Elisa E. Konofagou

Elastography: Ultrasonic estimation and imaging of the elastic properties of tissues

Abstract The basic principles of using sonographic techniques for imaging the elastic properties of tissues are described, with particular emphasis on elastography. After some preliminaries that describe some basic tissue stiffness measurements and some contrast transfer limitations of strain images are presented, four types of elastograms are described, which include axial strain, lateral strain, modulus and Poissons ratio elastograms. The strain filter formalism and its utility in understanding the noise performance of the elastographic process is then given, as well as its use for various image improvements. After discussing some main classes of elastographic artefacts, the paper concludes with recent results of tissue elastography in vitro and in vivo.

A new elastographic method for estimation and imaging of lateral displacements, lateral strains, corrected axial strains and poisson's ratios in tissues

A major disadvantage of the current practice of elastography is that only the axial component of the strain is estimated. The lateral and elevational components are basically disregarded, yet they corrupt the axial strain estimation by inducing decorrelation noise. In this paper, we describe a new weighted interpolation method operating between neighboring RF A-lines for high precision tracking of the lateral displacement. Due to this high lateral-tracking precision, quality lateral elastograms are generated that display the lateral component of the strain tensor. These precision lateral-displacement estimates allow a fine correction for the lateral decorrelation that corrupts the axial estimation. Finally, by dividing the lateral elastogram by the axial elastogram, we are able to produce a new image that displays the distribution of Poissons ratios in the tissue. Results are presented from finite-element simulations and phantoms as well as in vitro and in vivo experiments.

Elastography : Imaging the Elastic Properties of Soft Tissues with Ultrasound

Elastography is a method that can ultimately generate several new kinds of images, called elastograms. As such, all the properties of elastograms are different from the familiar properties of sonograms. While sonograms convey information related to the local acoustic backscatter energy from tissue components, elastograms relate to its local strains, Youngs moduli or Poissons ratios. In general, these elasticity parameters are not directly correlated with sonographic parameters, i.e. elastography conveys new information about internal tissue structure and behavior under load that is not otherwise obtainable. In this paper we summarize our work in the field of elastography over the past decade. We present some relevant background material from the field of biomechanics. We then discuss the basic principles and limitations that are involved in the production of elastograms of biological tissues. Results from biological tissues in vitro and in vivo are shown to demonstrate this point. We conclude with some observations regarding the potential of elastography for medical diagnosis.

Myocardial elastography: A feasibility study in vivo

Early detection of cardiovascular diseases has been a very active research area in the medical imaging field. Assessment of the local and global mechanical functions is one of the major goals of accurate diagnosis. In this study, we investigated the feasibility of elastography for estimation and imaging of the local cardiac muscle displacement and strain in a human heart in vivo. In its noninvasive applications, elastography has been typically used to determine local tissue strain through the use of externally applied compression. For our study, we utilized the cardiac muscle motion during a cardiac cycle as the mechanical stimulus, and acquired successive radiofrequency (RF) data frames of the septal and posterior walls over a few cardiac cycles in parasternal and apical views, respectively. High-quality ciné-loop elastograms were obtained due to high frame rates and the resulting low decorrelation noise. Furthermore, the strain contrast was higher in the parasternal case, when only the posterior wall was imaged, and strain estimation was more robust in the apical view. High repeatability of the results was observed through elastographic measurements over several cardiac cycles. Finally, an M-mode version of elastography was used to follow part of the interventricular septum or the posterior wall over the course of two cardiac cycles. Not only do these preliminary results show that elastography is feasible in cardiac applications in vivo, but also that it can provide new information regarding cardiac motion and mechanical function. Future prospects include assessment of the role of elastography in detection of ischemia and infarction.

An adaptive strain estimator for elastography

Elastography is based on the estimation of strain due to applied tissue compression. In conventional elastography, strain is computed from the gradient of the displacement estimates between gated pre- and postcompression echo signals. Gradient-based estimation methods are known to be susceptible to noise. In elastography, in addition to the electronic noise, a principal source of estimation error is the decorrelation of the echo signal as a result of tissue compression (decorrelation noise). Temporal stretching of postcompression signals previously was shown to reduce the decorrelation noise. In this paper, we introduce a novel estimator that uses the stretch factor itself as an estimator of the strain. It uses an iterative algorithm that adaptively maximises the correlation between the pre- and postcompression echo signals by appropriately stretching the latter. We investigate the performance of this adaptive strain estimator using simulated and experimental data. The estimator has exhibited a vastly superior performance compared with the conventional gradient-based estimator.

Two-dimensional ultrasonic strain rate measurement of the human heart in vivo

A study is presented in which the feasibility of two-dimensional strain rate estimation of the human heart in vivo has been demonstrated. To do this, ultrasonic B-mode data were captured at a high temporal resolution of 3.8 ms and processed off-line. The motion of the RF signal patterns within the two-dimensional sector image was tracked and used as the basis for strain rate estimation. Both axial and lateral motion and strain rate estimates showed a good agreement with the results obtained by more established, one-dimensional techniques.

A fast normalized cross-correlation calculation method for motion estimation

High-precision motion estimation has become essential in ultrasound-based techniques such as time-domain Doppler and elastography. Normalized cross-correlation (NCC) has been shown as one of the best motion estimators. However, a significant drawback is its associated computational cost, especially when RF signals are used. In this paper, a method based on sum tables developed elsewhere is adapted for fast NCC calculation in ultrasound-based motion estimation, and is tested with respect to the speed enhancement of the specific application of ultrasound-based motion estimation. Both the numerator and denominator in the NCC definition are obtained through pre-calculated sum tables to eliminate redundancy of repeated NCC calculations. Unlike a previously reported method, a search region following the principle of motion estimation is applied in the construction of sum tables. Because an exhaustive search and high window overlap are typically used for highest quality imaging, the computational cost of the proposed method is significantly lower than that of the direct method using the NCC definition, without increasing bias and variance characteristics of the motion estimation or sacrificing the spatial resolution. Therefore, high quality, high spatial resolution, and high calculation speed can be all simultaneously obtained using the proposed methodology. The high efficiency of this method was verified using RF signals from a human abdominal aorta in vivo. For the parameters typically used, a real-time, very high frame rate of 310 frames/s was achieved for the motion estimation. The proposed method was also extended to 2-D NCC motion estimation and motion estimation with other algorithms. The technique could thus prove very useful and flexible for real-time motion estimation as well as in other fields such as optical flow and image registration.

Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in Mice In Vivo

The therapeutic efficacy of neurological agents is severely limited, because large compounds do not cross the blood-brain barrier (BBB). Focused ultrasound (FUS) sonication in the presence of microbubbles has been shown to temporarily open the BBB, allowing systemically administered agents into the brain. Until now, polydispersed microbubbles (1-10 ¿m in diameter) were used, and, therefore, the bubble sizes better suited for inducing the opening remain unknown. Here, the FUS-induced BBB opening dependence on microbubble size is investigated. Bubbles at 1-2 and 4-5 ¿m in diameter were separately size-isolated using differential centrifugation before being systemically administered in mice (n = 28). The BBB opening pressure threshold was identified by varying the peak-rarefactional pressure amplitude. BBB opening was determined by fluorescence enhancement due to systemically administered, fluorescent-tagged, 3-kDa dextran. The identified threshold fell between 0.30 and 0.46 MPa in the case of 1-2 ¿m bubbles and between 0.15 and 0.30 MPa in the 4-5 ¿m case. At every pressure studied, the fluorescence was greater with the 4-5 ¿m than with the 1-2 ¿m bubbles. At 0.61 MPa, in the 1-2 ¿m bubble case, the fluorescence amount and area were greater in the thalamus than in the hippocampus. In conclusion, it was determined that the FUS-induced BBB opening was dependent on both the size distribution in the injected microbubble volume and the brain region targeted.

In vivo transcranial cavitation threshold detection during ultrasound-induced blood–brain barrier opening in mice

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice and IC may not be required for BBB opening at relatively low pressures.

Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound

The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.