Currently, the only clinically relevant methods available for monitoring cavitation activity are ultrasonic, such as passive cavitation mapping. This technique employs the FUS device as a source and uses an array of receivers to passively record the acoustic emissions produced during sonication to produce maps of cavitation activity. These emissions and reconstructed maps provide information regarding the location, strength and type of microbubble oscillation and, importantly, can be obtained fast enough to provide real-time control over clinical procedures.

With this aim, researchers from Harvard Medical School (Boston, MA) have integrated a passive cavitation imaging system into a clinical MR-guided focused ultrasound (MRgFUS) system and, for the first time, performed transcranial mapping of microbubble activity in the brain (Phys. Med. Biol. 58 4749).

"Passive cavitation mapping allows us to visualize microbubble activity during treatment, to ensure that the effect is not occurring outside the targeted area and, we hope, to provide an effective method to monitor and control BBB disruption and other FUS therapies that involve microbubbles in real-time," explained Costas Arvanitis, from Harvard's Focused Ultrasound Laboratory.

Cavitation processes

Acoustic cavitation occurs when a microbubble expands and contracts in an ultrasound field, with stably oscillating microbubbles (stable cavitation) producing strong harmonic and/or ultraharmonic emissions. At higher acoustic pressures (above about 300 kPa), the microbubbles can collapse, a phenomena known as inertial cavitation and which produces characteristic broadband emissions.

To study the cavitation process, which occurs over millisecond or microsecond timescales, Arvanitis and colleagues used a clinical MRgFUS system (ExAblate 4000), modified to provide low-power sonications. For passive cavitation mapping, they incorporated a 128-element linear ultrasound array into the therapeutic phased array.

The researchers tested FUS-induced BBB disruption in three macaques. They delivered two 50 s sonications (applied in 10 ms bursts with a repetition frequency of 1 Hz) to each target, combined with infusion of microbubble ultrasound contrast agent.

The acoustic power level was set initially to achieve BBB disruption without inertial cavitation – as desired in clinical applications. For subsequent sonications, the researchers used higher powers, including those slightly above the inertial cavitation threshold where minor vessel damage is expected. Overall, they sonicated 20 targets in the cingulate cortex of the three animals, with acoustic powers of 0.5–2.2 W (estimated pressure amplitudes of 190–330 kPa).

The researchers generated cavitation activity maps for each ultrasound burst. The maps revealed the strength and position of the emissions produced by microbubble oscillations. Analysis of the corresponding normalized power spectra enabled distinction between stable cavitation (harmonic components only) and inertial cavitation (harmonic and broadband components). The size of the region with detected activity was more localized for inertial than for stable cavitation, due to differences in the bandwidth of the recorded emissions.


Arvanitis and colleagues then compared the location of the cavitation maps with the site of BBB disruption, as measured using post-sonication MRI. Fusing the cavitation maps with MR images showed that microbubble activity was indeed confined to the targeted area, and that the peak cavitation activity overlapped with the location of MR-evident BBB disruption. The mean axial and transverse distances between the locations of the maximum cavitation activity and the MR contrast enhancement were 0.5±7.5 and 0.3±1.5 mm, respectively.

Each targeted location was classified as having BBB disruption only or BBB disruption plus tissue damage (assessed using T2*-weighted imaging, which is hypointense when significant red blood cell extravasation occurs). When broadband emissions were observed, hypointense spots were also seen, indicative of minor vascular damage induced by inertial cavitation.

In a clinical situation, this approach could be used to ensure that BBB disruption occurs without inducing inertial cavitation. "We anticipate that one can increase the pressure amplitude until strong harmonic emissions are detected, and then if broadband emissions are detected, immediately reduce it or stop the sonication," Arvanitis explained. "Moreover, the correlation we found previously between the strength of the harmonic emissions and the amount of agent delivered to the brain suggests that such monitoring might be able to control the 'level' of the disruption to ensure a predictable and uniform treatment."

The authors conclude that their study demonstrated the feasibility of constructing maps of stable and inertial cavitation in a large animal model, under clinically relevant conditions. They note that introducing the ultrasound imaging probe into the MRgFUS system did not significantly affect either the MR image quality or the ability to produce localized BBB disruption.

They are now developing ways to account for skull thickness and other subject-specific factors, to enable quantification of acoustic emissions. "We are also interested in expanding this integrated ultrasound/MRI system to other FUS applications in the brain and elsewhere," Arvanitis told medicalphysicsweb.

Related articles in PMB
Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain
Costas D Arvanitis et al Phys. Med. Biol. 58 4749
Suitability of a tumour-mimicking material for the evaluation of high-intensity focused ultrasound ablation under magnetic resonance guidance
S Pichardo et al Phys. Med. Biol. 58 2163
The design of a focused ultrasound transducer array for the treatment of stroke: a simulation study
Daniel Pajek and Kullervo Hynynen Phys. Med. Biol. 57 4951
Experimental investigation of MRgHIFU sonication with interleaved electronic and mechanical displacement of the focal point for transrectal prostate application
Lorena Petrusca et al Phys. Med. Biol. 57 4805

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