Participation in exercise during early life (i.e., childhood through adolescence) enhances response inhibition; however, it is unclear whether participation in exercise during early life positively predicts response inhibition in later life. This historical cohort study was designed to clarify whether participation in exercise (e.g., structured sports participation) during early life predicts response inhibition in adulthood and if so, to reveal the brain connectivity and cortical structures contributing to this association. We analyzed data derived from 214 participants (women = 104, men = 110; age: 26‒69 years). Results indicated that participation in exercise during childhood (before entering junior high school; ≤ 12 years old) significantly predicted better response inhibition. No such association was found if exercise participation took place in early adolescence or later (junior high school or high school; ≥ 12 years old). The positive association of exercise participation during childhood with response inhibition was moderated by decreased structural and functional connectivity in the frontoparietal (FPN), cingulo-opercular (CON), and default mode networks (DMN), and increased inter-hemispheric structural networks. Greater cortical thickness and lower levels of dendritic arborization and density in the FPN, CON, and DMN also moderated this positive association. Our results suggest that participation in exercise during childhood positively predicts response inhibition later in life and that this association can be moderated by changes in neuronal circuitry, such as increased cortical thickness and efficiency, and strengthened inter-hemispheric connectivity.

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