Secondary effects on brain physiology caused by focused ultrasound-mediated disruption of the blood-brain barrier.

Focused ultrasound (FUS) combined with microbubbles is a non-invasive method for targeted, reversible disruption of the blood-brain barrier (FUS-BBB opening). This approach holds great promise for improving delivery of therapeutics to the brain. In order to achieve this clinically important goal, the approach necessarily breaks a protective barrier, temporarily, which plays a fundamental role in maintaining a homeostatic environment in the brain. Preclinical and clinical research has identified a set of treatment parameters under which this can be performed safely, whereby the BBB is disrupted to the point of being permeable to normally non-penetrant agents without causing significant acute damage to endothelial or neuronal cells. Much of the early work in this field focused on engineering questions around how to achieve optimal delivery of therapeutics via BBB disruption. However, there is increasing interest in addressing biological questions related to whether and how various aspects of neurophysiology might be affected when this fundamental protective barrier is compromised by the specific mechanisms of FUS-BBB opening. Improving our understanding of these secondary effects is becoming vital now that FUS-BBB opening treatments have entered clinical trials. Such information would help to safely expand FUS-BBB opening protocols into a wider range of drug delivery applications and may even lead to new types of treatments. In this paper, we will critically review our current knowledge of the secondary effects caused by FUS-BBB opening on brain physiology, identify areas that remain understudied, and discuss how a better understanding of these processes can be used to safely advance FUS-BBB opening into a wider range of clinical applications.