Ultrafast three-dimensional microbubble imaging <i>in vivo</i> predicts tissue damage volume distributions during nonthermal brain ablation.
Authors: Jones RM, McMahon D, Hynynen K
Transcranial magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) thermal ablation is under clinical investigation for non-invasive neurosurgery, though its use is restricted to central brain targets due primarily to skull heating effects. The combination of FUS and contrast agent microbubbles greatly reduces the ultrasound exposure levels needed to ablate brain tissue and may help facilitate the use of transcranial FUS ablation throughout the brain. However, sources of variability exist during microbubble-mediated FUS procedures that necessitate the continued development of systems and methods for online treatment monitoring and control, to ensure that excessive and/or off-target bioeffects are not induced from the exposures. <b>Methods:</b> Megahertz-rate three-dimensional (3D) microbubble imaging <i>in vivo</i> was performed during nonthermal ablation in rabbit brain using a clinical-scale prototype transmit/receive hemispherical phased array system. <b>Results:</b><i>In-vivo</i> volumetric acoustic imaging over microsecond timescales uncovered spatiotemporal microbubble dynamics hidden by conventional whole-burst temporal averaging. Sonication-aggregate ultrafast 3D source field intensity data were predictive of microbubble-mediated tissue damage volume distributions measured post-treatment using MRI and confirmed via histopathology. Temporal under-sampling of acoustic emissions, which is common practice in the field, was found to impede performance and highlighted the importance of capturing adequate data for treatment monitoring and control purposes. <b>Conclusion:</b> The predictive capability of ultrafast 3D microbubble imaging, reported here for the first time, will enable future microbubble-mediated FUS treatments with unparalleled precision and accuracy, and will accelerate the clinical translation of nonthermal tissue ablation procedures both in the brain and throughout the body.
Introduction
Purpose
mechanical ablation
Study Objective
To demonstrate that ultrafast megahertz-rate 3D microbubble imaging can predict the volumetric tissue damage distributions induced during microbubble-mediated nonthermal focused ultrasound brain ablation in vivo.
Animal model / Human subject
Rabbit; strain None; age None; sex None
Disease model
Healthy
MRI or image guidance method
Ultrafast 3D microbubble acoustic imaging using a clinical-scale hemispherical transmit/receive phased array (MRI used for post-treatment assessment)
Outcomes and Safety
Summary of Outcomes
Microbubble-mediated transcranial focused ultrasound produced focal nonthermal brain ablation characterized by RBC extravasation, tissue necrosis, BBB opening, edema and (at higher dose/exposure) glial scarring in rabbits. Successful sonication parameters were calibrated to the in‑situ subharmonic pressure threshold (p_sub ≈ 0.57–0.67 MPa) using a 612 kHz carrier with 10 ms bursts at 1 Hz: exposures at 100% and 150% p_sub produced consistent MRI- and histology-confirmed tissue damage (150% produced damage at all targets, 100% at most), whereas 50% and 0% p_sub produced minimal or only small histologic effects; microbubble dose (0.02–0.20 ml/kg) did not alter the in‑situ threshold.
Duration of biological effect
0.3 ± 0.5 ms
Safety-related matter
Microbubble-mediated FUS produced adverse effects at higher exposure levels, including T2*-MRI hypointensities co-localized with RBC extravasation and focal necrosis, increased BBB permeability, substantial edema/brain swelling at 24 h, and glial scar formation at 150% p_sub, with small RBC extravasations and overt tissue damage also detected histologically at some lower exposure sites. The authors note these off-target/undesired bioeffects and emphasize the need for real-time monitoring and closed-loop control to minimize adverse events.
Brain Region
Ultrasound Parameters
Ultrasound instrument
clinical-scale prototype transmit/receive hemispherical phased array system (manufacturer: None; aperture/diameter: None)
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
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