The Impacts of FLASH Radiation Therapy and Conventional Radiation Therapy on the Cognitive Abilities of Mice.

Purpose: Preclinical studies have demonstrated that FLASH radiation therapy (RT) delivered at ultrahigh-dose rates exerts a preferential normal tissue-sparing effect. This study aimed to delineate the disparities in delayed cognitive function and biological outcomes of whole-brain irradiation in healthy mice, comparing FLASH-RT with conventional RT (CONV-RT). Methods and Materials: Eighty adult male C57BL/6J mice were divided into 5 groups: Sham, CONV-RT10Gy, CONV-RT20Gy, FLASH-RT10Gy, and FLASH-RT20Gy. Whole-brain irradiation was conducted on mice using a miniaturized x-ray FLASH platform at field-average dose rates of 2 Gy/min for CONV-RT and 213 Gy/s for FLASH-RT. Two months after irradiation, we assessed the mice's cognitive function and the number of astrocytes and neurons in the hippocampus, then conducted proteomic analyses of their hippocampus. Results: Following the administration of a 20 Gy FLASH-RT dose, the incidence of radiodermatitis was markedly lower than that observed with CONV-RT, accompanied by an improvement in survival rates. Compared with the Sham and FLASH-RT groups, the CONV-RT group exhibited reduced exploration of the open arms in the elevated plus maze, diminished preference for the novel arm in the Y-maze, a lower discrimination index in the novel object recognition test, and prolonged latency to reach the platform in the water maze test. Compared with the FLASH-RT group, the CONV-RT group exhibited an increase in astrocytes and a decrease in neurons in the hippocampus. Proteomic analysis revealed that FLASH-RT may improve the oxidative stress damage caused by CONV-RT. Conclusions: This study demonstrated that FLASH-RT conferred significant advantages over CONV-RT in preserving delayed cognitive function and reducing radiation-induced toxicity in healthy mice. Compared with CONV-RT, FLASH-RT mitigated behavioral deficits across multiple cognitive domains and attenuated hippocampal oxidative stress, highlighting its neuroprotective potential. These findings provided compelling preclinical evidence supporting the therapeutic promise of FLASH-RT as a safer alternative to conventional RT for protecting normal brain function.