Microbubble cavitation in low-intensity focused ultrasound stimulation: A multi-scale computational study

Low-intensity transcranial focused ultrasound (LIFUS) has emerged as a promising approach for non-invasive brain stimulation and blood-brain barrier (BBB) opening in combination with microbubbles (MBs). Although ultrasound propagation in LIFUS and MB dynamics have been investigated in previous studies, they are often examined separately; thus, it remains challenging to establish safe and effective acoustic thresholds given the nonlinear nature of MB oscillations and distortions introduced by the skull. To address this gap, in this study, we developed a multi-scale computational model that integrates three-dimensional LIFUS simulations with MB dynamics modeled using the Marmottant equation.

We conducted LIFUS simulations using 3D human skull models derived from computed tomography and magnetic resonance imaging data of male and female subjects. Simulations were performed at two frequencies (250 and 500 kHz) with two transducer placements (back and upper side of the head). The resulting 3D acoustic pressure fields were subsequently coupled to the Marmottant equations, incorporating four clinically relevant microbubble sizes (0.82, 1.0, 1.75, and 2.15 μm), to quantify the spatial volumes of stable (V_SC) and inertial cavitation (V_IC).

Both V_SC and V_IC increased with the acoustic amplitude and bubble radius but decreased with the frequency. Skull-induced distortions further enlarged the cavitation volumes relative to free water at the same peak pressure amplitude and temporally advanced the onset of cavitation by approximately 5 μs. When skull-induced attenuation was considered, acoustic pressures were reduced by 75%-85%, leading to smaller cavitation volumes at the same transducer output amplitude compared with free water. This attenuation effect also elevated the inertial cavitation threshold by approximately 3-5 fold.

These findings highlight the critical role of skull anatomy in LIFUS and the effect of skull-induced distortion on MB cavitation. Using multi-scale modeling techniques, we obtained results similar to those of previous studies, thus providing a basis for safe and effective BBB opening and therapeutic applications.