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Background Mnemonic discrimination is very vulnerable to aging. Previous studies have reported that aerobic exercise and enriched cognitive stimulation (e.g., video game) could improve mnemonic discrimination in older adults. The animal model suggested that combining the two training methods could result in a larger improvement. However, there is limited evidence on the potential superior efficacy of combined intervention with human subjects. Moreover, the neural basis of this potential superior is poorly understood. Methods We conducted a 16-week intervention trial with ninety-eight community-dwelling older adults assigned to one of four groups (combined training, aerobic cycling alone, video game along, or passive control). Mnemonic discrimination was measured as the primary behavioral outcome, hippocampal volume and functional connectivity of the default mode network (DMN) were measured as neural indicators. Results Participants receiving the combined intervention demonstrated the largest effect size of mnemonic discrimination improvement. MRI results indicated aerobic exercising increased left hippocampal volume, while video game training counteracted the decline of DMN functional connectivity with aging. The synergy of hippocampal structural and functional plasticity observed in the combined training group explained why the largest intervention benefits were obtained by this group. Conclusions Despite the non-randomized design (i.e., likely self-selection bias), our results provide new evidence that combined intervention of exercise and cognitive training is more effective than single intervention for older adults. Parallel to animal studies, aerobic exercise and the video game with enriched cognitive stimulation could induce hippocampal plasticity through separately structural and functional pathways.

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