Charles Tremblay-Darveau

Combined perfusion and doppler imaging using plane-wave nonlinear detection and microbubble contrast agents.

Plane-wave imaging offers image acquisition rates at the pulse repetition frequency, effectively increasing the imaging frame rates by up to two orders of magnitude over conventional line-by-line imaging. This form of acquisition can be used to achieve very long ensemble lengths in nonlinear modes such as pulse inversion Doppler, which enables new imaging trade-offs that were previously unattainable. We first demonstrate in this paper that the coherence of microbubble signals under repeated exposure to acoustic pulses of low mechanical index can be as high as 204 ± 5 pulses, which is long enough to allow an accurate power Doppler measurement. We then show that external factors, such as tissue acceleration, restrict the detection of perfusion at the capillary level with linear Doppler, even if long Doppler ensembles are considered. Hence, perfusion at the capillary level can only be detected with ultrasound through combined microbubbles and Doppler imaging. Finally, plane-wave contrast-enhanced power and color Doppler are performed on a rabbit kidney in vivo as a proof of principle. We establish that long pulse-inversion Doppler sequences and conventional wall-filters can create an image that simultaneously resolves both the vascular morphology of veins and arteries, and perfusion at the capillary level with frame rates above 100 Hz.

Dynamic contrast enhanced ultrasound for therapy monitoring

Quantitative imaging is a crucial component of the assessment of therapies that target the vasculature of angiogenic or inflamed tissue. Dynamic contrast-enhanced ultrasound (DCE-US) using microbubble contrast offers the advantages of being sensitive to perfusion, non-invasive, cost effective and well suited to repeated use at the bedside. Uniquely, it employs an agent that is truly intravascular. This papers reviews the principles and methodology of DCE-US, especially as applied to anti-angiogenic cancer therapies. Reproducibility is an important attribute of such a monitoring method: results are discussed. More recent technical advances in parametric and 3D DCE-US imaging are also summarised and illustrated.

Fast Vascular Ultrasound Imaging With Enhanced Spatial Resolution and Background Rejection

Ultrasound super-localization microscopy techniques presented in the last few years enable non-invasive imaging of vascular structures at the capillary level by tracking the flow of ultrasound contrast agents (gas microbubbles). However, these techniques are currently limited by low temporal resolution and long acquisition times. Super-resolution optical fluctuation imaging (SOFI) is a fluorescence microscopy technique enabling sub-diffraction limit imaging with high temporal resolution by calculating high order statistics of the fluctuating optical signal. The aim of this work is to achieve fast acoustic imaging with enhanced resolution by applying the tools used in SOFI to contrast-enhance ultrasound (CEUS) plane-wave scans. The proposed method was tested using numerical simulations and evaluated using two in-vivo rabbit models: scans of healthy kidneys and VX-2 tumor xenografts. Improved spatial resolution was observed with a reduction of up to 50% in the full width half max of the point spread function. In addition, substantial reduction in the background level was achieved compared to standard mean amplitude persistence images, revealing small vascular structures within tumors. The scan duration of the proposed method is less than a second while current super-localization techniques require acquisition duration of several minutes. As a result, the proposed technique may be used to obtain scans with enhanced spatial resolution and high temporal resolution, facilitating flow-dynamics monitoring. Our method can also be applied during a breath-hold, reducing the sensitivity to motion artifacts.

Measuring Absolute Blood Pressure Using Microbubbles

Gas microbubbles are highly compressible, which makes them very efficient sound scatterers. As another consequence of their high compressibility, the radii of the microbubbles are affected by the pressure of the fluid around them, which changes their resonance frequency. Although the pressures present within the human body cause only minor variations in the radii of uncoated microbubbles (∼0.2% per 10 mmHg) and, therefore, very small variations in the resonance frequency (∼1 kHz per 10 mmHg), it was found in the work described here, through both simulations and in vitro measurements, that large changes in resonance frequency can occur in phospholipid-coated microbubbles for small blood pressure variations because of the exotic buckling dynamics of phospholipid monolayers (up to 240 kHz per 10 mmHg). This method should allow non-invasive measurement of the gauge blood pressure in deep blood vessels as long as the microbubble physical properties are well controlled.

Visualizing the Tumor Microvasculature With a Nonlinear Plane-Wave Doppler Imaging Scheme Based on Amplitude Modulation

Imaging with ultrasonic plane waves enables the combination of Doppler and microbubble contrast-enhanced imaging without compromising the Doppler ensemble length, as is the case for conventional line-by-line imaging, thus maintaining flow sensitivity. This permits the separation of conduit flow in large vessels from the perfusion background and the presentation of velocity estimates in real-time. However, the ability to differentiate perfusion from the tissue signal is limited by the contrast-to-tissue (CTR) ratio achieved with the contrast-enhanced pulsing sequence, independently of the acquisition length. One way to improve the CTR is to use a Doppler sequence based on amplitude modulation instead of one based on pulse inversion. In this work, we discuss how amplitude modulation can be adapted to Doppler processing. We show that amplitude modulation Doppler, like pulse inversion Doppler, can separate the signal of moving tissue from that of moving microbubbles, while achieving a better contrast-to-tissue ratio than pulse inversion Doppler, both in vitro and in vivo. Both amplitude modulation Doppler and pulse inversion Doppler yield similar velocity estimates when the bandwidth of the RF echo is properly compensated. Finally, we demonstrate how amplitude modulation Doppler can be used to reveal both the conduit flow and the capillary perfusion at high frame rates in an in vivo tumor.

Concepts and Tradeoffs in Velocity Estimation With Plane-Wave Contrast-Enhanced Doppler

While long Doppler ensembles are, in principle, beneficial for velocity estimates, short acoustic pulses must be used in microbubble contrast-enhanced (CE) Doppler to mitigate microbubble destruction. This introduces inherent tradeoffs in velocity estimates with autocorrelators, which are studied here. A model of the autocorrelation function adapted to the microbubble Doppler signal accounting for transit time, the echo frequency uncertainty, and contrast-agent destruction is derived and validated in vitro. It is further demonstrated that a local measurement of the center frequency of the microbubble echo is essential in order to avoid significant bias in velocity estimates arising from the linear and nonlinear frequency-dependent scattering of microbubbles and compensate for the inherent speckle nature of the received echo frequency. For these reasons, broadband Doppler estimators (2-D autocorrelator and Radon projection) are better suited than simpler narrow-band estimators (1-D autocorrelator and 1-D Fourier transform) for CE flow assessment. A case study of perfusion in a VX-2 carcinoma using CE plane-wave Doppler is also shown. We demonstrate that even when considering all uncertainties associated with microbubble-related decorrelation (destruction, pulse bandwidth, transit time, and flow gradient) and the need for real-time imaging, a coefficient of variation of 4% on the axial velocity is achievable with plane-wave imaging.

Ultrafast Doppler imaging of micro-bubbles

Plane-wave synthetic ultrasound considerably increases the imaging frame rate, which in turn can be used to improve the SNR or the frequency resolution of Doppler estimators. Ultrafast imaging also allows the implementation of bubble selective multi-pulse imaging sequences, such as pulse inversion, at frame rates sufficient for Doppler processing. It will be demonstrated in an in-vivo rabbit kidney that non-linear contrast enhanced Doppler permits the real-time segmentation of fast flow (arteries and veins), from the slow moving flow in capillaries, using a Doppler frequency filters analogous to conventional wall-filters.

Impact of Encapsulation on in vitro and in vivo Performance of Volatile Nanoscale Phase-Shift Perfluorocarbon Droplets.

Phase-shift droplets can be converted by sound from low-echogenicity, liquid-core agents into highly echogenic microbubbles. Many proposed applications in imaging and therapy take advantage of the high spatiotemporal control over this dynamic transition. Although some studies have reported increased circulation time of the droplets compared with microbubbles, few have directly explored the impact of encapsulation on droplet performance. With the goal of developing nanoscale droplets with increased circulatory persistence, we first evaluate the half-life of several candidate phospholipid encapsulations in vitro at clinical frequencies. To evaluate in vivo circulatory persistence, we develop a technique to periodically measure droplet vaporization from high-frequency B-mode scans of a mouse kidney. Results show that longer acyl chain phospholipids can dramatically reduce droplet degradation, increasing median half-life in vitro to 25.6 min-a 50-fold increase over droplets formed from phospholipids commonly used for clinical microbubbles. In vivo, the best-performing droplet formulations showed a median half-life of 18.4 min, more than a 35-fold increase in circulatory half-life compared with microbubbles with the same encapsulation in vivo. These findings also point to possible refinements that may improve nanoscale phase-shift droplet performance beyond those measured here.

Contrast enhanced ultrasound(CEUS) imaging of rat spinal cord injury

Traumatic spinal cord injury (tSCI) often leads to debilitating neurological disabilities that in addition to the loss of sensory and motor capabilities, also includes other issues with the bladder, heart and respiration. Overall, tSCI results in a drastic decrease in the quality of life. Traumatic spinal cord injury causes an almost complete loss of blood flow at the site of injury (primary injury) as well as significant ischemia surrounding the injury, resulting in progressive additional cell death over time (secondary injury). Counteracting secondary injury of spinal cord tissue surrounding tSCI is an active area of research to improve outcomes. There are no existing techniques to assess simultaneously both temporal and spatial changes in blood flow of contused spinal cord tissue in experimental settings. The goal of this work was to visualize temporal and spatial changes in blood flow following tSCI in a rat spinal cord injury model.

Improved Contrast-Enhanced Power Doppler Using a Coherence-Based Estimator

While plane-wave imaging can improve the performance of power Doppler by enabling much longer ensembles than systems using focused beams, the long-ensemble averaging of the zero-lag autocorrelation R(0) estimates does not directly decrease the mean noise level, but only decreases its variance. Spatial variation of the noise due to the time-gain compensation and the received beamforming aperture ultimately limits sensitivity. In this paper, we demonstrate that the performance of power Doppler imaging can be improved by leveraging the higher lags of the autocorrelation [e.g., R(1), R(2),…] instead of the signal power (R(0)). As noise is completely uncorrelated from pulse-to-pulse while the flow signal remains correlated significantly longer, weak signals just above the noise floor can be made visible through the reduction of the noise floor. Finally, as coherence decreases proportionally with respect to velocity, we demonstrate how signal coherence can be targeted to separate flows of different velocities. For instance, we show how long-time-range coherence of microbubble contrast-enhanced flow specifically isolates slow capillary perfusion (as opposed to conduit flow).