Focused ultrasound pulse repetition frequency impacts bubble activity and tracer delivery during blood-brain barrier opening

Abstract

The impact of pulse repetition frequency (PRF) on microbubble activity and blood-brain barrier (BBB) opening, for a fixed total number of pulses, is unclear. We studied bubble response to a range of PRFs (0.125, 0.25, 0.5, 1, and 2 Hz) by monitoring bubble emissions during focused ultrasound (FUS) sonications of the rat brain (274.3 kHz). When a location was treated with a test PRF and a control PRF of 1 Hz, at the same pressure, the change in the harmonic amplitude compared to the control decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and −38.3% at 2 Hz. Significant changes were not observed with repeated sonications at the same PRF. Furthermore, between PRFs of 0.25 and 1 Hz, no difference was observed in the threshold for broadband emissions, which are linked to the potential for tissue damage. Fluorescence imaging was used to estimate the concentration of Trypan Blue (TB) dye following a fixed-pressure 75-pulse exposure for PRFs of 1 and 0.25 Hz in rats. A 0.25 Hz PRF led to a 68.2% increase in the mean concentration measured at the target, with a 53.9% increase in the mean harmonic sum compared with a 1 Hz PRF. Finally, a harmonic emissions-based controller at a PRF of 0.25 Hz yielded similar TB delivery, with fewer instances of petechiae observed through histology, compared to the same controller at 1 Hz. These results may be adapted to improve the clinical safety margin of FUS-mediated BBB opening and to improve the sensitivity to detecting small harmonic signals from cavitating microbubbles.