As space-faring nations across the globe are fueling a new race of human space exploration that goes well beyond the Moon, national agencies and private entities across the globe have accelerated the research and development that will promote the safety and success of such missions. Prolonged body unloading and reduced physical activity levels associated with space travel could adversely affect brain and behavior. Long-duration bed rest in –6° head-down tilt (>1 month) is an established spaceflight analog on Earth to simulate the physiological and psychological adaptations of prolonged inactivity and headward fluid shift during space travel. The present work investigated the effects of long-duration bed rest on brain function and cognitive performance. In a series of five studies combining behavioral, electrocortical and magnetic resonance imaging data it was shown that bed rest can induce significant functional brain changes and cognitive impairments including emotion processing, memory formation, and selective attention, and that these effects may not recover quickly. Structured physical activity programs superimposed to bed rest were found to mitigate cognitive impairments. The benefits of antioxidant supplementation and artificial gravity or their combination with exercise remain to be determined. Some caution is warranted when behavioral data are collected in different body positions, i.e., seated vs. head-down tilt, because the neurophysiological reactions associated with postural changes may mask the effects attributed to physical inactivity. Future work in this field should be characterized by an interdisciplinary approach, integrating multimodal brain imaging, psychological and behavioral, neurovestibular, cardiovascular, biochemical, and circadian data. Such an approach could promote a holistic understanding of intellectual frameworks that together exceed individual disciplinary perspectives. The knowledge from such approaches could go beyond their application to spaceflight. It can translate to the prevention and treatment of various clinical conditions associated with cognitive impairments, and for which reduced physical activity levels are a critical risk factor
