Long term effects of low intensity pulsed focused ultrasound treatment with microbubbles on brain metabolism in a rat model.

Objectives Ultrasound techniques could serve as potential tools for blood brain barrier (BBB) disruption allowing delivery of therapeutic molecules to localized disease sites such as malignant brain tumors. However, there is lack of data regarding the molecular sequelae of these treatment strategies on brain functions such as glucose metabolism. The aim of our study was to determine the long-term effects of low intensity pulsed focused ultrasound treatment with microbubbles (pFUS+MB) on the metabolic activity of rat brains.

Methods A cohort of 6 female rats received one session of pFUS+MB (Optison TM, GE Healthcare, Little Chalfont, UK) targeting the left striatum and adjacent insular cortex. 200 μl of microbubbles were administered intravenously over 1 minute starting 30 sec before pFUS. 0.3 MPa acoustic pressure was applied in 10 ms burst length and 1% duty cycle (9 focal points, 120 sec/9 focal points - striatum, 120 sec/4 focal points - hippocampus) using a single-element spherical FUS transducer (center frequency: 589.636 kHz; focal number: 0.8; aperture: 7.5 cm; FUS Instruments, Toronto, Ontario, Canada). T1-weighted gadolinium-enhanced images were obtained using 3.0 T MRI (Philips, Amsterdam, Netherlands), immediately after pFUS+MB. The animals underwent static brain 18F-FDG microPET/CT studies at 6 and 12 weeks post treatment. The animals were fasted for at least 6 hours before receiving 0.7 - 0.9 mCi of 18F-FDG via tail vein injection, while anesthetized. Subsequently, the animal was allowed to regain consciousness for an uptake period of 30 minutes in total, and then was anesthetized and scanned using Inveon Multimodality PET/CT scanner (Siemens Medical Solutions USA, Inc.). CT scan was performed for localization and attenuation correction purposes. SUV values were obtained from volumes of interest (VOI) corresponding to the sonicated left striatum/insular cortex, and contralateral brain (green contours in Fig 1b). The ratios of uptake (ipsilateral/contralateral) were then calculated.

Results Enhanced T1-weighted MRI scans performed immediately after pFUS+MB showed contrast enhancement in the targeted brain regions (left striatum and adjacent insular cortex), suggestive of BBB disruption (arrows in Fig. 1a). 18F-FDG microPET/CT studies performed at 6 and 12 weeks after the initial treatment with pFUS+MB did not reveal glucose metabolism discrepancies between ipsilateral (targeted) and contralateral brain upon qualitative evaluation. The ratios of SUV values (ipsilateral/contralateral) were 0.993 (0.017) at 6 weeks and 0.994 (0.007) at 12 weeks (Fig. 1b). There were no statistically significant differences between the two sides.

Conclusions Low intensity pFUS+MB does not cause long-term changes in rat brain metabolic activity at 6 and 12 weeks after sonication. Those findings suggest preserved neuronal integrity and function in the sonicated brain regions. However, the short-term effects (24h, 3 days, 1 week) as well as the effects of repeated pFUS+MB treatments need to be further explored.

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