## 2 A Synopsis of High Frame Rate Ultrasound Technology  
Before we proceed to discuss how in vivo investigation protocols for HiFRUS can be designed, let us first briefly review the current state-of-the-art in HiFRUS technology. While the notion of HiFRUS imaging with sub-millisecond time resolution has been in conception since the 1980s [17], the technology has garnered significant attention since the turn of this decade [18]. Such a rapid surge of interest is technically attributed to two engineering innovation trends. First, in the past decade, reconfigurable ultrasound scanners have become more prevalent [19; 20; 21; 22; 23; 24], as opposed to non-programmable clinical systems that are designed via an embedded system approach [25]. These open-architecture systems have enabled researchers to readily implement different variants of unfocused pulsing sequences that are essential for realizing HiFRUS [26]. Second, high-throughput computing hardware such as graphical processing units have greatly matured [27]. These parallel processing devices have served well to achieve real-time execution of HiFRUS-related computation tasks, such as pixel-by-pixel beamforming [28; 29; 30], Doppler processing [31; 32; 33], and post hoc filtering [34]. At present, a number of academic labs have developed in-house research scanners with HiFRUS capabilities. Worth particular mention are the in-house systems built at the Technical University of Denmark [19; 23], the University of Florence [21; 24], the Langevin Institute in Paris [35], and the Polish Academy of Sciences [36]. A few commercially available research platforms also allow similar HiFRUS implementations, such as Analogic Ultrasound (Peabody, MA, USA) [37], Verasonics (Kirkland, WA, USA) [22], US4 US (Warsaw, Poland), and Cephasonics (Santa Clara, CA, USA). Note that most conventional ultrasound scanners cannot be readily reconfigured to implement HiFRUS because their architecture is typically developed through an embedded system design approach that only specializes in performing beamline-based imaging [25]; this is why research scanners have become essential for advances in diagnostic ultrasound. Another point worth noting is that one clinical scanner developer (Supersonic Imagine, Aux-du-Province, France) is currently dedicated to the development of the HiFRUS market [38]. Also, specialized HiFRUS flow vector imaging modes are available on clinical scanners developed by Analogic Ultrasound (Peabody, MA, USA) [39] and Mindray (Shenzhen, China) [40]. In terms of its technical principles, HiFRUS imaging is fundamentally instituted upon the pulse-echo sensing paradigm, similar to conventional ultrasound imaging. However, instead of using focused beams for transmission, HiFRUS instead uses unfocused pulsing strategies in the forms of spherical waves [41] or plane waves [18; 38], as shown in Figure 1. On reception, the pulse echoes returned from the imaging plane of interest are recorded on every array transducer channel. Pixel-by-pixel beamforming is then performed using the channel-domain pulse-echo data, in which each image pixel value is derived through a \"delay and sum\" approach [28]. One salient point to be noted is that the lateral spatial resolution of HiFRUS is inherently not as fine as conventional ultrasound because unfocused transmit firings are used. Nonetheless, the temporal resolution is significantly improved because, from each transmit event's channel-domain data set, it is possible to form one image frame based on pulse-echoes returned from the entire imaging view. To improve the lateral resolution of HiFRUS images, one strategy that can be leveraged is to perform coherent compounding of low-resolution image frames derived from different spherical firing positions [41] or different plane wave steering angles [42]. While this compounding operation would unavoidably reduce the frame rate, it may be carried out recursively to limit the loss in frame rate [43].