A new in silico model to precisely design focused ultrasound brain therapies

Focused ultrasound (FUS) combined with microbubbles enables transient and noninvasive blood-brain barrier (BBB) opening, facilitating targeted drug delivery. However, accurate treatment planning remains difficult due to inter-patient anatomical variability and the common assumption in simulations that brain tissues behave like water.

To develop and evaluate MODFUS ( $MODel$ $to$ $precisely$ $design$ $Focused$ $UltraSound$ $experiments$ ), an in silico acoustic simulation framework that integrates a high-resolution anatomical head model to quantify the impact of intracranial tissue heterogeneity and probe alignment on transmitted acoustic pressure, supporting treatment planning for BBB opening.

MODFUS integrates an anatomical head model comprising 115 tissue types and Computed Tomography (CT)-derived skull properties. FUS simulations were conducted using a 250 kHz single-element transducer at 13 distinct skull entry locations. Two modeling approaches were evaluated: a classical model, in which the skull was embedded in water and brain tissues were homogenized as water, and an heterogeneous anatomical model. To further assess robustness, an additional set of 50 simulations introduced controlled perturbations in probe positioning, consisting of angular deviations ( $\pm {18}^{\circ }$ ) and translational offsets ( $\pm$ 7 mm) relative to the reference configuration. Model- and configuration-dependent differences were quantified using peak positive pressure (PPP), peak negative pressure (PNP), and potential therapeutic volume. Statistical significance was assessed using Wilcoxon rank-sum or Wilcoxon signed-rank tests ( $\alpha$ = 0.05). For Classical vs Realistic models, Wilcoxon rank-sum tests were applied to PPP, PNP, and BBB exposure volume, and Levene's test assessed variance differences across 13 positions. Multiple testing was controlled using the Holm-Bonferroni procedure ( $\alpha$ = 0.05) across all tests. Effect sizes were quantified using Cohen's d with 95% confidence intervals.

Compared to the classical "skull+water" benchmark model, the heterogeneous model predicted up to 11% lower PPP, slightly lower PNP ( $\sim$ -5%), and 35% smaller potential BBB exposure volumes across the 13 paired sonication positions. After Bonferroni correction, Paired statistical testing (Wilcoxon signed-rank, two-sided) showed significant differences for PPP (p = 0.0270) and potential BBB exposure volume (p = 0.0015), while differences in PNP were not statistically significant (p = 0.8286). Levene's test for variance confirmed significant heteroscedasticity for PPP (p = 0.027) and PNP (p = 3.2 $\times$ 10), but not for BBB exposure volume (p = 0.2680). Cohen's d effect sizes indicated a large positive effect for PPP, a small negative effect for PNP, and a very large positive effect for BBB exposure volume.

MODFUS demonstrates the influence of incorporating detailed tissue heterogeneity on simulation outcomes, including pressure distribution and potential BBB exposure volume. These results highlight the importance of realistic soft tissue modeling and stereotaxic probe alignment for safe and effective FUS treatment planning. The study serves as a preliminary proof-of-concept. Future studies incorporating in vivo experiments will be required to quantify the accuracy of this approach.