Advances in acoustic monitoring and control of focused ultrasound-mediated increases in blood-brain barrier permeability

Abstract

Transcranial focused ultrasound (FUS) combined with intravenously circulating microbubbles can transiently and selectively increase blood–brain barrier permeability to enable targeted drug delivery to the central nervous system, and is a technique that has the potential to revolutionize the way neurological diseases are managed in medical practice. Clinical testing of this approach is currently underway in patients with brain tumors, early Alzheimer’s disease, and amyotrophic lateral sclerosis. A major challenge that needs to be addressed in order for widespread clinical adoption of FUS-mediated blood–brain barrier permeabilization to occur is the development of systems and methods for real-time treatment monitoring and control, to ensure that safe and effective acoustic exposure levels are maintained throughout the procedures. This review gives a basic overview of the oscillation dynamics, acoustic emissions, and biological effects associated with ultrasound-stimulated microbubbles in vivo, and provides a summary of recent advances in acoustic-based strategies for detecting, controlling, and mapping microbubble activity in the brain. Further development of next-generation clinical FUS brain devices tailored towards microbubble-mediated applications is warranted and required for translation of this potentially disruptive technology into routine clinical practice.

Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent

“…FUS has been explored as a method to deliver therapies across the BBB for malignancies 13 , neurodegenerative diseases 14 , 15 , and movement disorders 15 – 17 . The technology has also been shown to be safe and efficacious in patients with Alzheimer’s Disease and brain tumors 18 , 19 .…”

A local difference in blood–brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound

“…Meanwhile, the Th region located dorsal to the hippocampus is a potential target for Alzheimer's disease treatment 13,20 . Recent advances in acoustic monitoring and feedback-controlled sonication demonstrated in a pre-clinical and clinical study may mitigate location-specific variability and safely control the BBB permeability [21][22][23][24][25] . Yet even with the feedback-controlled sonication, inter-and intra-subject variation was reported, hence understanding the sources of variability is important 21,26 .…”

Focused Ultrasound for Noninvasive, Focal Pharmacologic Neurointervention

“…Interestingly, another study developed a skull localization and registration routine based entirely on ultrasound data, toward the implementation of an ultrasound-guided FUS platform ( Crake et al, 2018 ). For a comprehensive review of methods for treatment monitoring and control, see Jones and Hynynen (2019) .…”