Acoustic emissions dose and spatial control of blood-brain barrier opening with focused ultrasound

Focused ultrasound (FUS), when combined with circulating microbubbles (MB), enables transient blood-brain barrier opening (BBBO). Numerous trials using different devices, treatment parameters, and monitoring technologies have created a need for approaches enabling comparative evaluation and standardization of MB-enhanced FUS treatments (MB-FUS). Analyzing 972 MB-FUS sonications performed with closed-feedback loop (CFL) power control in patients with high-grade gliomas, we investigated patient-specific, operator-adjusted, and device-related variables contributing to BBBO with a transcranial multi-element device with integrated acoustic emissions (AE) detectors and image-guidance. Real-time monitoring of AE signals and CFL-controller-automated adaptive adjustment allowed for spatiotemporal power control, along with enabling a dosing paradigm for gauging MB-FUS BBBO treatments. We find that 'AE dose' is an independent, continuous, and robust predictor of BBBO. We identify a dynamic dose range where BBBO increase per unit was maximized. This work provides comprehensive technical descriptions of AE-based CFL control and dosing of transcranial, targeted MB-FUS.