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.