Microvascular Imaging with Super-Resolution Ultrasound

Super-resolution ultrasound imaging (SRUS) is a branch of ultrasound techniques aiming to image and quantify the vasculature beyond the diffraction limit [1]. Going beyond the diffraction limit of conventional ultrasound entails the possibility of imaging the microvasculature, namely arterioles, venules, and maybe even the smallest vessels in the body: the capillaries. In one of the main SRUS techniques, also called ultrasound localization microscopy, isolated microbubbles from ultrasound contrast agents are used to acquire data for SRUS image formation. Super-resolution ultrasound imaging using isolated microbubbles was inspired by one of the Nobel prize-winning approaches for super-resolution microscopy [2]. In one of these approaches, the ability to turn the fluorescence of single molecules on and off was used. By capturing numerous images of the same object, each image with a different group of molecules fluorescently turned on and superposing the resultant image stack, a super-resolved microscopy image, i. e., an image showing structures below the diffraction limit of light, could be created. Likewise, the SRUS images are created by superposing thousands of successive ultrasound images of isolated microbubbles as they move through the vasculature. More specifically, the SRUS images are created using a series of post-processing steps. After scanning the organ or tissue of interest, the sparsely distributed intravascular microbubbles must be detected. Detection can be done with, e. g., contrast-enhancing sequences, such as pulse inversion or amplitude modulation, or with singular value decomposition (SVD) techniques [3]. Next, the single microbubbles are isolated and localized [4]. The precision of this localization is a critical step in obtaining super-resolution [5]. Instead of merely superposing each of the microbubble localizations, as done in super-resolution microscopy, the movements of the microbubbles as they follow the bloodstream between frames are used to create trajectories that can reveal microbubble velocity and direction [6–10]. Lastly, another essential difference between super-resolved microscopy and ultrasound is motion. In order to localize the microbubbles precisely, it is necessary to compensate for the motion that stems from, e. g., breathing and heart beating during scanning [11, 12]. The resulting trajectory-based images, created from localizing and tracking the isolated microbubbles, are used to reveal physiological or pathological changes in the vasculature. The majority of studies that have been published are preclinical studies, many of which have investigated technical feasibilities and developments. As microvascular disease can occur anywhere in the body, SRUS has been applied to various anatomical structures, from the eyes to the heart to the prostate [13–15]. However, the largest areas of interest have been the vasculature of the brain, the kidneys, and malignant tumors. In the brain, SRUS has been used to evaluate age-related vascular alterations, which revealed that microbubble velocities were slower and vessels more tortuous in old mouse brains compared with younger ones [16]. It has also been used to measure cerebral arterial pulsatility in mice to improve our understanding of the effects of increased pulse pressure on the brain’s microvasculature [17]. As a last example, SRUS has been acquired through an intact human skull at the temporal acoustic window [18], demonstrating cerebrovascular hemodynamics, including turbulent flow in an aneurism and chaotic flow Sofie Bech Andersen Charlotte Mehlin Sørensen Jørgen Arendt Jensen Michael Bachmann Nielsen Editorial