between BWT and seepage of methane from the seafloor covering the period ~ 50-6 ka. Beneath Vestnesa Ridge, gas hydrates containing vast amounts of methane are kept stable due to the high pressure and low temperatures. Release of gas is shown by numerous pockmarks on the seafloor. The pockmarks at 1,300 m water depth are presently inactive, but they bear witness of earlier activity. Our study shows that from ~ 50-6 ka, the core site experienced repeated increases in BWT and in the emissions of gas, both following the pattern of the DO events. This correspondence in time scale indicates that BWT was the primary forcing factor for the variability in methane release. However, the releases were delayed by up to > 1,000 years compared to the initial increase in BWT.

Diverging Polymer Acoustic Lens Design for High-Resolution Row-Column Array Ultrasound Transducers.

Spherical diverging acoustic lenses mounted on flat 2-D row-column-addressed (RCA) ultrasound transducers have shown the potential to extend the field of view (FOV) from a rectilinear to a curvilinear volume region and, thereby, enable 3-D imaging of large organs. Such lenses are usually designed for small aperture low-frequency transducers, which have limited resolution. Moreover, they are made of off-the-shelf pieces of materials, which leaves no room for optimization. We hypothesize that acoustic lenses can be designed to fit high-resolution transducers, and they can be fabricated in a fast, cost-effective, and flexible manner using a combination of 3-D printing and casting or computer numerical control (CNC) machining techniques. These lenses should increase the FOV of the array while preserving the image quality. In this work, such lenses are made in concave, convex, and compound spherical shapes and from thermoplastics and thermosetting polymers. Polymethylpentene (TPX), polystyrene (PS), polypropylene (PP), polymethyl methacrylate (PMMA), polydimethylsiloxane (PDMS), and room-temperature-vulcanizing (RTV) silicone diverging lenses have been fabricated and mounted on a 128 + 128 6-MHz RCA transducer. The performances of the lenses have been assessed and compared in terms of FOV, signal-to-noise ratio (SNR), bandwidth, and potential artifacts. The largest FOV (24.0.) is obtained with a 42.64-mm radius PMMA-RTV compound lens, which maintains a decent fractional bandwidth (53%) and SNR at 6 MHz (.9.1-dB amplitude drop compared with the unlensed transducer). The simple PMMA TPX, PS, PP, PDMS, and RTV lenses provide an FOV of 12.2°, 6.3°, 8.1°, 11.7°, 0.6°, and 10.4°; a fractional bandwidth of 97%, 46%, 103%, 46%, 97%, 53%, and 49%; and an amplitude drop of -5.2, -4.4, -2.8, -15.4, -6.0, and -1.8 dB, respectively. This work demonstrates that thermoplastics are suitable materials for fabricating low-attenuation convex diverging lenses for large-aperture, high-frequency 2-D transducers. This is highly desired to achieve high-resolution volumetric imaging of large organs.

Underestimation of Flow Velocity in 2-D Super-Resolution Ultrasound Imaging.

Velocity estimation in ultrasound imaging is a technique to measure the speed and direction of blood flow. The flow velocity in small blood vessels, i.e., arterioles, venules, and capillaries, can be estimated using super-resolution ultrasound imaging (SRUS). However, the vessel width in SRUS is relatively small compared with the full-width-half-maximum of the ultrasound beam in the elevation direction (FWHMy), which directly impacts the velocity estimation. By taking into consideration the small vessel widths in SRUS, it is hypothesized that the velocity is underestimated in 2-D super-resolution ultrasound imaging when the vessel diameter is smaller than the FWHMy. A theoretical model is introduced to show that the velocity of a 3-D parabolic velocity profile is underestimated by up to 33% in 2-D SRUS, if the width of the vessel is smaller than the FWHMy. This model was tested using Field II simulations and 3-D printed micro-flow hydrogel phantom measurements. A Verasonics Vantage 256™ scanner and a GE L8-18i-D linear array transducer with FWHMy of approximately 770 µm at the elevation focus were used in the simulations and measurements. Simulations of different parabolic velocity profiles showed that the velocity underestimation was 36.8%±1.5% (mean±standard deviation). The measurements showed that the velocity was underestimated by 30%±6.9%. Moreover, the results of vessel diameters, ranging from 0.125×FWHMy to 3×FWHMy, indicate that velocities are estimated according to the theoretical model. The theoretical model can, therefore, be used for the compensation of velocity estimates under these circumstances.

Super-Resolution Ultrasound Imaging Using the Erythrocytes-Part I: Density Images.

A new approach for vascular super-resolution (SR) imaging using the erythrocytes as targets (SUper-Resolution ultrasound imaging of Erythrocytes (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 (MI) for ultrasound scanning for an increased penetration depth. A synthetic aperture (SA) ultrasound sequence was employed with 12 virtual sources (VSs) using a 10-MHz GE L8-18i-D linear array hockey stick probe. The axial resolution was [Formula: see text]m) and the lateral resolution was [Formula: see text]m). Field IIpro simulations were conducted on 12.5- µ m radius vessel pairs with varying separations. A vessel pair with a separation of 70 µ m 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 SR imaging with a SonoVue contrast agent. Afterward, the renal vasculature was filled with the ex vivo micro-computed tomography (CT) contrast agent Microfil, excised, and scanned in a micro-CT scanner at both a 22.6- µ m voxel size for 11 h and for 20 h in a 5- µ m voxel size for validating the SURE images. Comparing the SURE and micro-CT images revealed that vessels with a diameter of 28 µ m, 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 and 10 s. The vessel structure in the cortex was also similar to the SURE and SR images. Fourier ring correlation (FRC) indicated a resolution capability of 29 µ m. 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-Part 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 with 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 article 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 (SA) imaging, motion estimation, echo canceling, peak detection, and recursive nearest-neighbor (NN) tracker. The SURE tracking pipeline is capable of distinguishing the flow direction and separating tubes of a simulated Field II phantom with 125-25- [Formula: see text] wall-to-wall tube distances, as well as a 3-D printed hydrogel micr-flow phantom with 100-60- [Formula: see text] wall-to-wall channel distances. The comparison of an in vivo SURE scan of a Sprague-Dawley rat kidney with ULM and micro-computed tomography (CT) scans with voxel sizes of 26.5 and [Formula: see text] 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.

Dynamics of Mid-Palaeocene North Atlantic rifting linked with European intra-plate deformations.

The process of continental break-up provides a large-scale experiment that can be used to test causal relations between plate tectonics and the dynamics of the Earth's deep mantle. Detailed diagnostic information on the timing and dynamics of such events, which are not resolved by plate kinematic reconstructions, can be obtained from the response of the interior of adjacent continental plates to stress changes generated by plate boundary processes. Here we demonstrate a causal relationship between North Atlantic continental rifting at approximately 62 Myr ago and an abrupt change of the intra-plate deformation style in the adjacent European continent. The rifting involved a left-lateral displacement between the North American-Greenland plate and Eurasia, which initiated the observed pause in the relative convergence of Europe and Africa. The associated stress change in the European continent was significant and explains the sudden termination of a approximately 20-Myr-long contractional intra-plate deformation within Europe, during the late Cretaceous period to the earliest Palaeocene epoch, which was replaced by low-amplitude intra-plate stress-relaxation features. The pre-rupture tectonic stress was large enough to have been responsible for precipitating continental break-up, so there is no need to invoke a thermal mantle plume as a driving mechanism. The model explains the simultaneous timing of several diverse geological events, and shows how the intra-continental stratigraphic record can reveal the timing and dynamics of stress changes, which cannot be resolved by reconstructions based only on plate kinematics.

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.

Solving the Helmholtz equation in conformal mapped ARROW structures using homotopy perturbation method.

The scalar wave equation, or Helmholtz equation, describes within a certain approximation the electromagnetic field distribution in a given system. In this paper we show how to solve the Helmholtz equation in complex geometries using conformal mapping and the homotopy perturbation method. The solution of the mapped Helmholtz equation is found by solving an infinite series of Poisson equations using two dimensional Fourier series. The solution is entirely based on analytical expressions and is not mesh dependent. The analytical results are compared to a numerical (finite element method) solution.

MEMS Bragg grating force sensor.

We present modeling, design, fabrication and characterization of a new type of all-optical frequency modulated MEMS force sensor based on a mechanically amplified double clamped waveguide beam structure with integrated Bragg grating. The sensor is ideally suited for force measurements in harsh environments and for remote and distributed sensing and has a measured sensitivity of -14 nm/N, which is several times higher than what is obtained in conventional fiber Bragg grating force sensors.

Plate-wide stress relaxation explains European Palaeocene basin inversions.

During Late Cretaceous and Cenozoic times, many Palaeozoic and Mesozoic rifts and basin structures in the interior of the European continent underwent several phases of inversion (the process of shortening a previously extensional basin). The main phases occurred during the Late Cretaceous and Middle Palaeocene, and have been previously explained by pulses of compression, mainly from the Alpine orogen. Here we show that the main phases differed both in structural style and cause. The Cretaceous phase was characterized by narrow uplift zones, reverse activation of faults, crustal shortening, and the formation of asymmetric marginal troughs. In contrast, the Middle Palaeocene phase was characterized by dome-like uplift of a wider area with only mild fault movements, and formation of more distal and shallow marginal troughs. A simple flexural model explains how domal, secondary inversion follows inevitably from primary, convergence-related inversion on relaxation of the in-plane tectonic stress. The onset of relaxation inversions was plate-wide and simultaneous, and may have been triggered by stress changes caused by elevation of the North Atlantic lithosphere by the Iceland plume or the drop in the north-south convergence rate between Africa and Europe.

All-optical frequency modulated high pressure MEMS sensor for remote and distributed sensing.

We present the design, fabrication and characterization of a new all-optical frequency modulated pressure sensor. Using the tangential strain in a circular membrane, a waveguide with an integrated nanoscale Bragg grating is strained longitudinally proportional to the applied pressure causing a shift in the Bragg wavelength. The simple and robust design combined with the small chip area of 1 × 1.8 mm2 makes the sensor ideally suited for remote and distributed sensing in harsh environments and where miniaturized sensors are required. The sensor is designed for high pressure applications up to 350 bar and with a sensitivity of 4.8 pm/bar (i.e., 350 ×10(5) Pa and 4.8 × 10(-5) pm/Pa, respectively).

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.

Novel designs for application specific MEMS pressure sensors.

In the framework of developing innovative microfabricated pressure sensors, we present here three designs based on different readout principles, each one tailored for a specific application. A touch mode capacitive pressure sensor with high sensitivity (14 pF/bar), low temperature dependence and high capacitive output signal (more than 100 pF) is depicted. An optical pressure sensor intrinsically immune to electromagnetic interference, with large pressure range (0-350 bar) and a sensitivity of 1 pm/bar is presented. Finally, a resonating wireless pressure sensor power source free with a sensitivity of 650 KHz/mmHg is described. These sensors will be related with their applications in harsh environment, distributed systems and medical environment, respectively. For many aspects, commercially available sensors, which in vast majority are piezoresistive, are not suited for the applications proposed.

Detection and Localization of Ultrasound Scatterers Using Convolutional Neural Networks.

Delay-and-sum (DAS) beamforming is unable to identify individual scatterers when their density is so high that their point spread functions overlap. This paper proposes a convolutional neural network (CNN)-based method to detect and localize high-density scatterers, some of which are closer than the resolution limit of delay-and-sum (DAS) beamforming. A CNN was designed to take radio frequency channel data and return non-overlapping Gaussian confidence maps. The scatterer positions were estimated from the confidence maps by identifying local maxima. On simulated test sets, the CNN method with three plane waves achieved a precision of 1.00 and a recall of 0.91. Localization uncertainties after excluding outliers were ±46 [Formula: see text] (outlier ratio: 4%) laterally and ±26 [Formula: see text] (outlier ratio: 1%) axially. To evaluate the proposed method on measured data, two phantoms containing cavities were 3-D printed and imaged. For the phantom study, the training data were modified according to the physical properties of the phantoms and a new CNN was trained. On an uniformly spaced scatterer phantom, a precision of 0.98 and a recall of 1.00 were achieved with the localization uncertainties of ±101 [Formula: see text] (outlier ratio: 1%) laterally and ±37 [Formula: see text] (outlier ratio: 1%) axially. On a randomly spaced scatterer phantom, a precision of 0.59 and a recall of 0.63 were achieved. The localization uncertainties were ±132 [Formula: see text] (outlier ratio: 0%) laterally and ±44 [Formula: see text] with a bias of 22 [Formula: see text] (outlier ratio: 0%) axially. This method can potentially be extended to detect highly concentrated microbubbles in order to shorten data acquisition times of super-resolution ultrasound imaging.

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.

Agricultural lime disturbs natural strontium isotope variations: Implications for provenance and migration studies.

The application of 87Sr/86Sr in prehistoric mobility studies requires accurate strontium reference maps. These are often based from present-day surface waters. However, the use of agricultural lime in low to noncalcareous soils can substantially change the 87Sr/86Sr compositions of surface waters. Water unaffected by agriculture in western Denmark has an average 87Sr/86Sr ratio of 0.7124 as compared to an average of 0.7097 in water from nearby farmland. The 87Sr/86Sr ratio obtained from samples over 1.5 km along a stream, which originates in a forest and flows through lime-treated farmland, decreased from 0.7131 to 0.7099. Thus, 87Sr/86Sr-based mobility and provenance studies in regions with low to noncalcareous soils should be reassessed. For example, reinterpreting the iconic Bronze Age women at Egtved and Skrydstrup using values unaffected by agricultural lime indicates that it is most plausible that these individuals originated close to their burial sites and not far abroad as previously suggested.