Real-time transcranial mapping in non-human primates and human subjects during opening of the blood-brain barrier

Abstract

Opening of the blood-brain barrier (BBB) with focused ultrasound and microbubbles has been shown repeatedly in several preclinical disease models and clinical studies. Transcranial 2D mapping of the cavitation mechanism responsible for BBB opening is however challenging in primate brains due to the skull thickness. A real-time cavitation mapping system will be presented that can transcranially map the cavitation occurrence and dose in real time throughout the BBB opening procedure in Alzheimer’s disease (AD) adult and diffuse intrinsic pontine glioma (DIPG) pediatric patients. Passive acoustic mapping (PAM) with coherence factor (CF) correction is used to passively map the microbubble activity within the brain. Compared to passive cavitation detection (PCD), multi-element CF-PAM allows us to determine the exact location of the BBB opening without the need of contrast-enhanced MRI. An open-architecture ultrasound imager (Vantage, Verasonics, Redmond, WA) with a P4-2 (ATL, Philips) is used to provide the best tradeoff between transcranial propagation, spatial resolution and depth penetration. The system is first optimized in targeting the putamen during BBB opening in non-human primates followed by feasibility in the prefrontal cortex in AD and the pons in DIPG patients, achieving feedback rates of 2 Hz during the clinical procedures.