The effect of transcranial focused ultrasound target location on the acoustic feedback control performance during blood-brain barrier opening with nanobubbles

Bingbing Cheng,Chenchen Bing,Rajiv Chopra

doi:10.1038/s41598-019-55629-2

Abstract

Real-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may be important for facilitating the clinical adoption of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening, both to ensure safe acoustic exposures, and to achieve repeatable and consistent opening. Previously our group demonstrated that successful BBB opening was achievable with both commercially available microbubbles and custom-made nanobubbles under acoustic feedback control. In a recent study, we demonstrated the acoustic control performance was not sensitive to the nanobubble concentration within 109–1011 bubbles/ml. The goal of this study was to examine the effect of the ultrasound target location in the rat brain on the acoustic control quality during BBB opening with nanobubbles. Temporal analysis of the received acoustic signals during each ultrasound pulse indicated that stable nanobubble oscillation was present throughout the entire 10 ms ultrasound exposure. The acoustic feedback control signals were very sensitive to the brain spatial location in rats. There appears to be a shared pattern of acoustic control stability in the brain across different animals, suggesting anatomical features are an underlying cause. The findings emphasize the importance of tuning acoustic feedback control algorithms for specific rodent brain regions of interest to ensure optimal performance.

Highlights

Real-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may be important for facilitating the clinical adoption of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening, both to ensure safe acoustic exposures, and to achieve repeatable and consistent opening
There are some shared features across these algorithms: (1) they are all based on monitoring 1 or more harmonic bands to adjust the ultrasound exposure level compared to a pre-defined threshold; (2) acoustic emissions outside the expected harmonic frequency bands are used as indicators of inertial cavitation which is believed to be associated with tissue damage; and (3) a bolus of microbubbles are administered into the bloodstream intravenously, which results in a time varying concentration during application of the control signal
We recently developed a feedback control algorithm based on the first ultra-harmonic emissions of stimulated microbubbles by maintaining the ultra-harmonic emission at a threshold level for a fixed duration during an infusion of microbubbles

Summary

Introduction

Real-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may be important for facilitating the clinical adoption of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening, both to ensure safe acoustic exposures, and to achieve repeatable and consistent opening. Even within a single patient, the ultrasound pressure required to open the BBB in different brain locations will vary due www.nature.com/scientificreports to variations in skull anatomy and brain vasculature To address this challenge, several groups including ours are investigating the utility of non-linear acoustic emissions from stimulated microbubbles as a feedback indicator to achieve safe and consistent BBB opening. There are some shared features across these algorithms: (1) they are all based on monitoring 1 or more harmonic bands to adjust the ultrasound exposure level compared to a pre-defined threshold; (2) acoustic emissions outside the expected harmonic frequency bands are used as indicators of inertial cavitation which is believed to be associated with tissue damage; and (3) a bolus of microbubbles are administered into the bloodstream intravenously, which results in a time varying concentration during application of the control signal. The overall goal of these investigations is to develop a robust strategy for BBB opening in rodents to facilitate neuroscience research into the applications of this novel bioeffect

Objectives

Methods

Results

Discussion

Conclusion