An in vivo range verification technology for proton beam cancer therapy, preferably in real-time and with submillimeter resolution, is desired to reduce the present uncertainty in dose localization. Acoustical imaging technologies exploiting possible local interactions between protons and microbubbles or nanodroplets might be an interesting option. Unfortunately, a theoretical model capable of characterising the acoustical field generated by an individual proton on nanometer and micrometer scales is still missing. In this work, such a model is presented. The proton acoustic field is generated by the adiabatic expansion of a region that is locally heated by a passing proton. To model the proton heat deposition, secondary electron production due to protons has been quantified using a semi-empirical model based on Rutherford's scattering theory, which reproduces experimentally obtained electronic stopping power values for protons in water within 10% over the full energy range. The electrons transfer energy into heat via electron-phonon coupling to atoms along the proton track. The resulting temperature increase is calculated using an inelastic thermal spike model. Heat deposition can be regarded as instantaneous, thus, stress confinement is ensured and acoustical initial conditions are set. The resulting thermoacoustic field in the nanometer and micrometer range from the single proton track is computed by solving the thermoacoustic wave equation using k-space Green's functions, yielding the characteristic amplitudes and frequencies present in the acoustic signal generated by a single proton in an aqueous medium. Wavefield expansion and asymptotic approximations are used to extend the spatial and temporal ranges of the proton acoustic field.

Transcranial ultrasound imaging (TUI) is a diagnostic modality with numerous applications, but unfortunately, it is hindered by phase aberration caused by the skull. In this article, we propose to reconstruct a transcranial B-mode image with a refraction-corrected synthetic aperture imaging (SAI) scheme. First, the compressional sound velocity of the aberrator (i.e., the skull) is estimated using the bidirectional headwave technique. The medium is described with four layers (i.e., lens, water, skull, and water), and a fast marching method calculates the travel times between individual array elements and image pixels. Finally, a delay-and-sum algorithm is used for image reconstruction with coherent compounding. The point spread function (PSF) in a wire phantom image and reconstructed with the conventional technique (using a constant sound speed throughout the medium), and the proposed method was quantified with numerical synthetic data and experiments with a bone-mimicking plate and a human skull, compared with the PSF achieved in a ground truth image of the medium without the aberrator (i.e., the bone plate or skull). A phased-array transducer (P4-1, ATL/Philips, 2.5 MHz, 96 elements, pitch $=$ 0.295 mm) was used for the experiments. The results with the synthetic signals, the bone-mimicking plate, and the skull indicated that the proposed method reconstructs the scatterers with an average lateral/axial localization error of 0.06/0.14 mm, 0.11/0.13 mm, and 1.0/0.32 mm, respectively. With the human skull, an average contrast ratio (CR) and full-width-half-maximum (FWHM) of 37.1 dB and 1.75 mm were obtained with the proposed approach, respectively. This corresponds to an improvement of CR and FWHM by 7.1 dB and 36% compared with the conventional method, respectively. These numbers were 12.7 dB and 41% with the bone-mimicking plate.

The utility of ultrasound imaging and therapy with microbubbles may be greatly enhanced by determining their impulse-response dynamics as a function of size and composition. Prior methods for microbubble characterization utilizing high-speed cameras, acoustic transducers and laser-based techniques typically scan a limited frequency range. Here, we report on the use of a novel photoacoustic technique to measure the impulse response of single microbubbles. Individual microbubbles are driven with a broadband photoacoustic wave generated by a nanosecond-pulse laser illuminating an optical absorber. The resulting microbubble oscillations were detected by following transmission of a second laser as it passes twice through the microbubble. The system could even resolve oscillations resulting from a single-shot. As a proof-of-concept study, the size-dependent, linear impulse response of lipid-coated microbubbles was characterized using this technique. This unique method of microbubble characterization with exceptional spatiotemporal resolution opens new avenues for capturing and analyzing microbubble system dynamics.

Skeletal muscles generate force, enabling movement through a series of fast electro-mechanical activations coordinated by the central nervous system. Understanding the underlying mechanism of such fast muscle dynamics is essential in neuromuscular diagnostics, rehabilitation medicine and sports biomechanics. The unique combination of electromyography (EMG) and ultrafast ultrasound imaging (UUI) provides valuable insights into both electrical and mechanical activity of muscle fibers simultaneously, the excitation-contraction (E-C) coupling. In this feasibility study we propose a novel non-invasive method to simultaneously track the propagation of both electrical and mechanical waves in muscles using high-density electromyography and ultrafast ultrasound imaging (5000 fps). Mechanical waves were extracted from the data through an axial tissue velocity estimator based on one-lag autocorrelation. The E-C coupling in electrically evoked twitch contractions of the Biceps Brachii in healthy participants could successfully be tracked. The excitation wave (i.e. action potential) had a velocity of 3.9±0.5ms-1 and the subsequent mechanical (i.e. contraction) wave had a velocity of 3.5±0.9ms-1. The experiment showed evidence that contracting sarcomeres that were already activated by the action potential (AP) pull on sarcomeres that were not yet reached by the AP, which was corroborated by simulated contractions of a newly developed multisegmental muscle fiber model, consisting of 500 sarcomeres in series. In conclusion, our method can track the electromechanical muscle dynamics with high spatio-temporal resolution. Ultimately, characterizing E-C coupling in patients with neuromuscular diseases (e.g. Duchenne or Becker muscular dystrophy) may assess contraction efficiency, monitor the progression of the disease, and determine the efficacy of new treatment options.

Transcranial ultrasound imaging is a suitable technology for diagnosis of strokes as it is safe, portable, relatively inexpensive and available in emergency medicine services, however it currently offers poor image quality due to the phase aberration caused by the human skull. In this work, we evaluate an approach for two-dimensional transcranial ultrasound imaging through the temporal window of a sagittally-cut human skull using the commercial P4-1 phased-array probe, where the position and true geometry of the bone layer is estimated for accurate phase aberration correction. The medium is described with four layers (probe lens, soft tissue, skull, soft tissue). A synthetic aperture imaging scheme is used as the transmission of spherical wave-fronts facilitates the modeling of refraction. First, the bidirectional headwave method estimates the compressional wave-speed in the temporal bone. Next, a fast marching method calculates the travel times between individual array elements and image pixels to be used with delay-and-sum reconstruction algorithm. Sound speed maps are generated with adaptive beamforming including the successive segmentation of the near and far surfaces of the cortical bone layer. The proposed method reconstructs the scatterers with an average lateral and axial localization error of about 1.25 mm and 0.37 mm, compared to the ground truth, respectively. In average, it improves the contrast ratio and lateral resolution by 7 dB and 36%, compared to the conventional method, respectively.

In the above article [1], the authors regret that there was a mistake in calculating the mol% of the microbubble coating composition used. For all experiments, the unit in mg/mL was utilized and the conversion mistake only came when converting to mol% in order to define the ratio between the coating formulation components. The correct molecular weight of PEG-40 stearate is 2046.54 g/mol [2], [3], not 328.53 g/mol. On page 556, Table I should read as shown here.

The potential of proton therapy to improve the conformity of the delivered dose to the tumor volume is currently limited by range uncertainties. Injectable superheated nanodroplets have recently been proposed for ultrasound-based in vivo range verification, as these vaporize into echogenic microbubbles on proton irradiation. In previous studies, offline ultrasound images of phantoms with dispersed nanodroplets were acquired after irradiation, relating the induced vaporization profiles to the proton range. However, the aforementioned method did not enable the counting of individual vaporization events, and offline imaging cannot provide real-time feedback. In this study, we overcame these limitations using high-frame-rate ultrasound imaging with a linear array during proton irradiation of phantoms with dispersed perfluorobutane nanodroplets at 37°C and 50°C. Differential image analysis of subsequent frames allowed us to count individual vaporization events and to localize them with a resolution beyond the ultrasound diffraction limit, enabling spatial and temporal quantification of the interaction between ionizing radiation and nanodroplets. Vaporization maps were found to accurately correlate with the stopping distribution of protons (at 50°C) or secondary particles (at both temperatures). Furthermore, a linear relationship between the vaporization count and the number of incoming protons was observed. These results indicate the potential of real-time high-frame-rate contrast-enhanced ultrasound imaging for proton range verification and dosimetry.

In the above article [1], we mentioned that the superposition of the different symmetric (S) modes in the frequencywavenumber (f-k) domain results in a high-intensity region where its slope corresponds to the longitudinal wave speed in the slab. However, we have recently understood that this highintensity region belongs to the propagation of a wave called lateral wave or head wave [2]-[5]. It is generated if the longitudinal sound speed of the aberrator (i.e., the PVC slab) is larger than that of water and if the incident wavefront is curved. When the incidence angle at the interface between water and PVC is near the critical angle, the refracted wave in PVC reradiates a small part of its energy into the fluid (i.e., the head wave). As discussed in [4], if the thickness of the waveguide is larger than the wavelength, the first arriving signal is the head wave. This is also the case in our study [1] where the ultrasound wavelength of a compressional wave in PVC was close to 1 mm, and a PVC slab with a thickness of 8 mm was used. In this Erratum, numerical simulations (with SimSonic solver [5]) and experimental measurements (with the same PVC slab used in [1]) are conducted to investigate the propagation of the Lamb waves and head wave in detail, for the specific configuration studied in [1]. The pitch and element width of the P4-1 probe were used to assemble the numerical signals [see Fig. 1(a)]. If all the data simulated for the P4-1 probe is used, there indeed is a region with a slope [see Fig. 1(b)], but this has a low intensity, meaning that the head wave has a relatively low amplitude compared to the specular reflections. Once the head wave is isolated, the sound speed can be estimated with a 0.3% error from the f-k domain plot [see Fig. 1(c)]. No significant difference is observed between Fig. 1(b) and (d), in which the head wave is muted. Our experimental results show that if only the head wave (the first arriving signal) is used [see Fig. 2(b)], the slope of the linear fitting in the f-k domain also yields the longitudinal sound speed of the PVC with a 0.3% error. Of note, the signal processing (i.e., linear fitting in the f-k domain) used in our study [1] still works for the head wave and is correct provided that the aberrator is parallel to the probe [6]. Also, in [1, p. 6], it is mentioned that “the curved structure of the skull might lead to other types of modes, such as the torsional modes.” Here, we acknowledge that this sentence is not correct, as torsional modes only exist in cylindrical waveguides or rectangular bars. We would like to mention that Guillaume Renaud is added as a coauthor to acknowledge his contribution to the findings reported in this Erratum.

The interaction between an acoustically driven microbubble and a surface is of interest for a variety of applications, such as ultrasound imaging therapy. Prior investigations have mainly focused on acoustic effects of a rigid boundary, where it was generally observed that the wall increases inertia and reduces the microbubble resonance frequency. Here we investigate the response of a lipid-coated microbubble adherent to a rigid wall. Firm adhesion between the microbubble and a glass surface was achieved through either specific (biotin/avidin) or nonspecific (lipid/glass) interactions. Total internal reflection fluorescence microscopy was used to verify conditions leading to either adhesion or non-adhesion of the bubble to a glass or rigid polymer surface. Individual microbubbles were driven acoustically to sub-nanometer-scale radial oscillations using a photoacoustic technique. Remarkably, adherent microbubbles were shown to have a higher resonance frequency than non-adherent microbubbles resting against the wall. Analysis of the resonance curves indicates that adhesion stiffens the bubble by an apparent increase in the shell elasticity term and decrease in the shell viscosity. Based on these results, we conclude that surface adhesion is dominant over acoustic effects for low-amplitude microbubble oscillations.

Phase aberration in transcranial ultrasound imaging (TUI) caused by the human skull leads to an inaccurate image reconstruction. In this article, we present a novel method for estimating the speed of sound and an adaptive beamforming technique for phase aberration correction in a flat polyvinylchloride (PVC) slab as a model for the human skull. First, the speed of sound of the PVC slab is found by extracting the overlapping quasi-longitudinal wave velocities of symmetrical Lamb waves in the frequency-wavenumber domain. Then, the thickness of the plate is determined by the echoes from its front and back side. Next, an adaptive beamforming method is developed, utilizing the measured sound speed map of the imaging medium. Finally, to minimize reverberation artifacts caused by strong scatterers (i.e., needles), a dual probe setup is proposed. In this setup, we image the medium from two opposite directions, and the final image can be the minimum intensity projection of the inherently co-registered images of the opposed probes. Our results confirm that the Lamb wave method estimates the longitudinal speed of the slab with an error of 3.5% and is independent of its shear wave speed. Benefiting from the acquired sound speed map, our adaptive beamformer reduces (in real time) a mislocation error of 3.1, caused by an 8 mm slab, to 0.1 mm. Finally, the dual probe configuration shows 7 dB improvement in removing reverberation artifacts of the needle, at the cost of only 2.4-dB contrast loss. The proposed image formation method can be used, e.g., to monitor deep brain stimulation procedures and localization of the electrode(s) deep inside the brain from two temporal bones on the sides of the human skull.

This paper presents the integration steps towards a prototype forward-looking intra-vascular ultrasound probe. An ASIC (Application Specific Integrated Circuit) is laser cut to create a 1.6mm circular shaped die that can be integrated at the tip of a small catheter. The ASIC is designed such that it can be used to transmit and receive on 64 piezo-electric transducers while using a single cable for the supply, communication, transmit signals and amplified receive signals. Piezo elements are directly integrated on top of the ASIC to create a miniature probe.Electrical tests show that the circuitry still operates correctly after laser cutting. The functionality of a prototype has been successfully demonstrated in a 3D imaging experiment.

Current methods to track the progression and evaluate treatment of muscular dystrophies are scarce. The electromechanical delay (EMD), defined as the time lag from muscle electrical activity to motion onset, has been proposed as a biomarker, but provides only limited insight in the pathophysiol-ogy of muscle function. This work proposes and evaluates a novel method to track the propagation of electromechanical waves in muscles, using high density electromyography and ultrafast ultrasound imaging. Muscle contractions in three healthy subjects were evoked by electrical stimulation, and the subsequent propagating action potentials were successfully tracked in all 90 trials. Contractile waves were detected in 83 recordings. Detection rate varied across muscle depth. Mean (SD) velocities for the action potential were 3.71 (0.08) m/s, 4.73 (0.35) m/s and 3.27 (0.09) m/s for participant 1, 2 and 3 respectively. Velocities for the contractile wave were 3.83 (1.07) m/s, 3.32 (0.78) m/s and 3.41 (0.69) m/s for participant 1, 2 and 3 respectively. In conclusion, our technique can track the fast muscular electromechanical dynamics with high spatiotemporal resolution by combining ultrafast ultrasound imaging and high-density electromyography.

Deep brain stimulation (DBS) is used to modify the brain function. Localization of the electrode(s) used in DBS is an important mater since the success of the treatment highly depends on it. Transcranial ultrasound imaging (TUI) can be a proper candidate to monitor the electrode(s), but it is affected by the phase aberration caused by the skull bone. To address this issue, in this paper, we propose a novel beamforming method based on the sound velocity map of the imaging medium. For each combination of the imaging grid and element of the array, an averaged sound speed (ASD) is calculated. Then, the ASD is used inside a delay-and-sum beamforming method. The numerical results show that the proposed method compensates the phase aberration caused by the skull having a thickness of 5 mm with a sound speed twice of the imaging medium (i.e., water). The proposed method can be implemented in a real-time manner, which makes it a great candidate to be used in operation rooms for surgeries.

We show here that adhesion to a solid substrate increases the resonance frequency of a lipid-coated microbubble by causing an apparent increase in shell stiffness. Using our previously developed photoacoustic measurement technique to drive individual microbubbles into small-amplitude oscillations, we found that biotinylated microbubbles adherent to a streptavidin-coated glass coverslip had much higher resonance frequencies than unbound microbubbles. The frequency responses of the bound microbubbles agree well with a linearized form of the modified Rayleigh-Plesset model with an added increase of shell elasticity. The apparent shell elasticity increased from 0.5 N/m for unbound microbubbles to 2.6 N/m. These findings may be used to better understand microbubble dynamics for applications in ultrasound imaging and therapy.

Effective treatment of movement disorders requires thorough understanding of human limb control. Joint dynamics can be assessed using robotic manipulators and system identification. Due to tendon compliance, joint angle and muscle length are not proportional. This study uses plane-wave ultrasound imaging to investigate the dynamic relation between ankle joint angle and muscle fiber stretch. The first goal is to determine the feasibility of using ultrasound imaging with system identification; the second goal is to assess the relation between ankle angle, muscle stretch, and reflex size. Soleus and gastrocnemius muscle stretches were assessed with ultrasound imaging and image tracking. For small (1° SD) continuous motions, muscle stretch was proportional to ankle angle during a relax task, but images were too noisy to make that assessment during an active position task. For transient perturbations with high velocity (> 90°/s) the muscle length showed oscillations that were not present in the ankle angle, demonstrating a non-proportional relationship and muscle-tendon interaction. The gastrocnemius velocity predicted the size of the short-latency reflex better than the ankle angle velocity. Concluding, plane-wave ultrasound muscle imaging is feasible for system identification experiments and shows that muscle length and ankle angle are proportional during a relax task with small continuous perturbations.

Phase aberration of focused ultrasound by tissue structure causes focus degradation and reduces the quality of B-mode images. Refraction at the boundary between subcutaneous fat and muscle is one of the dominant factors behind such degradation. To correct this, we propose a refraction compensation method in which ultrasound is transmitted and received twice. The boundary shape between different tissues is detected by the first ultrasound transmission. Next, ultrasound rays from probe elements to the target are calculated taking refraction into account. Corrected delay times are calculated from the length of the rays and the sound velocity of the medium. Finally, ultrasound is transmitted a second time using the corrected delay time and a B-mode image is created. We evaluate the correction effect of the proposed method by numerical simulation and experiments with non-compensated and refraction-compensated cases of intensity distribution of the focused ultrasound. Results show that focus degradation is effectively corrected by the proposed method.

This paper presents the design, fabrication and characterization of a miniature PZT-on-CMOS matrix transducer for real-time pediatric 3-dimensional (3D) transesophageal echocardiography (TEE). This 3D TEE probe consists of a 32 × 32 array of PZT elements integrated on top of an Application Specific Integrated Circuit (ASIC). We propose a partitioned transmit/receive array architecture wherein the 8 × 8 transmitter elements, located at the centre of the array, are directly wired out and the remaining receive elements are grouped into 96 sub-arrays of 3 × 3 elements. The echoes received by these sub-groups are locally processed by micro-beamformer circuits in the ASIC that allow pre-steering up to ±37°. The PZT-on-CMOS matrix transducer has been characterized acoustically and has a centre frequency of 5.8 MHz, -6 dB bandwidth of 67%, a transmit efficiency of 6 kPa/V at 30 mm, and a receive dynamic range of 85 dB with minimum and maximum detectable pressures of 5 Pa and 84 kPa respectively. The properties are very suitable for a miniature pediatric real-time 3D TEE probe.

3D ultrasound imaging is costly and complicated mostly due to the need of controlling 2D probes with high numbers of elements (≥1024). Sparse arrays are a convenient way to reduce system complexity maintaining reasonable performance. A 256-element density tapered spiral array has been recently designed and realized in a piezoelectric probe prototype. The probe has been connected to the ULA-OP 256 open scanner, which can be programmed to permit volumetric scanning in real-time. This paper reports on the first experimental measurements of transmit ultrasound fields produced by such prototype system, including multi-line transmit fields that, in combination with parallel receive beamforming, may permit real-time volumetric imaging. An average −21.3dB side-lobe level (SLL) was measured on the transmit fields., while volume rates of 35 volumes per second can be achieved.

This paper presents an area- and power-efficient application-specified integrated circuit (ASIC) for 3-D forward-looking intravascular ultrasound imaging. The ASIC is intended to be mounted at the tip of a catheter, and has a circular active area with a diameter of 1.5 mm on the top of which a 2-D array of piezoelectric transducer elements is integrated. It requires only four micro-coaxial cables to interface 64 receive (RX) elements and 16 transmit (TX) elements with an imaging system. To do so, it routes high-voltage (HV) pulses generated by the system to selected TX elements using compact HV switch circuits, digitizes the resulting echo signal received by a selected RX element locally, and employs an energy-efficient load-modulation datalink to return the digitized echo signal to the system in a robust manner. A multi-functional command line provides the required sampling clock, configuration data, and supply voltage for the HV switches. The ASIC has been realized in a 0.18-μm HV CMOS technology and consumes only 9.1 mW. Electrical measurements show 28-V HV switching and RX digitization with a 16-MHz bandwidth and 53-dB dynamic range. Acoustical measurements demonstrate successful pulse transmission and reception. Finally, a 3-D ultrasound image of a three-needle phantom is generated to demonstrate the imaging capability.

Until now, no matrix transducer has been realized for 3D transesophageal echocardiography (TEE) in pediatric patients. In 3D TEE with a matrix transducer, the biggest challenges are to connect a large number of elements to a standard ultrasound system, and to achieve a high volume rate (>200 Hz). To address these issues, we have recently developed a prototype miniaturized matrix transducer for pediatric patients with micro-beamforming and a small central transmitter. In this paper we propose two multiline parallel 3D beamforming techniques (μBF25 and μBF169) using the micro-beamformed datasets from 25 and 169 transmit events to achieve volume rates of 300 Hz and 44 Hz, respectively. Both the realizations use angle-weighted combination of the neighboring overlapping sub-volumes to avoid artifacts due to sharp intensity changes introduced by parallel beamforming. In simulation, the image quality in terms of the width of the point spread function (PSF), lateral shift invariance and mean clutter level for volumes produced by μBF25 and μBF169 are similar to the idealized beamforming using a conventional single-line acquisition with a fully-sampled matrix transducer (FS4k, 4225 transmit events). For completeness, we also investigated a 9 transmit-scheme (3 × 3) that allows even higher frame rates but found worse B-mode image quality with our probe. The simulations were experimentally verified by acquiring the μBF datasets from the prototype using a Verasonics V1 research ultrasound system. For both μBF169 and μBF25, the experimental PSFs were similar to the simulated PSFs, but in the experimental PSFs, the clutter level was ∼10 dB higher. Results indicate that the proposed multiline 3D beamforming techniques with the prototype matrix transducer are promising candidates for real-time pediatric 3D TEE.