Purpose: As a cavitation enhancer, low boiling point phase-change contrast agents (PCCA) offer potential for ultrasound-mediated drug delivery in applications including intracerebral hemorrhage or brain tumors. In addition to introducing cavitation, ultrasound imaging also has the ability to provide guidance and monitoring of the therapeutic process by localizing delivery events. However, the highly attenuating skull poses a challenge for achieving an image with useful contrast. In this study, the feasibility of transcranial activation and imaging of low boiling point PCCAs through the human temporal bone was investigated by using a low frequency ultrafast interframe activation ultrasound (UIAU) imaging sequence with singular value decomposition-based denoising. Methods: Lipid-shelled PCCAs filled with decafluorobutane were activated and imaged at 37°C in tissue-mimicking phantoms both without and with an ex vivo human skull using the new UIAU sequence and a low frequency diagnostic transducer array at frequencies from 1.5 to 3.5 MHz. A singular value decomposition-based denoising filter was developed and used to further enhance transcranial image contrast. The contrast-to-tissue ratio (CTR) and contrast enhancement (CE) of UIAU was quantitatively evaluated and compared with the amplitude modulation pulse inversion (AMPI) and vaporization detection imaging (VDI) approaches. Results: Image results demonstrate enhanced contrast in the phantom channel with suppressed background when the low boiling point PCCA was activated both without and with an ex vivo human skull using the UIAU sequence. Quantitative results show that without the skull, low frequency UIAU imaging provided significantly higher image contrast (CTR ≥ 18.56 dB and CE ≥ 18.66 dB) than that of AMPI and VDI (P < 0.05). Transcranial imaging results indicated that the CE of UIAU (≥18.80 dB) was significantly higher than AMPI for free-field activation pressures of 5 and 6 MPa. The CE of UIAU is also significantly higher than that of VDI when PCCAs were activated at 2.5 MHz and 3 MHz (P < 0.05). The CTR (23.30 [20.07-25.56] dB) of denoised UIAU increased by 12.58 dB relative to the non-denoised case and was significantly higher than that of AMPI at an activation pressure of 4 MPa (P < 0.05). Conclusions: Results indicate that low boiling point PCCAs can be activated and imaged at low frequencies including imaging through the temporal bone using the UIAU sequence. The UIAU imaging approach provides higher contrast than AMPI and VDI, especially at lower activation pressures with additional removal of electronic noise.

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