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).