In vivo transcranial cavitation detection during ultrasound-induced blood-brain barrier opening

The blood-brain barrier (BBB) has been shown capable being opened noninvasively through the combined application of focused ultrasound (FUS) and microbubbles. In order to better identify the underlying mechanism responsible for BBB opening as well as associated safety, the in vivo noninvasive and transcranial cavitation detection associated with FUS-induced BBB opening was studied. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity ^® microbubbles. After Definity ^® were injected intravenously, pulsed FUS was applied (frequency: 1.525 and 1.5 MHz, peak- negative pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with 30s interval) on the right hippocampus in twenty-six mice in vivo through their intact scalp and skull. T1-weighted MRI was used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the inertial cavitation onset and duration. The bubble behavior was shown detectable in vivo through the intact scalp and skull. We demonstrated that: 1) the inertial cavitation response could be detected transcranially during BBB opening; 2) the inertial cavitation pressure threshold lied at 0.45 MPa but the BBB was opened at 0.30 MPa so the BBB can be opened without requiring inertial cavitation; 3) the BBB could be opened without any cellular damage.