Nonthermal ablation of deep brain targets: A simulation study on a large animal model

Abstract

Purpose: Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently limited to central brain targets because of heating and other beam effects caused by the presence of the skull. Recently, it was shown that it is possible to ablate tissues without depositing thermal energy by driving intravenously administered microbubbles to inertial cavitation using low-duty-cycle burst sonications. A recent study demonstrated that this ablation method could ablate tissue volumes near the skull base in nonhuman primates without thermally damaging the nearby bone. However, blood–brain disruption was observed in the prefocal region, and in some cases, this region contained small areas of tissue damage. The objective of this study was to analyze the experimental model with simulations and to interpret the cause of these effects. Methods: The authors simulated prior experiments where nonthermal ablation was performed in the brain in anesthetized rhesus macaques using a 220 kHz clinical prototype transcranial MRI-guided FUS system. Low-duty-cycle sonications were applied at deep brain targets with the ultrasound contrast agent Definity. For simulations, a 3D pseudospectral finite difference time domain tool was used. The effects of shear mode conversion, focal steering, skull aberrations, nonlinear propagation, and the presence of skull base on the pressure field were investigated using acoustic and elastic wave propagation models. Results: The simulation results were in agreement with the experimental findings in the prefocal region. In the postfocal region, however, side lobes were predicted by the simulations, but no effects were evident in the experiments. The main beam was not affected by the different simulated scenarios except for a shift of about 1 mm in peak position due to skull aberrations. However, the authors observed differences in the volume, amplitude, and distribution of the side lobes. In the experiments, a single element passive cavitation detector was used to measure the inertial cavitation threshold and to determine the pressure amplitude to use for ablation. Simulations of the detector’s acoustic field suggest that its maximum sensitivity was in the lower part of the main beam, which may have led to excessive exposure levels in the experiments that may have contributed to damage in the prefocal area. Conclusions: Overall, these results suggest that case-specific full wave simulations before the procedure can be useful to predict the focal and the prefocal side lobes and the extent of the resulting bioeffects produced by nonthermal ablation. Such simulations can also be used to optimally position passive cavitation detectors. The disagreement between the simulations and the experiments in the postfocal region may have been due to shielding of the ultrasound field due to microbubble activity in the focal region. Future efforts should include the effects of microbubble activity and vascularization on the pressure field.

Neuromodulation with single‐element transcranial focused ultrasound in human thalamus

“…As such, computational models that take into account individual skull morphology are warranted for accurate beam location and intensity. Detailed computational models of the skull are used in applications including aberration correction in high intensity focused ultrasound for thermal ablation (Marquet et al, ) and nonthermal ablation with microbubble enhanced focused ultrasound (Top, White, & McDannold, ). We were not able to acquire CT scans of the participants in this study and given the initial model shown here (despite a good conservation of beam geometry) it is recommended for future subcortical single‐element transcranial ultrasound studies that CT scans of individuals are acquired and detailed computational models run to ensure accurate target localization and transducer placement (Mueller et al ).…”

“…As such, computational models that take into account individual skull morphology are warranted for accurate beam location and intensity. Detailed computational models of the skull are used in applications including aberration correction in high intensity focused ultrasound for thermal ablation (Marquet et al, 2009) and nonthermal ablation with microbubble enhanced focused ultrasound (Top, White, & McDannold, 2016).…”

Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound

“…Simulations were then carried out using software and services provided by the Minnesota Supercomputing Institute at the University of Minnesota. While these modeling methods may introduce uncertainties in results, such methods have been used successfully for aberration correction and forward problem simulations in previous literature [12,13,26,27].…”

“…It is the focus of this work to develop a model of transcranial focused ultrasound using detailed representations of the skull while regarding all other tissues as water, as the modeling of soft tissues has already been shown to have negligible effects [11]. Detailed computational models of the skull have been used previously in applications including aberration correction in high intensity focused ultrasound for thermal ablation [12] and non-thermal ablation with microbubble enhanced focused ultrasound [13]. In the present study, we developed computational models of the skull based on medical images to evaluate simulation methods for tFUS for noninvasive neuromodulation and to explore the differences in intracranial pressure maps between individuals.…”

Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma

“…It can be noted that we haven’t considered methods for drastically lowering the frequency (220 kHz) to open the blood–brain barrier (BBB) and improve drug delivery [127–130], with the use of microbubbles [131, 132], nanoparticles [133–135], or contrast media [136]. Such a strategy is highly problematic [137, 138]. …”