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Exposure to the spaceflight environment results in profound multi-system physiological adaptations in which there appears to be substantial inter-individual variability (IV) between crewmembers. However, performance of countermeasure exercise renders it impossible to separate the effects of the spaceflight environment  alone  from those associated with exercise, whilst differences in exercise programs, spaceflight operations constraints, and environmental factors further complicate the interpretation of IV. In contrast, long-term head-down bed rest (HDBR) studies isolate (by means of a control group) the effects of mechanical unloading from those associated with countermeasures and control many of the factors that may contribute to IV. In this perspective, we review the available evidence of IV in response to the spaceflight environment and discuss factors that complicate its interpretation. We present individual data from two 60-d HDBR studies that demonstrate that, despite the highly standardized experimental conditions, marked quantitative differences still exist in the response of the cardiorespiratory and musculoskeletal systems between individuals. We also discuss the statistical concept of “true” and “false” individual differences and its potential application to HDBR data. We contend that it is currently not possible to evaluate IV in response to the spaceflight environment and countermeasure exercise. However, with highly standardized experimental conditions and the presence of a control group, HDBR is suitable for the investigation of IV in the physiological responses to gravitational unloading and countermeasures. Such investigations may provide valuable insights into the potential role of IV in adaptations to the spaceflight environment and the effectiveness of current and future countermeasures.

The Role of Long-Term Head-Down Bed Rest in Understanding Inter-Individual Variation in Response to the Spaceflight Environment: A Perspective Review