Here we propose an ultrasound contrast-based imaging method that enables non-invasive quantitative assessment of ambient pressure changes inside the body (such as blood pressure). We subject the microbubbles in the contrast agent to two frequencies: A low-frequency (57 kHz) signal that dynamically manipulates the ambient pressure, and a series of high-frequency (4 MHz) pulses for exciting and imaging the bubble response. The imaging pulses exploit the ambient pressure sensitivity of the subharmonic microbubble response, while the low-frequency signal provided an intrinsic calibration for measurement of ambient pressure changes. We tested this approach in an in vitro setup and show that it can visualize and quantify ambient pressure differences with a sensitivity of 0.5 dB/kPa.

@en

Ultrasound contrast agents, comprised of phospholipid-coated microbubbles, can be produced as monodisperse populations using a microfluidic flow-focusing device. However, microbubble coalescence remains a significant challenge. High production temperatures (e.g., 55 °C) can be used to suppress coalescence, but it complicates the microfluidic device design and is incompatible with targeting agents and drug conjugates. This study investigates the production of monodisperse microbubbles at room temperature with the addition of the amphiphilic surfactant Pluronic F68. Two 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-based phospholipid formulations were investigated: F1, containing 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[carbonyl-methoxypolyethylene glycol] (DPPE-PEG5000), and F2, which included both DPPE-PEG5000 and polyoxyethylene(40) stearate (PEG40-stearate). We characterized the size stability and acoustic behavior of monodisperse microbubbles produced with various Pluronic F68 concentrations. Adding 5-10 mol % Pluronic F68 was found to effectively suppress coalescence and facilitated the production of monodisperse microbubbles that remained shelf stable for at least 7 days. Acoustic attenuation measurements revealed a shell stiffness ranging from 0.78 to 0.93 N/m for these microbubbles. The 10 mol % Pluronic F68 addition (10PF) demonstrated superior monodispersity and was selected for further experiments. Upon dilution, the size and resonance frequencies of both F1-10PF and F2-10PF decreased over time, though F2-10PF showed better stability compared to F1-10PF for both metrics. Both F1-10PF and F2-10PF exhibited a stronger subharmonic scattering intensity than SonoVue (clinical approved microbubbles), which offers potential for blood pressure sensing. Our study shows that incorporating Pluronic F68 facilitates the production of monodisperse microbubbles at room temperature that are stable long-term and have excellent acoustical properties, with the F2-10PF formulation demonstrating better stability than the F1-10PF.

@en

Phospholipid-coated microbubbles with a uniform acoustic response are a promising avenue for functional ultrasound sensing. A uniform acoustic response requires both a monodisperse size distribution and uniform viscoelastic shell properties. Monodisperse microbubbles can be produced in a microfluidic flow focusing device. Here, we investigate whether such monodisperse microbubbles have uniform viscoelastic shell properties and thereby a uniform “mono-acoustic” response. To this end, we visualized phase separation of the DSPC and DPPE-PEG5000 lipid shell components and measured the resonance curves of nearly 2000 single and freely floating microbubbles using a high-frequency acoustic scattering technique. The results demonstrate inhomogeneous phase-separated shell microdomains across the monodisperse bubble population, which may explain the measured inhomogeneous viscoelastic shell properties. The shell viscosity varied over an order of magnitude and the resonance frequency by a factor of two indicating both a variation in shell elasticity and in initial surface tension despite the relatively narrow size distribution.@en

Four-dimensional ultrasound imaging of complex biological systems such as the brain is technically challenging because of the spatiotemporal sampling requirements. We present computational ultrasound imaging (cUSi), an imaging method that uses complex ultrasound fields that can be generated with simple hardware and a physical wave prediction model to alleviate the sampling constraints. cUSi allows for high-resolution four-dimensional imaging of brain hemodynamics in awake and anesthetized mice.

@en

It has been previously demonstrated that applying an aberrating mask for 2D compressive imaging using a low number of sensors (elements) can significantly improve image resolution, as evaluated via the point spread function. Here we investigate the potential to apply a similar approach for 3D flow monitoring. We conducted a 3D k-Wave simulation using a 5x5 sensor array coupled to a physical coding mask, performing B-mode and power Doppler imaging on a 3D carotid artery flow model. An approximately three times smaller lateral PSF was achieved at the cost of increased background clutter level and slightly increased axial PSF. A better definition of the vessel border and finer flow speckle were observed in power Doppler imaging. Our results suggest that 3D compressive imaging using a very low sensor count of 25 with spatial coding mask has the potential to monitor 3D carotid artery flow.@en

Ultrasound (US) contrast agents consist of microbubbles ranging from 1 to 10 μm in size. The acoustical response of individual microbubbles can be studied with high-frame-rate optics or an "acoustical camera"(AC). The AC measures the relative microbubble oscillation while the optical camera measures the absolute oscillation. In this article, the capabilities of the AC are extended to measure the absolute oscillations. In the AC setup, microbubbles are insonified with a high- (25 MHz) and low-frequency US wave (1-2.5 MHz). Other than the amplitude modulation (AM) from the relative size change of the microbubble (employed in Renaud, Bosch, van der Steen, and de Jong (2012a). "An 'acoustical camera' for in vitro characterization of contrast agent microbubble vibrations,"Appl. Phys. Lett. 100(10), 101911, the high-frequency response from individual vibrating microbubbles contains a phase modulation (PM) from the microbubble wall displacement, which is the extension described here. The ratio of PM and AM is used to determine the absolute radius, R0. To test this sizing, the size distributions of two monodisperse microbubble populations (R 0 = 2.1 and 3.5 μm) acquired with the AC were matched to the distribution acquired with a Coulter counter. As a result of measuring the absolute size of the microbubbles, this "extended AC"can capture the full radial dynamics of single freely floating microbubbles with a throughput of hundreds of microbubbles per hour.

@en

We intend to develop an ultrasound compressive imaging device to perform carotid artery (CA) function and flow monitoring/imaging by using just a few single element transducers equipped with spatial coding masks. The spatially unique impulse responses can be exploited in compressive reconstructions. To explore the potential of different configurations, in this study we emulated such a device using a linear array system. We combined its elements with individual digital delays into a small number of groups. The results suggest our spatial coding mask approach based on reconstructions regularized with a least squares method has potential for CA monitoring with only 10 to 12 sensors.

@en

This paper presents an ultrasound transceiver application-specific integrated circuit (ASIC) directly integrated with an array of 12 × 80 piezoelectric transducer elements to enable next-generation ultrasound probes for 3D carotid artery imaging. The ASIC, implemented in a 0.18 µm high-voltage Bipolar-CMOS-DMOS (HV BCD) process, adopted a programmable switch matrix that allowed selected transducer elements in each row to be connected to a transmit and receive channel of an imaging system. This made the probe operate like an electronically translatable linear array, allowing large-aperture matrix arrays to be interfaced with a manageable number of system channels. This paper presents a second-generation ASIC that employed an improved switch design to minimize clock feedthrough and charge-injection effects of high-voltage metal–oxide–semiconductor field-effect transistors (HV MOSFETs), which in the first-generation ASIC caused parasitic transmis-sions and associated imaging artifacts. The proposed switch controller, implemented with cascaded non-overlapping clock generators, generated control signals with improved timing to mitigate the effects of these non-idealities. Both simulation results and electrical measurements showed a 20 dB reduction of the switching artifacts. In addition, an acoustic pulse-echo measurement successfully demonstrated a 20 dB reduction of imaging artifacts.

@en

Background and Purpose: Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection. Methods: During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest. Results: A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 μm and 1.5–2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics. Conclusion: The current study presents the potential of applying fUS during awake brain surgery. We illustrate the relevance of fUS for awake brain surgery based on its ability to capture both task-evoked functional cortical responses as well as differences in vascular characteristics between tumor and healthy tissue. As current neurosurgical practice is still pre-dominantly leaning on inherently limited pre-operative imaging techniques for tumor resection-guidance, fUS enters the scene as a promising alternative that is both anatomically and physiologically informative.

@en

Power Doppler (PD) imaging has become a staple in high frame rate ultrasound imaging due to its ability to image small vessels and slow-moving flows, such as in the case of imaging blood flow in the brain. Alternatively, color Doppler (CD) can be used to determine the one-dimensional directional information of the blood scatterers. This can help determine if the flow is arterial or venous, or distinguish between adjacent flows that have an opposite direction. Current methods for estimating 2D blood velocity vectors rely mostly on trigonometric solutions using synthetic apertures or, large plane-wave angles in transmission and sub-apertures in receive to be able to resolve the 2D vector. Relative to PD or CD techniques, these methods are more computationally expensive and have not been successfully used to image blood flow direction within micrometer sized vasculature. In this paper, we propose to use the orientations of the vessels derived from a directional spatial filter in combination with the CD signal to enhance the PD images with directional information. This approach was tested on simulated data as well as on a 2D image containing brain vasculature of a mouse.@en

We study the design of a coding mask for pulse-echo ultrasound imaging. We are interested in the scenario of a single receiving transducer with an aberrating layer, or ‘mask,’ in front of the transducer's receive surface, with a separate co-located transmit transducer. The mask encodes spatial measurements into a single output signal, containing more information about a reflector's position than a transducer without a mask. The amount of information in such measurements is dependent on the mask geometry, which we propose to optimize using an image reconstruction mean square error (MSE) criterion. We approximate the physics involved to define a linear measurement model, which we use to find an expression for the image error covariance matrix. By discretizing the mask surface and defining a discrete number of mask thickness levels per point on its surface, we show how finding the best mask can be posed as a variation of a sensor selection problem. We propose a convex relaxation in combination with randomized rounding, as well as a greedy optimization algorithm to solve this problem. We show empirically that both algorithms come close to the global optimum. Our simulations further show that the optimized masks have better a MSE than nearly all randomly shaped masks. We observe that an optimized mask amplifies echoes coming from within the region of interest (ROI), and strongly reduces the correlation between echoes of pixels within the ROI.@en

We consider the scenario of finding the transfer function of an aberrating layer in front of an ultrasound array. We are interested in blindly estimating this transfer function without prior knowledge of the unknown ultrasound sources or ultrasound contrast image. The algorithm gives an exact solution if the matrix representing the aberration layer’s transfer function is full rank, up to a scaling and reordering of its columns, which has to be resolved using some prior knowledge of the matrix structure. We provide conditions for the robustness of blind calibration in noise. Numerical simulations show that the method becomes more robust for shorter wavelengths, as the transfer function matrices then tend to be less ill-conditioned. Image reconstruction from simulated data using the k-Wave toolbox show that a well calibrated model removes some of the distortions introduced by an uncalibrated model, and improves the resolution for some of the sources.@en

We consider a model-based ultrasound imaging scenario using a single transducer with a coding mask, and assume that the pulse-echo model is erroneously estimated, resulting in decreased imaging performance. Although the pulse-echo Green's function to each pixel has to be measured to obtain a good model, typically only forward-field measurements are obtained for better SNR, from which the pulse-echo Green's functions are estimated. However, if the transducer's receive transfer function is different from the transmit transfer function, the forward-field measurements do not incorporate the receive transfer function, resulting in an incorrect pulse-echo model. We propose two calibration techniques that start with this erroneous model, and update it using pulse-echo measurements. In the first technique we assume the calibration phantom is known a priori, whereas in the second technique we use multiple random calibration phantoms of which only the second-order statistics are assumed to be known beforehand. Both methods are able to significantly improve the pulse-echo model, strongly improving imaging performance. Our simulation results show that the first technique works best, since there is no uncertainty about the calibration image, whereas the blind calibration technique requires no exact knowledge of the calibration phantom, making it robust to positioning or manufacturing errors.

@en

Treatment of abdominal aortic (AA) aneurysms and stenotic lesions may be improved by analyzing their associated blood flow patterns. Angle-independent blood flow patterns in the AA can be obtained by combining echo-particle image velocimetry (ePIV) with high frame rate contrast-enhanced ultrasonography. However, ePIV performance is affected by ultrasound contrast agent (UCA) concentration, microbubble stability and tissue clutter. In this study we assessed the influence of acoustic pressure and UCA concentration on image quality for ePIV analysis. We also compared amplitude modulation (AM) and singular value decomposition (SVD) as tissue suppression strategies for ePIV. Fourteen healthy volunteers were imaged in the region of the distal AA. We tested four different UCA bolus volumes (0.25, 0.5, 0.75 and 1.5 ml) and four different acoustic output pressures (mechanical indices: 0.01, 0.03, 0.06 and 0.09). As image quality metrics, we measured contrast-to-background ratio, bubble disruption ratio and maximum normalized cross-correlation value during ePIV. At mechanical indices ≥ 0.06, we detected severe bubble destruction, suggesting that very low acoustic pressures should be used for ePIV. SVD was able to suppress tissue clutter better than AM. The maximum tracking correlation was affected by both UCA concentration and flow rate, where at high flow rates, lower UCA concentrations resulted in slightly higher correlation values but more signal drop-outs during late diastole. High frame rate ePIV was successfully performed in the AA of healthy volunteers and shows promise for future studies in patients.

@en

We study the optimal design of an aperture coding mask, and the optimal sensing positions of a single ultrasound sensor with a scanning configuration. In previous works, we have shown that 3D ultrasound imaging is possible using a randomly shaped coding mask with randomly chosen sensing positions. Here we propose an optimization algorithm for the joint design of the coding mask and the sensing positions. We first define a linear measurement model and parameterize it with respect to the mask shape. To optimize the shape of the mask, we use a greedy descent algorithm to minimize the imaging MSE, assuming a Wiener estimate is used for image reconstruction. To optimize the sensing positions, we pre-define a set of such sensing positions by gridding the measurement plane, and regard each sensing position as a virtual sensor candidate. We then use a greedy sensor selection algorithm to find a good selection of sensing positions. To jointly optimize for both the mask and the sensing positions, we alternatingly optimize between them, keeping either the mask shape or the sensing positions fixed. Using simulations we show that the joint optimization results in better imaging performance than optimizing for the mask or the sensing positions alone, or using a completely random design.@en

Recent advances in ultrasound Doppler imaging have facilitated the technique of functional ultrasound (fUS) which enables visualization of brain-activity due to neurovascular coupling. As of yet, this technique has been applied to rodents as well as to human subjects during awake craniotomy surgery and human newborns. Here we demonstrate the first successful fUS studies on awake pigeons subjected to auditory and visual stimulation. To allow successful fUS on pigeons we improved the temporal resolution of fUS up to 20,000 frames per second with real-time visualization and continuous recording. We show that this gain in temporal resolution significantly increases the sensitivity for detecting small fluctuations in cerebral blood flow and volume which may reflect increased local neural activity. Through this increased sensitivity we were able to capture the elaborate 3D neural activity pattern evoked by a complex stimulation pattern, such as a moving light source. By pushing the limits of fUS further, we have reaffirmed the enormous potential of this technique as a new standard in functional brain imaging with the capacity to unravel unknown, stimulus related hemodynamics with excellent spatiotemporal resolution with a wide field of view.

@en

Purpose: To study the feasibility of high-frame-rate (HFR) contrast material-enhanced (CE) ultrasound particle image velocimetry (PIV), or echo PIV, in the abdominal aorta. Materials and Methods: Fifteen healthy participants (six men; median age, 23 years [age range, 18-34 years]; median body mass index, 20.3 kg/m² [range, 17.3-24.9 kg/m²]) underwent HFR CE US. US microbubbles were injected at incremental doses (0.25, 0.5, 0.75, and 1.5 mL), with each dose followed by US measurement to determine the optimal dosage. Different US mechanical index values were evaluated (0.09, 0.06, 0.03, and 0.01) in a diverging wave acquisition scheme. PIV analysis was performed via pairwise cross-correlation of all captured images. Participants also underwent phase-contrast MRI. The echo PIV and phase-contrast MRI velocity profiles were compared via calculation of similarity index and relative difference in peak velocity. Results: Visualization of the aortic bifurcation with HFR CE US was successful in all participants. Optimal echo PIV results were achieved with the lowest contrast agent dose of 0.25 mL in combination with the lowest mechanical indexes (0.01 or 0.03). Substantial bubble destruction occurred at higher mechanical indexes (>0.06). Flow patterns were qualitatively similar in the echo PIV and MR images. The echo PIV and MRI velocity profiles showed good agreement (similarity index, 0.98 and 0.99; difference in peak velocity, 8.5% and 17.0% in temporal and spatial profiles, respectively). Conclusion: Quantification of blood ow in the human abdominal aorta with US particle image velocimetry (echo PIV) is feasible. Use of echo PIV has potential in the clinical evaluation of aortic disease.

@en

Accurate assessment of carotid artery disease by measuring blood flow, plaque deformation and pulse wave velocity using ultrasound imaging requires 3D information. Additionally, the volume rates should be high enough (> 1 kHz) to capture the full range of these fast transient phenomena. For this purpose, we have built a programmable, tileable matrix array that is capable of providing 3D ultrasound imaging at such volume rates. This array contains an application-specific integrated circuit (ASIC) right beneath the acoustic piezo-stack. The ASIC enables fast programmable switching between various configurations of elements connected to the acquisition system via a number of channels far smaller than the number of transducer elements. This design also allows for expanding the footprint by tiling several of these arrays together into one large array. We explain the working principles and show the first basic imaging results of a 2-by-1 tiled array.

@en

Ultrafast 3D transesophageal echocardiographic (TEE) imaging, combined with 3D echo particle image velocimetry (ePIV), would be ideal for tracking the complex blood flow patterns in the heart. We are developing a miniature pediatric matrix TEE transducer that employs micro-beamforming (μBF) and allows high framerate in 3D. In this paper, we assess the feasibility of 3D ePIV with a high frame rate, small aperture transducer and the influence of the micro-beamforming technique. We compare the results of 3D ePIV on simulated images using the μBF transducer and an idealized, fully sampled (FS) matrix transducer. For the two transducers, we have simulated high-framerate imaging of an 8.4mm diameter artery having a known 4D velocity field. The simulations were performed in FieldII. 1000 3D volumes, at a rate of 1000 volumes/sec, were created using a single diverging transmission per volume. The error in the 3D velocity estimation was measured by comparing the ePIV results of both transducers to the ground truth. The results on the simulated volumes show that ePIV can estimate the 4D velocity field of the arterial phantom using these small-aperture transducers suitable for pediatric 3D TEE. The μBF transducer (RMSE 44.0%) achieved comparable ePIV accuracy to that of the FS transducer (RMSE 42.6%).

@en