Blood-Brain Barrier Disruption Induced by Focused Ultrasound and Circulating Preformed Microbubbles Appears to Be Characterized by the Mechanical Index

Abstract

This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using ultrasound pulses at 2.04 MHz using sonications with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrastenhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared to data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42-0.50). Histological examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

“…Recent studies have shown that larger microbubbles (4-5 and 6-8 μm) have a lower PRP threshold for BBB disruption than smaller bubbles (1-2 μm) (9, 20) when using PLs greater than 66.7 μs. Also, previous work, which analyzed concentrations of 0.01 to 0.25 μL∕g, did not show any significant differences in drug delivery concentration (16), which was in good agreement with other studies that used similar parameters (15).…”

“…A PRP threshold has been previously shown (2,14), and the present study also confirms it at short PLs. Second, previous work has demonstrated that lower center frequencies (e.g., 0.25 and 0.6 MHz) reduce the PRP threshold of BBB disruption (15,18). Third, effective BBB disruption requires a time interval where no ultrasound was emitted (i.e., intervals between pulses or bursts).…”

“…The PRP significantly influences the type and magnitude of cavitation activity an exposed microbubble undergoes. Molecular delivery requires a minimum PRP known as the cavitation threshold, which is typically lower than 1 MPa (2,14) and drops with the center frequency (15). Exposure of tissues above, but near, the threshold has so far yielded the most promising results with molecular delivery without any associated damage, as assessed using histological analysis (11).…”

Detecting blood–brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: A correlation study with contrast‐enhanced MRI

“…Indeed, FUS sonication could damage the brain tissue via FUS-induced edema, hemorrhage, ischemia, and apoptosis (10,18,19). To minimize brain damage, recent studies have focused on optimizing FUS parameters combined with intravascular preformed microbubbles to minimize sonication-induced hemorrhage (5,6,9,20,21). To ensure safe operation, the role of MRI becomes even more important; MRI not only aids FUS to localize the target region to gauge the BBB disruption but also provides simultaneous monitoring to detect incipient hemorrhage or neuronal dysfunction (18,22).…”

“…Recently, focused ultrasound (FUS) combined with intravascular ultrasound contrast agent (UCA) has been shown to transiently increase the transport of molecules across the BBB (4)(5)(6)(7). This increase in BBB permeability can be detected by contrast-enhanced MRI using gadolinium-based (8,9) or iron oxide-based contrast agents (10) or by single-photon emission computed tomography with 99m Tc-based radiotracers (11). Using these imaging methods to guide FUS sonication, BBB at the targeted brain regions can be disrupted accurately, facilitating the delivery of diagnostic or therapeutic agents (12)(13)(14)(15)(16)(17).…”