Reliable and safe blood–brain barrier opening by closed-loop feedback control of focused ultrasound

Abstract

Real-time cavitation monitoring and feedback controller is critical to safe and effective brain drug delivery by focused ultrasound (FUS)-mediated blood-brain barrier disruption (FUS-BBBD). However, existing controllers were either open-loop or using a generalized target cavitation level (TCL). This study aimed to develop a closed-loop feedback controller with TCL defined based on the baseline stable cavitation level (SCL) of each subject. A single-element FUS transducer with a coaxially aligned passive cavitation detector (PCD) was used. PCD signals were first acquired with “dummy” sonication to determine TCL defined to be 0.5, 1, 2, 3, or 4 dB above baseline SCL. A custom closed-loop feedback controller was developed to control SCL to be at each TCL. After sonication, wild-type mice were intravenously injected with Evans Blue (EB) to quantify FUS-BBBD using ex vivo fluorescence imaging. The fluorescence intensity of delivered EB increased in an average of 1.4-fold, 2.6-fold, and 3.9-fold at 1, 2, and 3dB respectively compared to the 0.5-dB group. No apparent hemorrhage was found in lower TCLs, and hemorrhage was consistently found in the 4-dB group. This study demonstrated that the individualized feedback controller achieved reliable and safe FUS-BBBD at selected TCL.