Contrast-enhanced ultrasound imaging for the detection of transient dynamics of blood-brain barrier opening induced by focused ultrasound

Focused ultrasound (FUS) in the presence of circulating microbubbles (MBs) has been confirmed to temporarily and locally enhance the permeability of the blood-brain barrier (BBB). However, improper FUS sonication parameters not only achieve BBB destruction (BBBD) but also induce brain damages such as intracerebral hemorrhage (ICH), brain edema, transient blood-supply shortage. Therefore, it is essential to develop a real-time imaging system to assess the dynamic perfusion changes during FUS-induced BBBD process. Here, we proposed a high-frequency microultrasound imaging system with sigmoid-based destruction and replenishment (D/R) technique for the observation of brain microcirculation changes after performing BBBD with or without hemorrhage. The BBB was disrupted by a 2.25-MHz FUS probe with acoustic pressure of 0.5 MPa and 0.7 MPa (for without and with hemorrhage group, respectively), pulse repetition frequency of 1 Hz, pulse length of 1 ms, and sonication duration of 60 s following intravenous injection of MBs. The results showed that the velocity of blood flow decreased after BBBD. The location of slowing down of the local flow velocity was consistent with the BBBD area and also the local enhanced permeability region detected by MR Ktrans imaging. In addition, the variation of blood flow depended on the applied acoustic pressure, and the position where flow velocity became particularly slow was associated with the occurrence of hemorrhage. In conclusion, our proposed ultrasound D/R imaging technique provides a useful tool for monitoring both the region and degree of BBBD and the presence of hemorrhage during BBBD process. This novel method provides an immediate feedback for the control of BBBD and avoiding or minimizing bioeffect in the future.