The Potential for Blood-Brain Barrier Disruption During Transcranial Ultrasound Super-Resolution Imaging

Super-resolution (SR) ultrasound imaging dramatically improves the resolution of microvascular images beyond the diffraction limit. It is well-established that ultrasound with contrast agents, such as those used in SR, can open the blood-brain barrier (BBB) under certain conditions. This study aimed to quantify potential BBB disruption (BBBD) during 3-D transcranial ultrasound SR as a function of mechanical index (MI) and pressure distribution. Mice were imaged using conventional 3-D SR sequences. BBBD was quantified through fluorescence imaging of dye extravasation for mechanical indices in the range of 0-0.78 (measured in water). The results suggest that when 3-D SR images are acquired at 0.78 MI, BBBD occurs; however, imaging was achievable without significant dye extravasation below 0.78. In addition, hydrophone measurements and 3-D simulations were performed to estimate local pressure distributions in the brain. For a transducer surface MI of 0.64, estimates of the local MI within the brain averaged 0.18 ± 0.09, ranging from 0.03 to 0.44, with no significant BBBD observed. However, for a transducer surface MI of 0.78, significant BBBD was observed (p < 0.05), where the values in the brain range from 0.04 to 0.53, averaging 0.22 ± 0.11. This suggests that the local MI that generates BBB bio-effects is within the range of 0.44-0.53 MI. For the 0.78 MI case, 4.8% of the total brain volume had a pressure above 0.44 MI according to hydrophone measurements (4.8 mm² of the 100 mm² 2-D plane scanned) and 11.10% according to simulations (74.6 mm³ of the 777.5 mm³ volume).