Characterization of the Targeting Accuracy of a Neuronavigation-Guided Transcranial FUS System In Vitro, In Vivo, and In Silico

Abstract

Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized in vitro, in vivo, and in silico. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized in vitro in a water tank using a hydrophone. The performance of the device in BBB disruption was verified in vivo using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated in silico using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 ± 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 ± 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 ± 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in GBM patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic.

Fig.1.

Experimental method for measuring the targeting accuracy of the neuronavigation-guided FUS in a water tank. (A) Setup used to calibrate the location of FUS transducer geometrical focus to the BrainSight system using a calibration block provided by BrainSight (left). The FUS transducer was inserted tightly into a 3D-printed cap (right). The cap was tightly inserted to the pin on the calibration block. (B) Experimental setup for measuring the targeting accuracy in a water tank. Position of the FUS transducer relative to the tank was tracked with BrainSight based on CT images of the water tank. The acoustic pressure fields generated by the FUS transducer was measured with a hydrophone mounted on a 3D motor stage. (C) Fiducial marker placement on the water tank.

Fig.2.

Methods for measuring the targeting registration error (TRE) in the water tank. (A) TRE in the lateral X–Y plane was measured by the distance between the planned target (black) and the actual measured target, which was the beam centroid (white). (B) TRE in the Z direction was measured by the difference between the time-of-arrival of signals acquired at the planned target (blue) and reference signal acquired at the actual target (red).

Fig.3.

Experimental setup for in vivo pig study. Both the animal and transducer were tracked by BrainSight neuronavigation system with an individual optical tracker. The pig head was immobilized by a bite bar and two side-supports. The transducer was coupled to the pig head through a water chamber. The location of one fiducial marker on the side of the pig head was marked by a circle. Fiducial markers were also attached to the side support and water chamber as backups.

Fig.4.

Method for quantifying the targeting accuracy of the FUS transducer in GBM patients. (A) Representative acoustic pressure field simulation for a GBM patient using k-Wave at the actual focus sagittal plan. (B) 3-D visualization of the acoustic beam (>50% peak pressure) relative to the tumor (yellow). Actual target location and planned target location were identified and 3-D visualized in 3D Sheer [28]. TA_GBM was calculated as the distance between the planned target and actual target location.

Fig.5.

Results of target registration error measured in the water tank. (A) 3D-visualization of actual focus locations relative to the planned target position (0, 0, 0). (B) Summary of the targeting accuracy in water tank along X, Y, Z directions and total Euclidean distances. Repeated measurements (N = 4) were performed during each of the 3 rounds of measurements.

Fig.6.

In vivo targeting accuracy measured by contrast-enhanced MRI in pigs. Representative pre- and post-FUS T1W MRI images in the coronal view are presented for each pig. Targeting accuracy was quantified as the difference between the target (white cross) and the centroid of the BBB opening location (orange cross).

Fig.7.

Summary of targeting accuracy measured in vivo. (A) 3D visualization of the BBB opening centroid locations. (B) Targeting accuracy in pigs along X, Y, Z directions and total Euclidean distances.

Fig. 8.

Simulated transcranial FUS beam dimensions in GBM patients. The lateral and axial full-width half-maximum (FWHM) dimensions of the focal region are plotted for all 54 patients.

Fig.9.

FUS transducer targeting accuracy in GBM patients and intracranial peak acoustic pressure normalized by that simulated in free field. (A) TA_GBM in lateral and axial directions. (B). TA_GBM for male and female (C). TA_GBM for different ages. (D). TA_GBM for different tumor incident brain lobes. (E) Overall beam peak pressure in GBM patients normalized to peak pressure in free field simulation. (F). Summary of normalized pressure versus gender. (G). Summary of normalized pressure vs. age. (H) Normalized pressure in different tumor incident brain lobes. Only groups with statistically significant differences were labeled with P-values.