Focused ultrasound and stereotactic radiosurgery: a preliminary investigation of a novel, combined therapy for noninvasive neurosurgery.

Objective.Microbubble-mediated focused ultrasound (FUS) has been used to sensitize tumors to radiation, but applications with precision stereotactic radiosurgery (SRS) remain relatively unexplored. We previously observed that FUS combined with radiation can ablate healthy brain tissue in rats. This work presents a preliminary investigation of FUS-SRS in brain tissue to (1) validate and reproduce FUS-SRS ablation with different parameters, (2) analyze how FUS-induced bioeffects contribute to lesions, and (3) investigate mechanisms.Approach.Targets in the striatum were sonicated with FUS (273 kHz; definity MBs, 20 μl kg-1; max 230 kPa). Within 1 h, SRS (8/12/15 Gy; 3 × 3 mm2) was delivered. Magnetic resonance imaging (MRI) was used for treatment planning and monitoring. Lesion progression was monitored until 21 d post-treatment across eight groups (n= 3-5 target/group): (1) controls, (2) FUS only, (3-5) SRS only (8/12/15 Gy), and (6-8) FUS-SRS. 72 h. after FUS-SRS (15 Gy), immunofluorescence staining was used to assess mechanisms of cell death.Results.The degree and consistency of FUS-SRS lesions increased with radiation dose, with 3/4, 2/3, and 4/4 lesions persisting at day 21 for doses of 8, 12, and 15 Gy, respectively. Lesions were observed as early as 3 d post-treatment and were well colocalized with the combined treatment. Edema in the FUS-only group generally resolved within 7 d, and no macroscopic changes were observed with SRS-only. Compared to SRS alone, markers of apoptosis, oxidative stress, ceramide, and astrogliosis were elevated 8.5- (p= 1.26 x 10-4), 4.8- (p= 0.001), 13.5- (p= 4.19 x 10-4), and 7.8-fold (p= 2.06 x 10-4), respectively for FUS-SRS at 72 h. Significant differences were also observed for FUS-SRS compared to the FUS and control groups.Significance.This novel approach may minimize radiation doses needed for SRS and potentially improve the ability to tailor surgery compared to FUS ablation. 300/300 words.