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

Abstract

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.

Figure 1

a) Illustration of the therapy and imaging beam configuration. b) Overview of the configuration for the in vivo experiments. A rabbit is located supine over a water tank and the coaxial imaging and therapy beams pass into the brain through a craniotomy window.

Figure 2

a) An example image taken with an L17-5 probe illustrates that brain imaging can be readily achieved in subjects with a craniotomy. b) Imaging with the L9-3 probe mounted within the therapy array has less resolution, but general features, such as the hemispheres and cortex can readily be distinguished. c) An example contrast image taken after the bolus injection of agent. Scale: 1cm between large hache marks.

Figure 3

a) An example ROI curve in an unexposed hemisphere. b) An example time-intensity curve in an exposed hemisphere (0.69 MPa) shows evidence of destruction-reperfusion effects.

Figure 4

An expanded view of the 0.1 Hz, 0.69 MPa case indicating destruction-reperfusion effects and variables used for quantification of isolated individual pulse exposures.

Figure 5

Example bolus curves for 10s multiple pulse sequences (pressure = 0.69 MPa) as a function of PRF. a) 0.1 Hz b) 1 Hz and c) 2 Hz. By decreasing pulse intervals, the agent recovery time is reduced resulting in general agent depletion.

Figure 6

Example bolus curves for 10s multiple pulse sequences (PRF=2 Hz) as a function of increasing transmit pressure. a) 0.30, b) 0.44 and c) 0.69 MPa.

Figure 7

An expanded view of the 0.5 Hz, 0.69 MPa 10s multiple pulse sequence case indicating destruction-reperfusion effects and variables used for quantification exposure effects.