How ultrasound is delivered matters when opening the blood-brain barrier

The schematic representation of the experimental setup employed in the study. Credit: Biomedical Physics & Engineering Express (2025). DOI: 10.1088/2057-1976/ae1f1f

Focused ultrasound combined with microbubbles is increasingly being used to safely and reversibly open the blood-brain barrier (BBB) for the treatment of brain tumors and neurodegenerative disorders. While much attention has been placed on acoustic pressure and total exposure time, less is known about how the temporal structure of ultrasound delivery influences microbubble activity.

In a study appearing in Biomedical Physics & Engineering Express , researchers from the Institute of Fundamental Technological Research at the Polish Academy of Sciences systematically examined how ultrasound parameters (i.e., pressure, pulse duration, and microbubble concentration) shape acoustic cavitation signals, which are widely used to guide BBB opening.

Using a controlled flow model, the authors confirmed known trends, such as optimal pressure windows for stable cavitation and the strong influence of microbubble concentration on acoustic emissions.

A particularly interesting finding was that the number of ultrasound pulses delivered can significantly affect cavitation behavior even when the total “on-time” is similar. This suggests that effective sonication time alone may not fully describe the dose experienced by microbubbles. Instead, pulse history—how many times bubbles are excited—may play an underappreciated role in how cavitation evolves during treatment.

“Before initiating the preclinical studies on ultrasound-mediated BBB opening, we aimed to better understand the nature of oscillating microbubbles so that we could later precisely control the acoustic parameters to achieve the desired stable oscillations,” said senior author Łukasz Fura, Ph.D., assistant professor of ultrasound at the Polish Academy of Sciences Institute of Fundamental Technological Research.

“Initially, we intended to investigate solely the effects of acoustic pressure, microbubble concentration, and pulse duration on the cavitation dose. The relationship between the number of pulses and cavitation was identified somewhat unexpectedly. This finding requires more extensive investigation, which we plan to undertake in the near future.”

These results are relevant to BBB opening strategies that rely on real-time acoustic feedback, reinforcing the idea that how ultrasound is delivered can matter as much as how long.

At the same time, the study was performed in a simplified experimental system, and many effects were most clearly observed at microbubble concentrations higher than those typically achieved in vivo, especially during clinical infusion protocols. Blood flow, vessel size, and replenishment dynamics were not varied and remain important factors for translation.

Overall, this work provides mechanistic insight into microbubble behavior and highlights pulse structure as a potential consideration for refining focused ultrasound-mediated BBB opening while underscoring the need for continued in vivo validation under clinically realistic conditions.