Iason Apostolakis

Piecewise Pulse Wave Imaging (pPWI) for Detection and Monitoring of Focal Vascular Disease in Murine Aortas and Carotids In Vivo

Atherosclerosis and Abdominal Aortic Aneurysms (AAAs) are two common vascular diseases associated with mechanical changes in the arterial wall. Pulse Wave Imaging (PWI), a technique developed by our group to assess and quantify the mechanical properties of the aortic wall in vivo, may provide valuable diagnostic information. This work implements piecewise PWI (pPWI), an enhanced version of PWI designed for focal vascular diseases. Localized, sub-regional PWVs and PWI moduli ( EPWI) were estimated within 2-4 mm wall segments of murine normal, atherosclerotic and aneurysmal arteries. Overall, stiffness was found to increase in the atherosclerotic cases. The mean sub-regional PWV was found to be 2.57±0.18 m/s for the normal aortas (n = 7) with a corresponding mean EPWI of 43.82±5.86 kPa. A significant increase ( (p ≤ 0.001)) in the group means of the sub-regional PWVs was found between the normal aortas and the aortas of mice on high-fat diet for 20 ( 3.30±0.36 m/s) and 30 weeks ( 3.56±0.29 m/s). The mean of the sub-regional PWVs ( 1.57±0.78 m/s) and EPWI values ( 19.23±15.47 kPa) decreased significantly in the aneurysmal aortas (p ≤ 0.05). Furthermore, the mean coefficient of determination (r2) of the normal aortas was significantly higher (p ≤ 0.05) than those of the aneurysmal and atherosclerotic cases. These findings demonstrated that pPWI may be able to provide useful biomarkers for monitoring focal vascular diseases.

An inverse approach to determining spatially varying arterial compliance using ultrasound imaging

The mechanical properties of arteries are implicated in a wide variety of cardiovascular diseases, many of which are expected to involve a strong spatial variation in properties that can be depicted by diagnostic imaging. A pulse wave inverse problem (PWIP) is presented, which can produce spatially resolved estimates of vessel compliance from ultrasound measurements of the vessel wall displacements. The 1D equations governing pulse wave propagation in a flexible tube are parameterized by the spatially varying properties, discrete cosine transform components of the inlet pressure boundary conditions, viscous loss constant and a resistance outlet boundary condition. Gradient descent optimization is used to fit displacements from the model to the measured data by updating the model parameters. Inversion of simulated data showed that the PWIP can accurately recover the correct compliance distribution and inlet pressure under realistic conditions, even under high simulated measurement noise conditions. Silicone phantoms with known compliance contrast were imaged with a clinical ultrasound system. The PWIP produced spatially and quantitatively accurate maps of the phantom compliance compared to independent static property estimates, and the known locations of stiff inclusions (which were as small as 7 mm). The PWIP is necessary for these phantom experiments as the spatiotemporal resolution, measurement noise and compliance contrast does not allow accurate tracking of the pulse wave velocity using traditional approaches (e.g. 50% upstroke markers). Results from simulations indicate reflections generated from material interfaces may negatively affect wave velocity estimates, whereas these reflections are accounted for in the PWIP and do not cause problems.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Pulse wave imaging using coherent compounding in a phantom and in vivo.

Pulse wave velocity (PWV) is a surrogate marker of arterial stiffness linked to cardiovascular morbidity. Pulse wave imaging (PWI) is a technique developed by our group for imaging the pulse wave propagation in vivo. PWI requires high temporal and spatial resolution, which conventional ultrasonic imaging is unable to simultaneously provide. Coherent compounding is known to address this tradeoff and provides full aperture images at high frame rates. This study aims to implement PWI using coherent compounding within a GPU-accelerated framework. The results of the implemented method were validated using a silicone phantom against static mechanical testing. Reproducibility of the measured PWVs was assessed in the right common carotid of six healthy subjects (n  =  6) approximately 10-15 mm before the bifurcation during two cardiac cycles over the course of 1-3 d. Good agreement of the measured PWVs (3.97  ±  1.21 m s-1, 4.08  ±  1.15 m s-1, p  =  0.74) was obtained. The effects of frame rate, transmission angle and number of compounded plane waves on PWI performance were investigated in the six healthy volunteers. Performance metrics such as the reproducibility of the PWVs, the coefficient of determination (r 2), the SNR of the PWI axial wall velocities ([Formula: see text]) and the percentage of lateral positions where the pulse wave appears to arrive at the same time-point, indicating inadequacy of the temporal resolution (i.e. temporal resolution misses) were used to evaluate the effect of each parameter. Compounding plane waves transmitted at 1° increments with a linear array yielded optimal performance, generating significantly higher r 2 and [Formula: see text] values (p  ⩽  0.05). Higher frame rates (⩾1667 Hz) produced improvements with significant gains in the r 2 coefficient (p  ⩽  0.05) and significant increase in both r 2 and [Formula: see text] from single plane wave imaging to 3-plane wave compounding (p  ⩽  0.05). Optimal performance was established at 2778 Hz with 3 plane waves and at 1667 Hz with 5 plane waves.

Feasibility and validation of 4D Pulse wave Imaging (PWI) in vitro: 3D automated estimation of regional Pulse Wave Velocity vector

Pulse wave Imaging (PWI) is a noninvasive technique for tracking the propagation of the pulse waves along the arterial wall. Estimation of regional Pulse Wave Velocity (PWV) using 2D long-axis views of arterial vessels assumes propagation parallel to the imaging plane. 3D ultrasound imaging would aid in objectively estimating the PWV vector. The aims of this study were to introduce a novel method for PWV estimation along the direction of the wave propagation, and validate it in phantoms. Silicone vessel phantoms consisting of stiff and soft segments along the longitudinal axis were constructed and embedded into a very soft silicone background. A 2D array with a center frequency of 2.5 MHz was used to image each section using plane wave transmissions. Static and dynamic mechanical testing was used for PWV validation. The propagation was successfully visualized in 3D. PWVs were estimated in both the stiff (3.42 ± 0.23 m/s) and soft (2.41 ± 0.07 m/s) sections of the phantoms. Good agreement was found between the estimated PWVs and the corresponding static testing values (stiff. 3.41 m/s, soft. 2.48 m/s). Additionally, PWI-derived vessel compliance values were validated with dynamic testing. Thus, 4D PWI was successfully implemented and validated in silicone phantoms with plane waves at high volume rates.

Cross-correlation analysis of pulse wave propagation in arteries: in vitro validation and in vivo feasibility

The stiffness of the arteries is known to be an indicator of the progression of various cardiovascular diseases. Clinically, the pulse wave velocity (PWV) is used as a surrogate for arterial stiffness. Pulse wave imaging (PWI) is a non-invasive, ultrasound-based imaging technique capable of mapping the motion of the vessel walls, allowing the local assessment of arterial properties. Conventionally, a distinctive feature of the displacement wave (e.g. the 50% upstroke) is tracked across the map to estimate the PWV. However, the presence of reflections, such as those generated at the carotid bifurcation, can bias the PWV estimation. In this paper, we propose a two-step cross-correlation based method to characterize arteries using the information available in the PWI spatio-temporal map. First, the area under the cross-correlation curve is proposed as an index for locating the regions of different properties. Second, a local peak of the cross-correlation function is tracked to obtain a less biased estimate of the PWV. Three series of experiments were conducted in phantoms to evaluate the capabilities of the proposed method compared with the conventional method. In the ideal case of a homogeneous phantom, the two methods performed similarly and correctly estimated the PWV. In the presence of reflections, the proposed method provided a more accurate estimate than conventional processing: e.g. for the soft phantom, biases of  -0.27 and -0.71 m · s-1 were observed. In a third series of experiments, the correlation-based method was able to locate two regions of different properties with an error smaller than 1 mm. It also provided more accurate PWV estimates than conventional processing (biases:  -0.12 versus -0.26 m · s-1). Finally, the in vivo feasibility of the proposed method was demonstrated in eleven healthy subjects. The results indicate that the correlation-based method might be less precise in vivo but more accurate than the conventional method.

Transcranial acoustic cavitation localization with ultrafast power cavitation imaging in non-human primates

Acoustic cavitation-guided blood-brain barrier (BBB) opening with focused ultrasound (FUS) and microbubbles is a promising technique for safe and controlled opening of the BBB. Passive cavitation imaging has the ability to monitor the spatial intensity of acoustic cavitation for targeting verification and treatment monitoring. However, isolating acoustic cavitation emissions from tissue and skull reflections is a major challenge. In this study, we perform transcranial passive cavitation imaging with a 1.5D imaging array (M5Sc-D, bandwidth: 1.5–4 MHz, GE Medical Systems) placed in the central opening of a 0.5 MHz FUS transducer (H204, Sonic Concepts) in non-human primates. Broadband FUS pulses were used along with synchronous transmit and receive sequences to perform delay and sum beamforming with absolute time delays. Image sets were acquired at ultrafast frame rates (>1000 frames per second) for calculation of mean intensity images, i.e., power cavitation images. Spatiotemporal clutter filtering of image...

Synchronized passive microbubble imaging for guidance and monitoring of focused ultrasound therapies

Detection of focused ultrasound (FUS)-stimulated microbubble activity (i.e. acoustic cavitation) is a key methodology for monitoring and guidance of FUS therapies that harness the bioeffects of acoustic cavitation. The intensity and location of secondary acoustic emissions emitted by microbubbles can be passively detected and imaged using diagnostic imaging arrays. In turn, ultrasound-guided FUS (USgFUS) systems can be used for planning and evaluating the outcome of microbubble-based FUS therapies. State-of-the-art passive imaging methodologies were developed for monitoring high-intensity focused ultrasound (HIFU) ablation but suffer from poor axial image resolution due to the use of long pulses and asynchronous transmit and receive sequences. The objective of this study was thus to implement passive microbubble imaging (PMI) with short pulses of FUS and synchronous acquisition for improved image resolution by implementing reconstruction techniques similar to B-mode ultrasound imaging. The efficacy of PMI was assessed during blood-brain barrier (BBB) opening with FUS and microbubbles in mice in vivo.

Passive microbubble imaging with short pulses of focused ultrasound and absolute time-of-flight information

Focused ultrasound (FUS)-stimulated microbubble activity has been proposed as an efficient technique in numerous therapeutic ultrasound applications. Passive imaging of microbubble activity is used to spatially map the intensity and location of microbubble activity for correlation with therapeutic outcomes. Current passive imaging methods were developed for application with continuous-wave FUS therapies and have inherent limitations including poor axial image resolution. This study seeks to implement a synchronous passive microbubble imaging method using short pulses of FUS (200-500 kPa peak negative pressures, 2-3 cycles) at high frame rates (500-5000 Hz pulse repetition rate) to preserve absolute time-of-flight and improve axial resolution. In vitro and in vivo studies were carried out using an 18-MHz imaging array (L22-14v LF, Verasonics, Inc.) and 1-MHz FUS transducer aligned off-axis relative to the imaging array. A research-based ultrasound system (Vantage 256, Verasonics, Inc.) was used for custom transmit and receive sequences. Results indicate that this technique is able to “localize” microbubbles with improved resolution compared to previous methods and create detailed microvascular maps of microbubble activity throughout the focal area. The application of this technique for monitoring FUS-mediated blood-brain barrier opening will be shown. [Work supported in part by NIH grants R01AG038961 and R01EB009041.]Focused ultrasound (FUS)-stimulated microbubble activity has been proposed as an efficient technique in numerous therapeutic ultrasound applications. Passive imaging of microbubble activity is used to spatially map the intensity and location of microbubble activity for correlation with therapeutic outcomes. Current passive imaging methods were developed for application with continuous-wave FUS therapies and have inherent limitations including poor axial image resolution. This study seeks to implement a synchronous passive microbubble imaging method using short pulses of FUS (200-500 kPa peak negative pressures, 2-3 cycles) at high frame rates (500-5000 Hz pulse repetition rate) to preserve absolute time-of-flight and improve axial resolution. In vitro and in vivo studies were carried out using an 18-MHz imaging array (L22-14v LF, Verasonics, Inc.) and 1-MHz FUS transducer aligned off-axis relative to the imaging array. A research-based ultrasound system (Vantage 256, Verasonics, Inc.) was used for custom ...

In vivo repeatability of the pulse wave inverse problem in human carotid arteries

Accurate arterial stiffness measurement would improve diagnosis and monitoring for many diseases. Atherosclerotic plaques and aneurysms are expected to involve focal changes in vessel wall properties; therefore, a method to image the stiffness variation would be a valuable clinical tool. The pulse wave inverse problem (PWIP) fits unknown parameters from a computational model of arterial pulse wave propagation to ultrasound-based measurements of vessel wall displacements by minimizing the difference between the model and measured displacements. The PWIP has been validated in phantoms, and this study presents the first in vivo demonstration. The common carotid arteries of five healthy volunteers were imaged five times in a single session with repositioning of the probe and subject between each scan. The 1D finite difference computational model used in the PWIP spanned from the start of the transducer to the carotid bifurcation, where a resistance outlet boundary condition was applied to approximately model the downstream reflection of the pulse wave. Unknown parameters that were estimated by the PWIP included a 10-segment linear piecewise compliance distribution and 16 discrete cosine transformation coefficients for each of the inlet boundary conditions. Input data was selected to include pulse waves resulting from the primary pulse and dicrotic notch. The recovered compliance maps indicate that the compliance increases close to the bifurcation, and the variability of the average pulse wave velocity estimated through the PWIP is on the order of 11%, which is similar to that of the conventional processing technique which tracks the wavefront arrival time (13%).