Nonlinear contrast imaging with an array-based micro-ultrasound system.

The main goal of this study was to determine the optimal strategy for a real-time nonlinear contrast mode for small-animal imaging at high frequencies, on a new array-based micro-ultrasound system. Previously reported contrast imaging at frequencies above 15 MHz has primarily relied on subtraction schemes involving B-mode image data. These approaches provide insufficient contrast to tissue ratios under many imaging conditions. In this work, pulse inversion, amplitude modulation and combinations of these were systematically investigated for the detection of nonlinear fundamental and subharmonic signal components to maximize contrast-to-tissue ratio (CTR) in the 18-24 MHz range. From in vitro and in vivo measurements, nonlinear fundamental detection with amplitude modulation provided optimal results, allowing an improvement in CTR of 13 dB compared with fundamental imaging. Based on this detection scheme, in vivo parametric images of murine kidneys were generated using sequences of nonlinear contrast images after intravenous bolus injections of microbubble suspensions. Initial parametric images of peak enhancement (PE), wash-in rate (WiR) and rise time (RT) are presented. The parametric images are indicative of blood perfusion kinetics, which, in the context of preclinical imaging with small animals, are anticipated to provide valuable insights into the progression of human disease models, where blood perfusion plays a critical role in either the diagnosis or treatment of the disease.

Molecular ultrasound imaging: current status and future directions.

Targeted contrast-enhanced ultrasound (molecular ultrasound) is an emerging imaging strategy that combines ultrasound technology with novel molecularly-targeted ultrasound contrast agents for assessing biological processes at the molecular level. Molecular ultrasound contrast agents are nano- or micro-sized particles that are targeted to specific molecular markers by adding high-affinity binding ligands onto the surface of the particles. Following intravenous administration, these targeted ultrasound contrast agents accumulate at tissue sites overexpressing specific molecular markers, thereby enhancing the ultrasound imaging signal. High spatial and temporal resolution, real-time imaging, non-invasiveness, relatively low costs, lack of ionising irradiation and wide availability of ultrasound systems are advantages compared to other molecular imaging modalities. In this article we review current concepts and future directions of molecular ultrasound imaging, including different classes of molecular ultrasound contrast agents, ongoing technical developments of pre-clinical and clinical ultrasound systems, the potential of molecular ultrasound for imaging different diseases at the molecular level, and the translation of molecular ultrasound into the clinic.

A method for differentiating targeted microbubbles in real time using subharmonic micro-ultrasound and interframe filtering.

This study introduces a new method for differentiating targeted microbubbles in the presence of flowing microbubbles and tissue using micro-ultrasound. The method relies on subharmonic (SH) imaging for segmenting microbubble signals from tissue signals, and low-pass interframe filtering for segmenting bound targeted microbubbles from flowing microbubbles. The method is evaluated with 30 frames per second SH B-mode imaging in vitro, using a wall-less vessel flow phantom. The SH B-mode cineloops were postprocessed using an interframe moving average filter to segment the regions of bound microbubbles on the inner surface of the vessel phantom. The bound bubbles were then disrupted with sufficiently high ultrasound pressures, so that the dynamic process of targeted microbubble binding under flowing conditions could be observed. These preliminary results show that the proposed method is a feasible solution to the challenge of differentiating targeted microbubbles in the presence of tissue and freely flowing microbubbles at high frequencies, which in turn should improve the specificity of targeted microbubble detection.

High-frequency subharmonic pulsed-wave Doppler and color flow imaging of microbubble contrast agents.

A recent study has shown the feasibility of subharmonic (SH) flow imaging at a transmit frequency of 20 MHz. This paper builds on these results by examining the performance of SH flow imaging as a function of transmit pressure. Further, we also investigate the feasibility of SH pulsed-wave Doppler (PWD) imaging. In vitro flow experiments were performed with a 1-mm-diameter wall-less vessel cryogel phantom using the ultrasound contrast agent Definity and an imaging frequency of 20 MHz. The phantom results show that there is an identifiable pressure range where accurate flow velocity and power estimates can be made with SH imaging at 10 MHz (SH10), above which velocity estimates are biased by radiation force effects and unstable bubble behavior, and below which velocity and power estimates are degraded by poor SNR. In vivo validation of SH PWD was performed in an arteriole of a rabbit ear, and blood velocity estimates compared well with fundamental (F20) mode PWD. The ability to suppress tissue signals using SH signals may enable the use of higher frame rates and improve sensitivity to microvascular flow or slow velocities near large vessel walls by reducing or eliminating the need for clutter filters.

Estimation methods for flow imaging with high frequency ultrasound.

This article proposes to estimate slow blood flow with high frequency ultrasound imaging. The proposed technique combines 2 methods. First, a statistical method, called Speckle Flow Imaging (SFI) based on the analysis of changes in the speckle pattern along time, gives an index directly related to the total velocity vector. Secondly, a block matching approach estimates the in-plane velocity components. Results on calibrated flow sequences of blood mimicking fluid have shown good agreement with the statistical model. The quantification of flow is achieved with pulsed flow and is also angle independent when the flow is perpendicular to the ultrasound beam. Speckle Tracking has been evaluated on the same data and has shown good estimation of the in-plane velocity vector when the component of velocity perpendicular to the imaging plane is inferior to 1mm/s. The results of these two methods permit the evaluation of the total 3D velocity field and the orthogonal velocity component relative to the imaging plane. This allows the quantification of blood flow (volumetric per time unit across the sequence).

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.