Microbubbles play a critical role in BBB opening, with FUS-induced oscillations facilitating the transient BBB opening. Two types of bubble oscillation occur, depending in part upon the applied acoustic pressure: stable oscillations (stable cavitation); and inertial cavitation, where the bubbles can collapse, and which can cause adverse effects such as tissue damage. Researchers from Columbia University have now investigated whether cavitation monitoring could be used to detect BBB opening and closing, and predict the potential for damage (Phys. Med. Biol. 60 9079).

"We hoped to find an acoustic way of real-time monitoring and controlling microbubble-mediated ultrasound therapy," explained first author Tao Sun. "MRI-guidance has been already utilized for treatment planning, monitoring and assessment. However, it lacks high temporal efficiency in monitoring characteristics such as BBB reversibility and permeability, which are vital in clinical drug delivery."

Animal investigations

To induce BBB opening, Sun and colleagues injected microbubble solution into 60 anaesthetized mice, and applied transcranial FUS pulses for 60 s at 1.5 MHz to the animals' right hippocampi. They studied microbubbles with diameter ranges of 1–2, 4–5 and 6–8 µm, using pressures of 0.30–0.60 MPa. During sonication, they monitored the cavitation activity and calculated two parameters: stable cavitation dose (SCD) and inertial cavitation dose (ICD).

Immediately after FUS treatment, and daily for 6 days, the researchers scanned the mice with a 9.4 T MR scanner. They used pre-contrast T2-weighted, dynamic contrast-enhanced (DCE) and T1-weighted MR sequences to assess oedema volume, brain tissue permeability and BBB opening volume, respectively.

The T1-weighted MR images confirmed BBB opening for all pressure and bubble size combinations. The opening volume and permeability coefficient (Ktrans) increased with increasing pressure and microbubble size. Looking at opening duration, the authors highlighted two parameter sets with no significant inter-animal variability: 0.60 MPa, 1–2 µm; and 0.30 MPa, 4–5 µm. All BBB openings closed on day 1 in the first group and on day 3 in the second group, implying that these two sets could potentially allow reliable control of BBB recovery time.

Next, the researchers investigated potential correlations between cavitation dose and BBB opening. They found that SCD correlated well with the duration of BBB opening, suggesting that it could be used to predict reversibility, but that ICD-based prediction was not as reliable. Both SCD and ICD were linearly correlated with the permeability coefficient on the sonication day. The opening duration was also bubble-size dependent, with smaller (1–2 µm) bubbles resulting in closing within 1 day, and larger bubbles producing openings of 2–6 days.

Safety predictions

The researchers observed that four mice had openings of 6 days or longer and defined these as long-term opening cases. T2-weighted MR images and histology (performed on day 7) revealed that these four cases also exhibited oedema on day 5 and neurovascular damage. They categorized all animals into three groups: no opening, safe opening and opening with damage. Analyses revealed significantly different SCD values across the three groups, indicating that SCD may provide a measure of likelihood for safe opening.

Finally, to investigate ICD-based prediction of safety, the researchers used higher-pressure FUS exposures (0.75 and 0.90 MPa) to induce more inertial cavitation events, with 4–5 µm bubbles. They observed successful opening in all cases, and significantly different SCD and ICD values across the three groups. While inertial cavitation is normally avoided by using low FUS pressure to open the BBB, it has been associated with successful delivery of larger agents. In such cases, ICD-based safety control could be employed.

The authors concluded that stable cavitation signals from oscillating microbubbles could potentially be used to predict the duration of BBB opening, the likelihood of safe opening and the permeability of the opened BBB. The next step in their research will involve setting up a closed-loop feedback control system, to realize cavitation-guided drug delivery.

Sun, who currently works at the Focused Ultrasound Laboratory at Brigham & Women's Hospital, notes that this technique has not yet been demonstrated in humans. "However, researchers have successfully disrupted the BBB in non-human primates, and FUS through the intact cranium has already been used to treat essential tremor in human patients," he told medicalphysicsweb. "I think we are very near."

Related articles in PMB
Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening
Tao Sun et al Phys. Med. Biol. 60 9079
Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain
Costas D Arvanitis et al Phys. Med. Biol. 58 4749
Gauging the likelihood of stable cavitation from ultrasound contrast agents
Kenneth B Bader and Christy K Holland Phys. Med. Biol. 58 127

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