Increasing BBB Permeability via Focused Ultrasound: Current Methods in Preclinical Research

Abstract

The tightly regulated permeance of the blood-brain barrier (BBB) greatly limits the range of therapeutic treatment options for central nervous system (CNS) diseases. The use of focused ultrasound (FUS), in conjunction with circulating microbubbles, is a unique approach whereby the transcranial application of acoustic energy, focused within targeted brain areas, can be used to induce a noninvasive, transient, and targeted increase in BBB permeability. This can provide an avenue for the delivery of therapeutic agents from the systemic circulation into the brain. While this approach continues to show great promise and has entered clinical testing, there remains a need for preclinical research to investigate the long-term effects of single and repeated FUS treatment on cerebrovascular health and neurological function, as well the pharmacokinetics of specific drugs following FUS. Additionally, there is a need for improved monitoring strategies that can precisely predict resulting bio-effects. This will allow the continued development of control algorithms that can further increase the safety profile of FUS. Here we will describe two approaches to study FUS-mediated increases in BBB permeability in rodent models: MRI-guided FUS and in vivo two-photon fluorescence microscopy FUS experiments. The goal of this chapter is to outline each procedure, present options for experimental design, and highlight important considerations for the collection and interpretation of data.