Thermal ablation with transcranial MRI-guided focused ultrasound (TcMRgFUS) is a rapidly advancing noninvasive alternative to functional neurosurgery and brain tumor resection that is in clinical trials^1,2. Current TcMRgFUS systems, which operate at 650-670 kHz, are limited by skull heating to a small central region in the brain. Use of a lower acoustic frequency will reduce skull heating, but at the same time the focal heating will decrease and the risks of uncontrolled cavitation (the formation of microbubbles) increase. The purpose of this study was to evaluate the feasibility of thermal ablation in nonhuman primates using a system that operates at a lower acoustic frequency and to determine whether it can increase the “treatment envelope” for TcMRgFUS.The experiments were approved by our institutional animal committee. Thermal ablation with the 230 kHz ExAblate Neuro system (InSightec) was tested over five sessions in three rhesus macaques. In each session a target in the thalamus was sonicated transcranially at 40-50 s at acoustic power levels ranging from 90-560 W. The TcMRgFUS system software modulated the acoustic power in real time with a closed-loop controller that maintained a low-level of acoustic emissions, which are correlated with cavitation activity. MR temperature imaging (MRTI)³ was acquired at 3T (LX, GE) in a single plane using a 14 cm surface coil (TR/TE: 29/13 ms; flip angle: 30°). Measurements of the peak temperature rise at the focus and on the brain surface were compared for the different animals as a function of the applied acoustic energy. For the brain surface we measured the average temperature at the hottest 5% of the voxels and of a two voxel wide strip, and we also normalized the measurement by the outer skull area. Temperature measurements were used to calculate the accumulated thermal dose⁴, which was then compared to post-sonication T2-weighted, T2*-weighted, and contrast-enhanced T1-weighted MRI. The focal and skull-induced heating on the brain surface were compared to an earlier study performed in macaques with a 650 kHz version of this system⁵.Focal heating sufficient to create an MRI-evident thermal lesion was achieved in 4/6 targets; the peak thermal dose exceeded 240 CEM43°C at these targets (Figure 1). Heating at the focus was slightly higher than that measured on the brain surface. The focal heating increased linearly as a function of the applied energy at a rate of 3.2 ± 0.4°C per kJ (R²: 0.81) (Figure 2). The surface area of the outer skull ranged from 47-55 cm². For the hottest 5% of the voxels in the MRTI imaging plane, the temperature rise increased linearly as a function of temperature at a rate of 126.6 ± 7.3°C per kJ/cm². For the entire brain surface, this increase was 62.7 ± 7.5°C per kJ/cm². The extent of MRI-evident changes (apparent edema in T2-weighted MRI, BBB disruption post-contrast, no petechiae in T2*-weighted MRI) were consistent with 240 CEM43°C contours. One lesion imaged one week after FUS increased in size.

Analyses of the MRTI and post-sonication MRI suggest that the lesions were consistent with thermal mechanisms. The temperature rise increased linearly with the applied energy, and no evidence of cavitation-related petechiae were evident after sonication. The MRI-evident lesions were consistent with isodose contours drawn at 240 CEM43°C, a conservative threshold often used to guide thermal ablation. However, since it is known that thermal damage can take several hours to manifest in MRI⁶ and the lesion we imaged at one week increased in size, it is likely that the size of the lesion was underestimated by this dose value.

Prior tests with a version of this system operating at 670 kHz measured skull-induced heating of 130°C per kJ/cm² of outer skull surface⁵, more than twice of that measured here (63°C per kJ/cm²). While no or minimal focal heating was observed at 670 kHz, with this 230 kHz system we were able to reach ablation-level thermal dose values at the focus. Thus, these preliminary results thus suggest that this low frequency system can expand the area of the brain that can be targeted for thermal ablation without overheating the skull. The closed-loop feedback system successfully maintained a low level of microbubble activity and immediately stopped the sonication when excessive levels were detected. However, additional work is needed to understand whether low-level cavitation activity played a role in the focal heating, to characterize the lesions in histology, and to examine whether safe cavitation levels can be maintained in tumors.