Blood-brain barrier opening


The blood-brain barrier (BBB) impedes the delivery of large drug molecules (> 400 Da). Several studies have shown that BBB can be non-invasively opened by applying low intensity focused ultrasound (FUS) following an intravenous injection of microbubbles (Burgess et al., 2016). Focused ultrasound-mediated BBB opening is temporary, reversible, and highly localized. 

The figure on the right illustrates how BBB opening requires applying FUS following a microbubble injection. Successful BBB opening can be validated by signal enhancement in the mouse brain on contrast-enhanced MR images (bottom), but the BBB remains intact if saline is injected instead of microbubbles (top).  Signal enhancement in the extraocular (eye) muscles occurs in both animals after contrast injection, as there is no barrier impeding its uptake there.

Large molecules, including therapeutic agents, antibodies, and gene therapy, can be delivered into brain tissue following BBB opening. This has potential for treating many brain diseases, such as tumors, Alzheimer's disease, and movement disorders. 

Inflammatory response following BBB opening

Our goal is to discover the optimal treatment parameters that allow for the delivery of therapeutic agents without causing damage to the brain tissue. While initial studies have shown promising results by achieving BBB opening without severe tissue damage or hemorrhage, there are still many open questions regarding its safety. For example, it has recently been shown that there is a physiological and immunological response following BBB opening in a rat model (Kovacs et al., 2017). One of our current projects focuses on characterizing how this response varies as a function of applied acoustic pressure.

A) Histology of mouse brain tissue. B) Immunohistochemistry showing inflammatory activation of microglia and astrocytes following FUS-mediated blood-brain barrier opening.

DAB staining reveals morphology of A) activated astrocytes and B) activated microglia about one hour after BBB opening.

Real-time monitoring of BBB opening

The applied acoustic pressure must be carefully controlled to ensure safe and effective BBB opening. Applying excessively high acoustic pressures could cause microbubbles implosions, which generate shock waves that cause tissue damage and severe hemorrhage. On the other hand, using more conservative acoustic pressure levels could result in low treatment efficacy. Determining the optimal acoustic pressure that results in both safe and effective BBB opening is difficult, as it depends on a variety of factors, including the patient's skull thickness, the target location, as well as the size and concentration of the microbubbles used. Acoustic emissions (AEs) from microbubble activity can be measured using passive cavitation detectors, and these AEs could be useful for predicting BBB opening and hemorrhage in real-time.

A) Broadband AEs centered at the subharmonic frequency were measured for all sonications during each treatment. The time of MB injection is represented by the vertical dashed line. B) Hemorrhage was associated with sonications containing broadband AEs.