# Enhancement of High-Intensity Focused Ultrasound Heating by Short-Pulse Generated Cavitation
## 2 Trigger HIFU Sequence  
The effect of bubble-enhanced heating was experimentally observed in a moderate intensity ultrasound field, such as \(I_{\text{SPTA}}\) of 400 W/cm\({}^{2}\) at a frequency of 2.18 MHz [15], \(I_{\text{SPTA}}\) of 290 W/cm\({}^{2}\) at 3.2 MHz [16], and acoustic power of 28.9 W at 1.85 MHz [19], when using ultrasound contrast agents (Levovist [15], Optison [16], and Definity [19]) consisting of encapsulated microbubbles. However, it is difficult to control the spatial distribution of such ultrasound contrast agents inside a body to locally enhance the ultrasonic heating. It causes the shift of the greatest heating position from the transducer focus to a pre-focal region [19]. To generate microbubbles containing slightly soluble gas inside a body, the usage of nanoparticles that can be vaporized into microbubbles by HIFU pulses or short bursts has been developed and investigated [23; 37; 38; 39]. Such phase change nanoparticles enable us to control the region of microbubbles induced by HIFU pulses. In the studies, HIFU pulses with a duration of less than 100 us and peak-negative-pressure of 2.4-15.5 MPa were used to vaporize nanoparticles. For the bubble-enhanced heating using nanoparticles [23], the pulse was followed by a long burst with a duration of 670 ms and acoustic power of 5.2 W, and this combination of the high intensity pulse and long burst was repeated for 30 s.  
Even without injecting ultrasound contrast agents nor nanoparticles, it is possible to induce microbubbles inside a body by extremely high-intensity ultrasound pulses. The cavitation thresholds for a single or two-cycle focused ultrasound pulse were measured in several media, such as water, blood, kidney tissue, and so on [40]. Bubble clouds will be formed in the region where the peak-negative pressure exceeds the threshold, called \"intrinsic threshold\" [41]. The threshold range of peak negative pressure was from \(-26\) to \(-30\) MPa in the media with high water content. In another study, a threshold of \(-33\) MPa was observed in water by a focused acoustic pulse, and it was considered that cavitation bubbles were originated from nanometer-sized nuclei [42]. In histotripsy, cavitation bubbles are induced by extremely high-intensity pulses with a peak-negative pressure exceeding the threshold range and a soft tissue is eroded by the collapse of the bubbles [43; 44; 45]. Although the intrinsic threshold is extremely high, an acoustic pulse with a longer duration can generate clouds of bubbles even at a lower intensity because of the mechanism called \"shock scattering\" [46]. The ultrasound waveform in a focal region at a high intensity has a steep and large peak-positive pressure and relatively small peak-negative pressure--for instance, +78 MPa and \(-15\) MPa, respectively [46]--owing to the focusing of nonlinearly propagated ultrasound. Once cavitation bubbles are generated, they provide a pressure release surface converting the positive pressure to negative pressure, which exceeds the intrinsic threshold. From a previous study for a cavitation-enhanced ultrasonic heating in 2003 [13], a trigger HIFU sequence consisting of high-intensity short pulses generate bubble clouds, named \"trigger pulses\", and following moderate-intensity long bursts for the enhancement of the ultrasonic heating, named \"heating bursts\" was evolved. The typical duration of the trigger pulse was 10-100 us. The duration time was set longer than the pulse duration of several us in histotripsy studies [40; 41; 43; 44; 45]. Since a peak negative pressure of a typical trigger pulse did not exceed the intrinsic threshold, typically around \(-30\) MPa, the relatively longer duration time was necessary to form bubble clouds through a shock scattering mechanism. The upper limit of the duration time was decided to avoid the effect of standing wave components--for instance, those caused by reflections between a HIFU transducer and HIFU focus or skin surface.