Therapeutic Potentials of Localized Blood–Brain Barrier Disruption by Noninvasive Transcranial Focused Ultrasound: A Technical Review

Abstract

Summary: The demands for region-specific, noninvasive therapies for neurologic/psychiatric conditions are growing. The rise of transcranial focused ultrasound technology has witnessed temporary and reversible disruptions of the blood–brain barrier in the brain with exceptional control over the spatial precisions and depth, all in a noninvasive manner. Starting with small animal studies about a decade ago, the technique is now being explored in nonhuman primates and humans for the assessment of its efficacy and safety. The ability to transfer exogenous/endogenous therapeutic agents, cells, and biomolecules across the blood–brain barrier opens up new therapeutic avenues for various neurologic conditions, with a possibility to modulate the excitability of regional brain function. This review addresses the technical fundamentals, sonication parameters, experimental protocols, and monitoring techniques to examine the efficacy/safety in focused ultrasound–mediated blood–brain barrier disruption and discuss its potential translations to clinical use.

A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer’s disease

“…In our study, DCE-MRI following the tFUS session showed no evidence of BBB disruption. As pressure and the associated mechanical index (MI) are important indicators for achieving BBB disruption [ 6 ], we conjecture that the acoustic pressure level used in this study ( in situ pressure of ~135 kPa and MI of 0.27), which was under the threshold for creating stable cavitation of MBs, was not high enough to cause BBB disruption. This conjecture is consistent with a previous investigation involving sheep in which localized enhancement of BBB permeability occurred in regions subjected to acoustic pressure levels greater than 480 kPa (MI, 0.96) after intravenous injection of the same type of MBs [ 21 ].…”

“…It is also in agreement with a study by Hynynen and colleagues [ 22 ], which reported that an in situ pressure of 200 kPa (MI of >0.4) was needed to induce BBB disruption when 0.05 mL/kg dose of MBs (Optison, GE Healthcare, Princeton, NJ, USA) was used in rabbits at a similar tFUS frequency (i.e., 260 kHz) and pulsing scheme (10 ms tone-burst duration, 1 Hz sonication for 20 s). As successful BBB disruption depends on many factors, such as the type of MBs, sonication parameters, and transducer configuration, and given that excessive disruption may cause deleterious effects such as microhemorrhage [ 6 ], cautionary countermeasures such as acoustic emission detection of undesirable inertial cavitation [ 23 ] are needed to promote the safety of the procedure.…”

“…Low-intensity transcranial focused ultrasound (tFUS) is an emerging brain stimulation method, which could excite or inhibit neural activity in a reversible and non-invasive manner without raising tissue temperature [ 5 ]. In conjunction with intravenous injection of microbubble ultrasound contrast agents (MBs), the use of tFUS has also been investigated as a non-invasive means to transiently open the blood-brain barrier (BBB) in a region-specific fashion [ 6 ]. Although the exact mechanism requires further study, acoustic cavitation of MBs induced by tFUS is believed to amplify local pressure waves and thereby temporarily stretch the endothelial walls of the BBB around the targeted brain area [ 6 ].…”

The Role of Ultrasound as a Diagnostic and Therapeutic Tool in Experimental Animal Models of Stroke: A Review

“…Both stable and inertial cavitation together with microbubbles can help open the BBB. However, whereas stable cavitation disrupts the BBB via wobbled expansion and contraction of microbubbles, inertial cavitation is caused by the violent collapse of the microbubbles, which could lead to vascular damage [ 49 ]. The first study of ultrasound-induced BBB opening showed small lesions with severe parenchymal damage [ 50 ].…”

ASIC1a is required for neuronal activation via low-intensity ultrasound stimulation in mouse brain

“…Transcranial ultrasound such as opening blood-brain barrier (BBB) ( Cammalleri et al, 2020 ) for localized drug release and modulating neural activity ( Nicodemus et al, 2019 ; Legon et al, 2014 ; David et al, 2014 ) has been used for therapeutic treatments of various brain diseases. Many in vivo animal experiments and human clinical trials ( Supplementary file 1 ) proved the clinical potential of transcranial ultrasound stimulation.…”