Towards Dynamic Contrast Specific Ultrasound Tomography - Nature, Scientific Reports (original) (raw)

We report on the first study demonstrating the ability of a recently-developed, contrast-enhanced, ultrasound imaging method, referred to as cumulative phase delay imaging (CPDI), to image and quantify ultrasound contrast agent (UCA) kinetics. Unlike standard ultrasound tomography, which exploits changes in speed of sound and attenuation, CPDI is based on a marker specific to UCAs, thus enabling dynamic contrast-specific ultrasound tomography (DCS-UST). For breast imaging, DCS-UST will lead to a more practical, faster, and less operator-dependent imaging procedure compared to standard echo-contrast, while preserving accurate imaging of contrast kinetics. Moreover, a linear relation between CPD values and ultrasound second-harmonic intensity was measured (coefficient of determination = 0.87). DCS-UST can find clinical applications as a diagnostic method for breast cancer localization, adding important features to multi-parametric ultrasound tomography of the breast. Nowadays, there is growing interest in the development of imaging techniques which are capable of detecting and localizing angiogenesis and neovascularization. These processes induce specific changes in the microvas-cular structure, represent an established marker for tumours, and also provide indications of tumour aggressiveness 1. In particular, dynamic contrast-enhanced ultrasound (DCE-US) imaging shows promise, with many novel approaches focusing on the direct and/or indirect characterization of the microvasculature. However, when considering the various imaging options, several challenges emerge for imaging the breast. Typical ultrasound contrast agents (UCAs) are gas-filled microbubbles with diameters ranging between 1 and 10 μ m; they are therefore suitable for intravenous injection and can flow through the smallest microvessels. This phenomenon is exploited by super-localization ultrasound techniques which overcome the diffraction limit and are capable of imaging the microvasculature with a spatial-resolution as small as 8–12 μ m 2,3. Additionally, these techniques provide access to accurate velocity maps, thus offering a powerful tool for the study of microvascu-lar blood flow. However, the relatively long imaging time needed (e.g., > 2 minutes per plane 2), the influence of motion, and the difficulties in imaging and localizing single microbubbles in deep tissue, pose limitations to the use of these modalities in large organs. Another recently-developed imaging method is acoustic angiography 4. With this technique, high spatial-resolution images (in the order of 100 μ m) are obtained using tenfold higher frequencies than with normal DCE-US echo-imaging. Once again, the key lies in the UCAs peculiar response to ultrasound. Because of their highly nonlinear behaviour, UCAs can backscatter high-frequency broadband echo signals (15–35 MHz), which can be used to achieve improved spatial-resolution 5. However, frequency-dependent attenuation practically constrains the applicability of this technique to relatively small depths, such as those required for imaging the peripheral zone of the prostate (1–2 cm). Other techniques chose a different path rather than targeting high spatial-resolution. Standard DCE-US imaging (i.e., Harmonic Imaging, Pulse Inversion, and Amplitude Modulation) is an echo graphic technique, which in essence exploits variations in the second harmonic amplitude to generate real-time images of UCA kinetics when flowing through the vasculature 6,7. In particular, the analysis of microbubble flow-dynamics through the vessels can be used to reveal changes in the vasculature itself. To this end, several techniques which are based on the quantification of parameters related to UCA perfusion and dispersion have been proposed 8–12. Although the typical DCE-US spatial resolution is in the order of 1 mm, hence unsuitable for imaging microvascular changes, these techniques are still able to infer relevant information in relation to the 'angiogenetic switch' (the transition from a pre-vascular to a vascularized tumour phenotype) required for cancer to grow beyond 1–2 mm in diameter 13,14 .