Phase-dependent dual-frequency contrast imaging at sub-harmonic frequency

Sub-harmonic imaging techniques have been shown to provide a higher contrast-to-tissue ratio (CTR) at the cost of relatively low signal intensity from ultrasound contrast agents (UCAs). In this study, we propose a method of dual-frequency excitation to further enhance the CTR of subharmonic imaging. A dual-frequency excitation pulse is an amplitude-modulated waveform which consists of two sinusoids with frequencies of f₁ (e.g., 9 MHz) and f₂ (e.g., 6 MHz) and the resulting envelope component at (f₁ - f₂) (e.g., 3 MHz) can serve as a driving force to excite the nonlinear response of UCAs. In this study, the f₂, at twice of the resonance frequency of UCAs, is adopted to efficiently generate a sub-harmonic component at half of the f₂ frequency, and f₁ is included to enhance the high-order nonlinear response of UCAs at the sub-harmonic frequency. The second- and third-order nonlinear components resulting from the envelope component would spectrally overlap at the sub-harmonic frequency when f₁ and f₂ are properly selected. We further optimize the generation of the sub-harmonic component by tuning the phase terms between second- and third-order nonlinear components. The results show that, with dual-frequency excitation, the CTR at sub-harmonic frequency improves compared with the conventional tone-burst method. Moreover, the CTR changes periodically with the relative phase of the separate frequency component in the dual-frequency excitation, leading to a difference of as much as 9.1 dB between the maximal and minimal CTR at 300 kPa acoustic pressure. The echo produced from the envelope component appears to be specific for UCAs, and thus the proposed method has the potential to improve both SNR and CTR in sub-harmonic imaging. Nevertheless, the dual-frequency waveform may suffer from frequency-dependent attenuation that degrades the generation of the envelope component. The deviation of the microbubble's resonance characteristics from the selection of dual-frequency transmission may also decrease the CTR improvement.