Permeability assessment of the focused ultrasound-induced blood-brain barrier opening using dynamic contrast-enhanced MRI.

Authors: Vlachos F, Tung YS, Konofagou EE

Focused ultrasound (FUS) in conjunction with microbubbles has been shown to successfully open the blood-brain barrier (BBB) in the mouse brain. In this study, we compute the BBB permeability after opening in vivo. The spatial permeability of the BBB-opened region was assessed using dynamic contrast-enhanced MRI (DCE-MRI). The DCE-MR images were post-processed using the general kinetic model (GKM) and the reference region model (RRM). Permeability maps were generated and the K(trans) values were calculated for a predefined volume of interest in the sonicated and the control area for each mouse. The results demonstrated that K(trans) in the BBB-opened region (0.02 +/- 0.0123 for GKM and 0.03 +/- 0.0167 min(-1) for RRM) was at least two orders of magnitude higher when compared to the contra-lateral (control) side (0 and 8.5 x 10(-4) +/- 12 x 10(-4) min(-1), respectively). The permeability values obtained with the two models showed statistically significant agreement and excellent correlation (R(2) = 0.97). At histological examination, it was concluded that no macroscopic damage was induced. This study thus constitutes the first permeability assessment of FUS-induced BBB opening using DCE-MRI, supporting the fact that the aforementioned technique may constitute a safe, non-invasive and efficacious drug delivery method.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To quantify and map blood–brain barrier permeability after focused ultrasound–induced opening in mice using dynamic contrast-enhanced MRI and kinetic modeling.

Animal model / Human subject Mouse (Mus musculus); strain: None; age: None; sex: None

Disease model healthy (BBB opening in normal mouse brain)

Targeted brain region(s) None (Sonicated Region In The Mouse Brain)

Cargo name and characteristics Focused ultrasound (FUS): a non‑invasive, targeted physical modality (focused acoustic energy) used in vivo in mice to transiently and locally open the blood–brain barrier, producing increased regional permeability measurable by DCE‑MRI; not a molecular cargo but an experimental physical agent.

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes Focused ultrasound with microbubbles transiently increased blood–brain barrier permeability by ~two orders of magnitude in the sonicated mouse brain regions (higher Ktrans) without inducing macroscopic tissue damage, supporting a safe noninvasive drug-delivery approach.

Safety-related matter Histological examination showed no macroscopic damage, and the authors conclude FUS-induced BBB opening may be a safe, non-invasive drug delivery method.

Brain Region

Ultrasound Parameters

FUS Mode pulsed

Duration of a single FUS session None.

Treatment frequency single session

We are open to feedback. If you see a mistake or have a suggestion, please contact us.