A MULTISCALE COMPUTATIONAL FRAMEWORK FOR MICROBUBBLE CAVITATION UNDER SKULL-DISTORTED TRANSCRANIAL FOCUSED ULTRASOUND

Focused ultrasound (FUS) combined with microbubbles enables transient BBB opening for enhanced drug delivery, but safe and reproducible control remains challenging because microbubble cavitation is highly sensitive to acoustic conditions and skull-induced waveform distortion. Most numerical studies assume idealized sinusoidal pressure fields and therefore neglect realistic transcranial effects. Here, we present a multi-scale computational framework that integrates 3D acoustic simulations with microbubble dynamics to quantify how skull-induced distortion alters cavitation behavior. Acoustic pressure fields were simulated using the k-Wave toolbox based on CT-derived head models from the Visible Human Project, with the thalamus selected as the target region. Skull acoustic properties were estimated from CT-derived porosity, while other tissues were modeled as water. A single-element focused transducer operating at 250kHz was modeled, and the resulting spatiotemporal pressure waveforms were coupled to the Marmottant microbubble model. Four clinically relevant initial bubble radii (0.82, 1.0, 1.75, and 2.15 μm) were evaluated under peak rarefactional pressures of 0.1–0.3 MPa. Stable cavitation consistently occupied larger spatial volumes than inertial cavitation, and inertial cavitation was absent at 0.1 MPa. Cavitation volumes increased with bubble radius and pressure amplitude. Compared with free-water simulations, skull-inclusive models exhibited enlarged cavitation regions despite equivalent peak pressures, reflecting skull-induced waveform distortion. At 0.3 MPa, inertial cavitation volume varied by up to 2.3-fold across bubble sizes and increased by approximately 33% relative to free water. These results demonstrate that skull-induced acoustic distortion significantly modulates microbubble cavitation and should be considered when defining safe operating windows for transcranial FUS-mediated BBB opening.