Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs). The outcome of BBBD enhances local drug or gene delivery for improving the treatment efficiency of brain diseases. However, over-excitation of FUS may cause brain damage such as shutdown blood flow, intracerebral hemorrhage and brain edema. Therefore, it is essential to develop a an imaging system to assess dynamic perfusion changes during FUS-induced BBBD process. Here, we used the high-frequency destruction/reperfusion contrast-enhanced imaging technique to observe the cerebral perfusion under the cases of with/without hemorrhage in BBBD procedure. The BBB was disrupted by a 2.25 MHz FUS combining with MBs at 0.5-0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of time-intensity curve was higher than prior to MBs destruction at 20 s after sonication and the blood flow would be obstructed due to the blood coagulates at 60s after sonication. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure. In conclusion, the blood flow velocity changes have potential as an in vivo tool for quantifying the extent of the FUS-induced BBBD and detecting intracerebral hemorrhage occurrence.

Focused ultrasound (FUS) in the presence of circulating microbubbles (MBs) has been confirmed to temporarily and locally enhance the permeability of the bloodbrain 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.