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Stimulating high-frequency nonlinear oscillations of ultrasound contrast agents is helpful to distinguish microbubbles from background tissues. Nevertheless, inefficiency of such oscillations from most commercially available contrast agents and intense attenuation of the resultant high-frequency harmonics limit microbubble detection with high-frequency ultrasound. To avoid this high-frequency nature, we devised and explored a dual-frequency difference excitation technique to induce efficiently low-frequency, rather than high-frequency, nonlinear scattering from microbubbles by using high-frequency ultrasound. The proposed excitation pulse is comprised of 2 high-frequency sinusoids with frequency difference subject to the microbubble resonance frequency. Its envelope, with frequency being the difference between the 2 frequencies, is used to stimulate nonlinear oscillation of microbubbles for the consonant low-frequency harmonic generation, whereas high-imaging resolution is retained because of narrow high-frequency transmit beams. Hydrophone measurements and phantom experiments of speckle-generating flow phantoms were performed to demonstrate the efficacy of the proposed technique. The results show that, especially when the envelope frequency is near the microbubbleiquests resonance frequency, the envelope of the proposed excitation pulse can induce significant nonlinear scattering from microbubbles, the induced nonlinear responses tend to increase with the pulse pressures, and up to 26 dB and 36 dB contrast-to-tissue ratios with second- and fourth-order nonlinear responses, respectively, can be obtained. Potential applications of this method include microbubble fragmentation and cavitation with high-frequency ultrasound.

The efficiency of high-frequency destruction of microbubble-based contrast agent is limited by the high pressure threshold, while the difficulty of spatially confining destruction induced by low-frequency excitation to a small sample volume potentially increases the risk of adverse bioeffects. The dual-frequency excitation method involves the simultaneous transmission of 2 high-frequency sinusoids to produce an envelope signal at the difference frequency. The envelope signal provides the low-frequency driving force for oscillating the contrast-agent microbubbles to improve destruction efficiency, while the destruction sample volume remains small due to the high frequency of the carrier signal. Experimental results indicate that dual-frequency excitation consistently results in destruction of contrast-agent microbubbles that is superior to using a tone burst at the carrier frequency. With 1 micros pulse length, the acoustic pressure threshold for 95% microbubble destruction markedly reduces from 2.6 MPa to 0.9 MPa when the dual-frequency pulse having envelope frequency of 3 MHz is utilized instead of the 10-MHz sinusoidal pulse. In addition, the dual-frequency pulse having lower envelope frequency generally provides more efficient microbubble destruction, especially when the excitation waveform is long enough to guarantee sufficient envelope component.

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