Introduction

Magnetic resonance imaging (MRI)-guided transcranial focused ultrasound noninvasively delivers targeted ultrasound energy through the skull to specific locations in the brain. However, the skull poses a major challenge by distorting and attenuating the ultrasound beam in patients, where pressure can vary by 4x^1,2, and even in rodent models where the skull is thin³. It is therefore critical to plan ultrasound targeting in the brain and to verify the targeting with imaging. In nonthermal applications such as neuromodulation^4-6, targeting without tissue heating can be done with magnetic resonance acoustic radiation force imaging (MR-ARFI)⁷. In a large animal model, we demonstrate in vivo focal spot targeting using MR-ARFI, ex vivo focal spot targeting across skull caps, and simulations and measurements of acoustic pressure transmitted through the skull. Results provide practical information on focal spot targeting through skulls of varying shape, thickness, and composition.

Methods

All experiments used a 1024 element, 550 kHz focused ultrasound transducer (ExAblate 2100, Insightec Ltd., Haifa, Israel). MRI-guided focused ultrasound was performed at 200 W (in vivo) and 170 W (ex vivo) acoustic power.

MR-ARFI FOCAL SPOT IMAGING
A 30 kg anesthetized male Dorset cross sheep was imaged at 3T (Signa Excite, GE Healthcare, Milwaukee, WI) with the transducer positioned above the head for targeting subcortical brain tissue prior to neuromodulation. MR-ARFI data were acquired using a 2DFT spin echo sequence with repeated bipolar motion encoding gradients and 500 ms repetition time (TR), 39 ms echo time, 20 x 20 x 0.7 cm³ field of view, and 256 x 128 acquisition matrix⁸. Ultrasound spanned 16 ms per TR across the second lobe of the first bipolar, the refocusing pulse, and the first lobe of the second bipolar gradient to encode ultrasound-induced tissue displacement as a phase shift. Two MR-ARFI data acquisitions with reversed motion encoding gradient polarities were combined to form the displacement phase image. Following the acute study, the skull cap was extracted.

Three ex vivo sheep skull caps, roughly 3.5 mm, 5.35 mm, and 5.4 mm in thickness, were positioned on a 4 inch diameter gel phantom and submerged in a water-filled cylinder, with the transducer positioned above. Focused ultrasound was targeted to locations over a 5x5 grid ranging from +/-20 mm in x and y, and imaged with the same MR-ARFI parameters as the in vivo study. The same measurements were collected in the phantom alone, and the ratios of peak displacement with and without the skull caps were computed at each location.

SIMULATING AND MEASURING ACOUSTIC PRESSURE
Computed tomography (CT) images of each skull cap were acquired at 120 kVp with a bone filter. Focal spot pressure was simulated using CT-derived estimates of skull acoustic properties and the hybrid angular spectrum method^2,9.

Four ex vivo sheep skull caps (the three above, and a fourth with 7 mm thickness) were degassed, affixed to the transducer, and placed in a water tank. A fiber optic hydrophone (Precision Acoustics, Dorchester, UK) directly measured acoustic pressure at the focal spot for sonications between 0 and 200 W acoustic power.

Results and Discussion

MR-ARFI results show in vivo focal spot imaging of subcortical brain tissue through the skull in an alive large animal, to our knowledge for the first time (Fig. 1).

Peak MR-ARFI displacement through each ex vivo skull cap was greatest where the skull was comparatively flat and thin (Fig. 2). Although the ex vivo skull caps in Fig. 2(b)-(c) are nearly equivalent in thickness, that in Fig. 2(b) had higher relative displacement and higher transmitted pressure (Fig. 3).

Skull thickness measures are a starting point for estimating acoustic pressure at a given power level (Figs. 3-4). MR-ARFI provides additional information relating to focal spot intensity, including how it varies through each skull based on its shape and its thickness. Simulations incorporate acoustic properties of the skull, providing important pre-treatment information. Variation in bone composition, indicated by distribution of Hounsfield units across the skull caps (Fig. 5), provides additional insight on MR-ARFI and hydrophone focal spot measurements.

Results highlight the need for treatment planning that is specific to individual skull properties, such as beam simulation^10,11, as thickness alone is insufficient for predicting focused ultrasound transmission through the skull. Future work will include more samples, additional simulation studies, and reproducibility studies. Our findings show MR-ARFI is valuable for imaging focal spot location and pressure through the skull, and enables non-invasive, non-thermal focal target verification in vivo.

Acknowledgements

This work was supported by NIH T32 EB009653, T32 CA009695, R01 MH111825, R01 EB019005, and P01 CA 159992. The authors would like to thank Yamil Saenz for help with sheep studies, Elias Godoy for help with tissue recovery, Jan Kubanek for help with experiments, and Lior Molvin for help with CT scans.

References

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