Dual frequency transcranial ultrasound for contrast enhanced ultrafast brain functional imaging

Ultrafast, high sensitivity Doppler imaging has led to the development of functional ultrasound (fUS), a novel functional imaging modality for detecting haemodynamic changes in cerebral blood vessels at high spatialtemporal resolution (∼100 μm, ∼1 ms). To allow for this blood tissue signal to be detected the skull either needs to be partially removed or thinned. To overcome this attenuation it has been shown that blood tissue signal can be enhanced using microbubble contrast agent, allowing for transcranial functional imaging to take place. By continuing to use a high frequency transmission, however, the attenuation in penetration will remain high and will limit imaging depths. Furthermore, by driving this microbubble oscillation with a frequency far greater than the resonance of the majority of microbubbles a suboptimal response is produced. We instead propose a dual frequency system which first transmits with a low frequency transducer to significantly decrease attenuation in transmit and to produce a stronger microbubble response, and to then receive with a second, higher frequency transducer set at an angle to detect the superharmonic component of the resulting broadband microbubble signal. From an ex vivo study it was found that the microbubble response for the dual frequency system increased relative to the conventional single frequency system with peak negative pressure (PNP) (starting from 140 kPa onwards) and showed excellent tissue suppression with a +12 dB gain in CTR when comparing the best performance of the two systems. This was followed by a promising in vivo pilot study demonstrating that the our dual frequency system was able to image cerebral blood flow in mice with intact skulls.