Angle-independent and multi-dimensional myocardial elastography--from theory to clinical validation

The angle-independent myocardial elastography, which shows good performance in our proposed theoretical framework using a three-dimensional, ultrasonic image formation model based on well-established, 3D finite-element, canine, left-ventricular models in both normal and left-circumflex ischemic cases, is employed as well as validated in vivo to assess the contractility of normal and pathological myocardia. Angle-independent myocardial elastography consists of: (1) iterative estimation of in-plane and out-of-plane cumulative displacements during systole using 1D cross-correlation and recorrelation techniques in a 2D search; (2) calculation of in-plane finite strains from the in-plane cumulative motion; and (3) computation of in-plane principal strains from the finite strains by eigen decomposition with a classification strategy. The in vivo raw data of healthy and pathological human left ventricles were acquired at 136 fps in a short-axis echocardiographic view. Similar to theory, the elastographic estimates in normal clinical cases showed radial wall thickening and circumferential shortening during systole through principal strain imaging, while those in a pathological case underwent opposite strains. The feasibility of angle-independent myocardial elastography with an automated contour tracking method was hereby demonstrated through imaging of the myocardial deformation, and principal strains were proven essential in the reliable characterization and differentiation of abnormal from normal myocardia, without any angular dependence.     

Quo vadis elasticity imaging?

In the past decade, an important field that has emerged as complementary to ultrasonic imaging is that of elasticity imaging. The term encompasses a variety of techniques that can depict a mechanical response or property of tissues. In ultrasound, its premise is built on two important facts: (a) that significant differences between mechanical properties of several tissue components exist and (b) that the information contained in the coherent scattering, or speckle, is sufficient to depict these differences following an external or internal mechanical stimulus. Parameters, such as velocity of vibration, displacement, strain, strain rate, velocity of wave propagation and elastic modulus, have all been demonstrated feasible in their estimation and have resulted in the accurate depiction of stiffer tissue masses, such as tumors, high-intensity focused ultrasound (HIFU) lesions and atherosclerotic plaques. More recently, through the development of ultrafast algorithms tailored to suitable hardware as well as the familiarity of the physician with the sensitivity of the methods used, one elasticity imaging technique in particular, elastography, has been shown applicable in a typical clinical ultrasound setting. In other words, elastograms can currently be obtained at quasi real-time (approximately at a frame rate of 8 frames/s) and with the use of a hand-held transducer (as opposed to the previously used frame-suspended setup) during and simultaneously with an ultrasound exam of, e.g., the breast or the prostate. The higher frame rate available with certain clinical ultrasound scanners has also resulted in the successful application of elasticity imaging techniques on the myocardium and monitoring its deformation over several cardiac cycles for the detection of ischemic regions. As a result, elasticity imaging with its ever increasing number of applications and demonstrated applicability in a typical, clinical ultrasound setting promises to make an important contribution to the ultrasound practice as we know it.     

Shear strain estimation and lesion mobility assessment in elastography

Elastography typically measures and images the normal strain component along the insonification/compression axis, i.e., in the axial direction. We have recently shown that, by using interpolation and cross-correlation methods of transversely displaced RF echo segments, it is possible to measure and image displacement and strain transversely to the beam with good precision. This enables the estimation and imaging of all three principal normal strain components. Generally, motion in a direction other than that in which strain is estimated may result in decorrelation noise, severely corrupting the estimates. Therefore, a correction method is applied to correct the displacement and strain estimates for decorrelating motion. In this paper, we show how corrected displacement estimates can also be used to estimate and image the shear strain components. This may allow us to identify regions of decorrelation noise in the normal strain measurement that are due to shear strain. Shear strain estimates provide supplementary information, which can characterize different tissue elements based on their mobility. In the case of breast lesions, low mobility is related to malignancy. Following an in vivo case, we show with 2D simulations how assessment of tumor mobility can be achieved with shear strain estimation.     

The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice

The activation of bubbles by an acoustic field has been shown to temporarily open the blood-brain barrier (BBB), but the trigger cause responsible for the physiological effects involved in the process of BBB opening remains unknown. Here, the trigger cause (i.e., physical mechanism) of the focused ultrasound-induced BBB opening with monodispersed microbubbles is identified. Sixty-seven mice were injected intravenously with bubbles of 1-2, 4-5, or 6-8 μm in diameter and the concentration of 10(7) numbers/ml. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5 MHz frequency, 100 cycles pulse length, 10 Hz pulse repetition frequency, 1 min duration). Peak-rarefactional pressures of 0.15, 0.30, 0.45, or 0.60 MPa were applied to identify the threshold of BBB opening and inertial cavitation (IC). Our results suggest that the BBB opens with nonlinear bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary wall to induce BBB opening without IC. BBB opening was shown capable of being induced safely with nonlinear bubble oscillation at the pressure threshold and its volume was highly dependent on both the acoustic pressure and bubble diameter.     

Estimating localized oscillatory tissue motion for assessment of the underlying mechanical modulus

The technique of harmonic motion imaging (HMI) uses the localized stimulus of the oscillatory ultrasonic radiation force as produced by two overlapping beams of distinct frequencies, and estimates the resulting harmonic displacement in the tissue in order to assess its underlying mechanical properties. In this paper, we studied the relationship between measured displacement and stiffness in gels and tissues in vitro. Two focused ultrasound transducers with a 100 mm focal length were used at frequencies of 3.7500 MHz and either 3.7502 (or 3.7508 MHz), respectively, in order to produce an oscillatory motion at 200 Hz in the gel or tissue. A 1.1 MHz diagnostic transducer (Imasonics, Inc.) was also focused at 100 mm and acquired 5 ms RF signals (pulse repetition frequency (PRF)=3.5 kHz) at 100 MHz sampling frequency during radiation force application. First, three 50x50 mm(2) acrylamide gels were prepared at concentrations of 4%, 8% and 16%. The resulting displacement was estimated using crosscorrelation techniques between successively acquired RF signals with a 2 mm window and 80% window overlap at 1260 W/cm(2). A normal 1-D indentation instrument (TeMPeST) applied oscillatory loads at 0.1-200 Hz with a 5 mm-diameter flat indenter. Then, 12 displacement measurements in 6 porcine muscle specimens (two measurements/case, as above) were made in vitro, before and after ablation which was performed for 10 s at 1260 W/cm(2). In all gel cases, the harmonic displacement was found to linearly increase with intensity and exponentially decrease with gel concentration. The TeMPeST measurements showed that the elastic moduli for the 4%, 8% and 16% gels equaled 3.93+/-0.06, 17.1+/-0.2 and 75+/-2 kPa, respectively, demonstrating that the HMI displacement estimate depends directly on the gel stiffness. Finally, in the tissues samples, the mean displacement amplitude showed a twofold decrease between non-ablated and ablated tissue, demonstrating a correspondence between the HMI response and an increase in stiffness measured with the TeMPeST instrument.     

The use of ultrasound-stimulated acoustic emission in the monitoring of modulus changes with temperature

It has been previously shown that the amplitude of the ultrasound-stimulated acoustic emission (USAE) signal is sensitive to tissue temperature and, therefore, can help detect it. Its amplitude, however, is sensitive to both acoustical and mechanical parameters, that at most frequencies have opposite effects due to temperature. In this paper, we explore the feasibility of using a frequency shift of the resonant peaks of the USAE signal for monitoring the tissue stiffness variation with temperature. In a numerical simulation, the variation of the frequency shift at different temperatures is shown. Then, in a series of experiments involving a gel phantom and porcine muscle tissue, the frequency shift variation is shown to follow the known stiffness changes due to temperature. It is also shown that this shift indicates reversible changes as well as the onset of thermal coagulative necrosis. The necrosis is marked by a monotonically increasing positive frequency shift. It was thus shown that the USAE spectrum peaks undergo a negative shift (or, downshift) when the stiffness decreases and a positive shift (or, upshift) when the stiffness increases. The experimental frequency shifted around a peak at 22.1-22.5 kHz within a range of -250 to 80 Hz and -200 to 250 Hz for the gel and muscle tissue for the temperatures of 25-70 and 30-70 degrees C, respectively. Simulation and ex vivo experimental results indicate that the USAE frequency shift method can help decouple the mechanical from the acoustical parameter dependence as well as detect the onset of thermal coagulative necrosis.     

Noninvasive electromechanical wave imaging and conduction-relevant velocity estimation in vivo

Electromechanical wave imaging is a novel technique for the noninvasive mapping of conduction waves in the left ventricle through the combination of ECG gating, high frame rate ultrasound imaging and radio-frequency (RF)-based displacement estimation techniques. In this paper, we describe this new technique and characterize the origin and velocity of the wave under distinct pacing schemes. First, in vivo imaging (30 MHz) was performed on anesthetized, wild-type mice (n = 12) at high frame rates in order to take advantage of the transient electromechanical coupling occurring in the myocardium. The RF signal acquisition in a long-axis echocardiographic view was gated between consecutive R-wave peaks of the mouse electrocardiogram (ECG) and yielded an ultra-high RF frame rate of 8000 frames/s (fps). The ultrasound RF signals in each frame were digitized at 160 MHz. Axial, frame-to-frame displacements were estimated using 1D cross-correlation (window size of 240 μm, overlap of 90%). Three pacing protocols were sequentially applied in each mouse: (1) sinus rhythm (SR), (2) right-atrial (RA) pacing and (3) right-ventricular (RV) pacing. Pacing was performed using an eight-electrode catheter placed into the right side of the heart with the capability of pacing from any adjacent bipole. During a cardiac cycle, several waves were depicted on the electromechanical wave images that propagated transmurally and/or from base to apex, or apex to base, depending on the type of pacing and the cardiac phase. Through comparison between the ciné-loops and their corresponding ECG obtained at different pacing protocols, we were able to identify and separate the electrically induced, or contraction, waves from the hemodynamic (or, blood-wall coupling) waves. In all cases, the contraction wave was best observed along the posterior wall starting at the S-wave of the ECG, which occurs after Purkinje fiber, and during myocardial, activation. The contraction wave was identified based on the fact that it changed direction only when the pacing origin changed, i.e., it propagated from the apex to the base at SR and RA pacing and from base to apex at RV pacing. This reversal in the wave propagation direction was found to be consistent in all mice scanned and the wave velocity values fell within the previously reported conduction wave range with statistically significant differences between SR/RA pacing (0.85 ± 0.22 m/s and 0.84 ± 0.20 m/s, respectively) and RV pacing (−0.52 ± 0.31 m/s; p < 0.0001). This study thus shows that imaging the electromechanical function of the heart noninvasively is feasible. It may therefore constitute a unique noninvasive method for conduction wave mapping of the entire left ventricle. Such a technology can be extended to 3D mapping and/or used for early detection of dyssynchrony, arrhythmias, left-bundle branch block, or other conduction abnormalities as well as diagnosis and treatment thereof.     

Spectral estimators in elastography

Like velocity, strain induces a time delay and a time scaling to the received signal. Elastography typically uses time delay techniques to indirectly (i.e. via the displacement estimate) measure tissue strain induced by an applied compression, and considers time scaling as a source of distortion. More recently, we have shown that the time scaling factor can also be spectrally estimated and used as a direct measure of strain. Strain causes a Doppler-like frequency shift and a change in bandwidth of the bandpass power spectrum of the echo signal. Two frequency shift strain estimators are described that have been proven to be more robust but less precise when compared to time delay estimators, both in simulations and experiments. The increased robustness is due to the insensitivity of the spectral techniques to phase decorrelation noise. In this paper we discuss and compare the theoretical and experimental findings obtained with traditional time delay estimators and with the newly proposed spectral methods.