# Enhancement of High-Intensity Focused Ultrasound Heating by Short-Pulse Generated Cavitation
## 3 High-Speed Observation of Cavitation Bubbles Induced by Trigger HIFU Exposure  
### Cloud Cavitation Formation by Dual-Frequency Ultrasound Exposure  
When the shock scattering phenomena is used to form bubble clouds, negative and positive pressures have different roles. After negative pressure generates cavitation bubbles enough to provide a pressure release surface, positive pressure is converted to negative pressure exceeding the intrinsic threshold and forms cavitation clouds. Either peak negative or positive pressure can be emphasized by superimposing the second-harmonic ultrasound onto the fundamental component [51; 52; 53; 54]. Figure 1: Schematic of three examples of a trigger high-intensity focused ultrasound (HIFU) sequence with intervals for ultrasonic imaging. (**a**) single spot focus sequence which is typically repeated for thermal treatments; (**b**) spot scanning trigger pulses followed by spot scanning heating bursts; (**c**) spot scanning trigger pulses followed by heating bursts with a directly synthesized focus with a ring shape to cover six foci of scanned trigger pulses. The focal plane of trigger pulses in (**b**,**c**) is shifted 7 mm forward from the geometric focal plane. Figure 3 shows the schematics of four kinds of second-harmonic superimposed sequences, PP, NN, PN, and NP sequences. 1.6-MHz ultrasound was superimposed onto a 0.8-MHz ultrasound to emphasize either peak positive pressure (P wave) or peak negative pressure (N wave) in the earlier and later periods of 62.5 \(\upmu\)s duration by adjusting the phase difference between the two frequency components. Cavitation bubbles generated in a poly(acryl amide) (PAA) gel at an acoustic intensity of 42 kW/cm\({}^{2}\) were observed with a high-speed camera (HPV-2A, Shimadzu, Kyoto, Japan) at a frame rate of 500 kfps with an exposure time of 250 ns. The results are shown in Figure 4 [54]. A 128-element array transducer with both diameter and focal length of 100 mm (Imasonic, Voray sur l'Ognon, France) was placed in a water tank so that the ultrasound focus was located in the gel phantom in degassed water. The second-harmonic superimposed voltage was applied from 128-channel stair case voltage drive amplifiers (Microsonic, Tokyo, Japan). The temperature and dissolved oxygen in water were kept at 37 \({}^{\circ}\)C and 20%-23%, respectively. The gel included 22.5% bovine serum albumin (BSA). Figure 3: Schematics of four kinds of dual-frequency ultrasound sequences. 1.6-MHz ultrasound was superimposed onto a 0.8-MHz ultrasound to emphasize either peak positive pressure (P wave) or peak negative pressure (N wave) by adjusting the phase difference between two frequency components. Figure 2: Ultrasound pressure field simulated by assuming linear propagation and neglecting attenuation. (**a**) without focal steering; (**b**) directly synthesized focus by a sector vortex method with a vortex mode number of 4. In the results with the NP sequence, cavitation clouds were formed immediately after the P-wave exposure started, while no cavitation clouds were observed in all five of the results with the NN and PN sequences. There was only one case in which the cavitation cloud formation was observed with the PP sequence. The clouds were formed by the NP sequence with the highest reproducibility among the four sequences. The measured peak-positive and negative pressures of the P-waves were \(+60\) and \(-8\) MPa, respectively, and those of the N-waves were \(+11\) and \(-9\) MPa, respectively, at an intensity of \(25\) kW/cm\({}^{2}\). Therefore, the N-waves did not produce a peak-negative pressure exceeding the intrinsic threshold even when the waves were reflected by bubbles. However, the slightly greater peak-negative pressure than that of the P-waves contributed to the production of significantly more scattered bubbles, which increased the probability of the cloud formation through a shock scattering mechanism during the exposure of the immediately following P-waves.