Evaluation of focused ultrasound modulation of the blood-brain barrier in gray and white matter

RATIONALE: Focused ultrasound (FUS) in combination with intravenous microbubbles is being studied clinically for modulation of the blood-brain barrier. Contrast-enhanced MRI can be used to visualize the enhanced permeability resulting from the treatment. However, contrast enhancement in the white matter (WM) are inconsistently observed compared to the gray matter (GM). Intrinsic tissue differences are believed to result in reduced treatment efficacy and insufficient drug delivery to the WM. In this study we evaluate the deposition of MRI contrast and clinically relevant antineoplastics in GM and WM tissues following single and repeated FUS and microbubble treatments. METHODS: The brains of Fischer-344 rats (n = 24) and Yorkshire pigs (n = 6) underwent FUS (rats: 580 kHz; pigs: 220 kHz) treatments targeting the internal capsule and thalamus, repeated at 30-min intervals. Definity microbubbles (rats: 20 μL/kg bolus; pigs: 4 μL/kg/5-min infusion) were administered intravenously for each sonication with MRI contrast to measure gadolinium-mediated signal change. Feedback-controlled algorithms were used to monitor treatments and modulate the pressure based on emitted microbubble signals to ensure safe and effective exposures. The delivery of methotrexate (MTX; 454.4 Da) and bevacizumab (BVZ; 149 kDa) was evaluated via immunofluorescence microscopy in rats, and respectively quantified via liquid chromatography mass spectrometry and enzyme-linked immunosorbent assay in pigs. RESULTS: Repeated FUS exposures successfully increased the vascular permeability of both gray and white matter tissues to MRI contrast and drugs of both small and large molecular sizes. In rats, single treatments showed statistically significant higher enhancements in the GM (23.5 ± 4.3 %; WM: 4.68 ± 3.75 %), however following a second sonication there were no between-tissue differences (GM: 38.0 ± 6.4 %; WM: 34.0 ± 8.7 %). In pigs, the smaller focus size relative to the brain enabled separate targeting of GM vs WM and the treatment controller used higher average power level in the WM to achieve the same cavitation dose. This resulted in no difference in gray and white matter permeability levels (to both contrast and pharmacological agents) after a single sonication. Repeated treatments sustained MRI enhancements for a longer time and enhanced drug deposition (MTX increased 6.5 and 8.3 folds after single and repeated treatment; BVZ increased 6.8 and 20.4 folds respectively). CONCLUSIONS: Feedback-controlled algorithms and the possibility to individually target gray and white matter highlighted the impact of tissue composition on treatment outcomes. Repeated FUS-mediated modulation of the brain microvasculature achieved higher levels of permeabilization to contrast and pharmacological agents in both gray and white matter.