Ex vivo brain MRI to assess conventional and FLASH brain irradiation effects.

Abstract

The FLASH effect expands the therapeutic ratio of tumor control to normal tissue toxicity observed after delivery of ultra-high (>100 Gy/s FLASH-RT) vs. conventional dose rate radiation (CONV-RT). In this first exploratory study, we assessed whether ex vivo Magnetic Resonance Imaging (MRI) could reveal long-term differences after FLASH-RT and CONV-RT whole-brain irradiation. Female C57BL/6 mice were divided into three groups: control (non-irradiated), conventional (CONV-RT 0.1 Gy/s), and ultra-high dose rates (FLASH-RT 1 pulse, 5.5 x 10^6 Gy/s), and received 10 Gy of whole-brain irradiation in a single fraction at 10 weeks of age. Mice were evaluated by Novel Object Recognition cognitive testing at 10 months post-irradiation and were sampled at 13 months post-irradiation. Ex vivo brains were imaged with a 14.1 Tesla/26 cm magnet with a multimodal MRI protocol, including T2-weighted TurboRare (T2W) and diffusion-weighted imaging (DWI) sequences. In accordance with previous results, cognitive tests indicated that animals receiving CONV-RT exhibited a decline in cognitive function, while FLASH-RT performed similarly to the controls. Ex vivo MRI showed decreased hippocampal mean intensity in the CONV-RT mice compared to controls, but not in the FLASH-RT group. Comparing CONV-RT to control, we found significant changes in multiple whole-brain diffusion metrics, including the mean Apparent Diffusion Coefficient (ADC) and Mean Apparent Propagator (MAP) metrics. By contrast, no significant diffusion changes were found between the FLASH-RT and control groups. In an exploratory analysis, compared to controls, regional diffusion metrics were primarily altered in the basal forebrain and the insular cortex after conventional radiation therapy (CONV-RT), and to a lesser extent after flash radiation therapy (FLASH-RT). This study presents initial evidence that ex vivo MRI uncovered changes in the brain after CONV-RT but not after FLASH-RT. The study indicates the potential use of ex vivo MRI to analyze the brain radiation responses at different dose rates.