Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound

Ultrasound-stimulated microbubbles are currently under investigation as a means of transiently disrupting the blood-brain barrier (BBB) and it has been shown that the strength of this effect is highly dependent on ultrasound exposure conditions. The objective of this study was to investigate the potential for contrast agent destruction in the brain under conditions relevant to BBB disruption with a view to determining its possible influence on effective exposure parameters. An ultrasound imaging array was mounted within the aperture of a 1.68-MHz focused therapy transducer. Pulse lengths of 10 ms were used at repetition rates of 0.1-2.0 Hz and pressures from 0.30-0.88 MPa. Contrast imaging was performed after the bolus injection of Definity, and contrast time-intensity curves were then analyzed for regions-of-interest exposed to the therapy beam. Individual therapy pulses resulted in microbubble destruction, with the degree of agent depletion and replenishment time increasing with transmit pressure. As the pulse repetition rate was increased, agent reperfusion between pulses was incomplete and the concentration within the beam was progressively diminished, to a degree dependent on both pressure and repetition rates. These results demonstrate that microbubble concentration can be substantially influenced by destruction induced by therapeutic ultrasound pulses. The kinetics of this effect may therefore be a significant factor influencing the efficiency of BBB disruption, suggesting that monitoring of the spatial and temporal distribution of contrast agents may be warranted to guide and optimize BBB disruption therapy in both preclinical and clinical contexts.