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.

FIG. 1.

Coronal T2-weighted MR image of a macaque superimposed on a diagram of the experimental setup drawn approximately to scale. The locations of the MRI coil and PCD’s are indicated. The phased array transducer was used to electronically steer the focal point from the geometric center of the FUS array to a target near the skull base.

FIG. 2.

Pressure fields obtained using (a) acoustic and (b) elastic wave simulations (sagittal view). To decrease the simulation domain dimensions, a fictitious 11 cm diameter hemispherical surface source closer to the skull was used in which the simulated array elements radiated using the Rayleigh integral. Pressure field was lower near skull base in the elastic simulation compared to the acoustic simulation case (*). Norm.: Normalized.

FIG. 3.

Coronal view showing simulated pressure fields for (a) acoustic wave simulation with the full NHP model, (b) elastic wave simulation with the full NHP model, (c) elastic wave simulation with the skull base removed from the NHP model, and (d) elastic wave simulation without the NHP model. Norm.: Normalized.

FIG. 4.

Axial beam plots obtained using the acoustic and elastic wave simulations with full NHP model, elastic wave simulation with the skull base removed from the NHP model, and elastic wave simulation without the NHP model.

FIG. 5.

Simulation results (elastic wave model) superimposed on contrast-enhanced T1-weighted contrast-enhanced images acquired shortly after sonication (left: coronal view; middle: sagittal view for the left hemisphere target; right: axial view in the focal plane) for Monkey 3. (A) Hyperintense regions show the disruption of the BBB. The extent of the disruption was manually segmented (dotted lines). BBB disruption was not observed in white matter (*). Greater signal enhancement was observed in a ventricle that was in the beam path (arrow). (B) The simulated pressure field was thresholded at −14 dB for the left hemisphere target, −15 dB for the right hemisphere target, and superimposed on the MRI as a colored region. The extent of the BBB disruption was consistent with the simulated side lobes in the prefocal region, but not in the postfocal region. The black circle indicates the −3.5 dB contour of the simulation, which matched the size of the lesion seen in T2*-weighted MRI.

FIG. 6.

Simulation results (elastic wave model) superimposed on contrast-enhanced T1-weighted contrast-enhanced images acquired shortly after sonication (left: coronal view; middle: sagittal view for the left hemisphere target; right: axial view in the focal plane) for Monkey 2. (A) Hyperintense regions show the disruption of the BBB. The extent of the disruption was manually segmented (dotted lines). BBB disruption was not observed in white matter (*). (B) The simulated pressure field was thresholded at −14 dB for the left hemisphere target, −14.6 dB for the right hemisphere target, and superimposed on the MRI as a colored region. The extent of the BBB disruption was consistent with the simulated side lobes in the prefocal region, but not in the postfocal region.

FIG. 7.

(a) Individual element voltages for amplitude correction and inverse amplitude correction. (b) Axial beam patterns for different aberration correction schemes.

FIG. 8.

Coronal view showing pressure field obtained using simulations (a) without correction, (b) phase-only correction, (c) amplitude and phase correction, and (d) inverse amplitude and phase correction. Norm.: Normalized.

FIG. 9.

Coronal view showing pressure field obtained using simulations in its original steered position (left) and for the case in which the target was moved to the geometrical center (right) of the hemispherical array. Norm.: Normalized.

FIG. 10.

Pressure field radiated by one of the PCD’s used in the experiments. The receive field is proportional to the transmit field. [(a) and (b)] Simulated field at 610 kHz; [(c) and (d)] simulated field at 110 kHz (half the frequency of the FUS device). The focal point is shown in the plots (+). [(a) and (c): sagittal view; (b) and (d): coronal view.] Norm.: Normalized.

FIG. 11.

PCD+FUS intensity pattern (normalized with −6 dB lower threshold) plotted on T1 weighted contrast images (a) for 610 kHz, (b) for 110 kHz frequency. The −6-dB intensity for PCD+FUS intensity for a uniform PCD pattern is outlined as an ellipse.