Elevated CBT in space has been earlier observed by Gundel et al.16,17, using 24-hours CBT recordings, however to much lower extent (0.06–0.16 °C). In this case the higher resting CBT remained elevated throughout the stay on the ISS and finally returned to baseline 10 days after landing; these findings are also in line with observations of Dijk et al.15. However, these studies were short-term missions, spanning a maximum of 8–16 days of spaceflight. Our data suggest that the shift in CBT seems to be a slow, gradual phenomenon that reaches its peak only after months of spaceflight. In addition, we also observed an increase of maximal CBT after short bouts of exercise, in some cases exceeding 40 °C. Remarkably, these increases occurred despite workloads were lower inflight compared to the preflight exercise protocol28. Moreover, the rate of the increase in CBT during exercise, i.e. the slope of CBT, was significantly steeper during spaceflight. These findings are very much in line with earlier studies, stating that after long-term spaceflight the sensitivity of the heat-loss responses is reduced, resulting in a faster rise in CBT10. Furthermore, our data indicate that the impairments in thermoregulation are still prevalent after return to Earth, and recovery occurs only very gradually. In our opinion, the diminished convective and evaporative heat loss in space called for an increase in skin perfusion to enhance radiative heat loss. This could happen by marked peripheral vasodilation as recently described by Norsk et al.29, and might be an attempt of the autonomic nervous system to increase heat loss through radiation even under resting conditions in space30.

CBT was determined using a novel, non-invasive heat flux sensor20,21,23,25,26. Major advantages and limitations of the different methods including the Double Sensor, their anatomical site, their applicability in the clinic and in the field, and the role of the hypothalamus in thermoregulation, as well as the ambiguous brain temperature concepts, have been intensively reviewed and discussed in the recent literature20,30,31,32,33,34. This method allowed to monitor CBT at the forehead, accounting for important factors of brain tissue temperature and skin perfusion adjacent to the skull. Brain temperature mainly depends on heat transfer from the peripheral organs to the brain via the arterial blood and on the removal of heat from the brain via the cerebral veins. Additional heat is removed by cooler arterial blood entering the brain. Due to high metabolic activity, deep brain temperature is slightly higher than central blood temperature in the pulmonary artery (~0.2 °C) or in the esophagus (~0.3 °C) under resting conditions on Earth33. However, vigorous physical exercise combined with extremely high regional neuronal activity (motor and supplementary motor areas), further increases cerebral metabolic rate and as such aggravate the heat strain on the brain35. Caputa reports that the limit of brain temperature is 44 °C for a short period of time, or 40 to 60 minutes when in the range of 42 to 42.5 °C36. Since we have shown that our crew members reached CBT > 40 °C during short submaximal exercise, the safety margins for heavy exercise in space seem to be smaller. To assess the impact of any inflammatory causes on the increased CBT, we also determined IL-1ra at 15, 30, 60, 120, and 180 days of spaceflight. IL-1ra was specifically targeted as it has been shown to be particularly sensitive during spaceflight with 300- to 600-fold higher increases during spaceflight compared to IL-1α or IL-1β13. In fact, IL-1ra appears to play a key role in local inflammatory processes37 and has been shown to be more sensitive than other cytokines such as IL-1β to peripheral changes in the blood compared to alterations of specific local tissues concentrations38. In line with our hypothesis, IL-1ra was significantly increased during spaceflight and exhibited a nearly identical pattern to the CBT data. Moreover, we also found a moderate relationship between IL-1ra and CBT, suggesting that cytokine dysregulation is associated with increased CBT in spaceflight. The activation of these immunological pathways might have an iatrogenic origin related to the strenuous exercise programs prescribed to astronauts during long-duration space missions. While the immune system is already affected by spaceflight per se39,40,41, vigorous exercise induces a marked impairment of the immune system39. Another possible explanation for any pro-inflammatory responses during spaceflight could be related to the increased radiation exposure of astronauts in low Earth orbit39. According to recent measurements, the daily exposure rates measured on board the ISS have been described to be 100 times higher that exposure rates on the Earth42. However, despite considerable evidence for spaceflight-related cytokine dysregulation, as well as the high sensitivity of IL-1ra for plasma concentrations, it should be noted that the increases were rather moderate. In this regard, a new line of research investigating the effects of acute and chronic increases in CBT without any inflammatory causes deserves consideration. Various animal, but also an increasing number of human studies, suggest psychological stress-induced, persistent hyperthermia. These data indicate that novelty stress, such as exposure to unfamiliar environments, can increase CBT by as much as 2 °C and chronic stress can lead to the so-called stress induced hyperthermia43. Currently, its neural mechanisms are unknown, but are likely to include altered sympathetic activity, changes in non-shivering thermogenesis via activation of brown tissue adipose, and possible interactions between the hypothalamic–pituitary–adrenal axis, the prefrontal cortex, amygdala, orexin neurons, and the preoptic nucleus of the hypothalamus.

In summary, we found that CBT rises higher and faster during physical exercise in space than on ground, and resting CBT is elevated in long-duration spaceflight. We concluded that, within the limits of a spaceflight experiment, these increases might be related to persistent low-grade pro-inflammatory responses to weightlessness, strenuous exercise protocols, radiation, psychological stress-induced hyperthermia or a combination thereof. Irrespective of its underlying causes, this space fever, as we may call it, has potential implications for long-term spaceflights in terms of astronauts’ health, well-being, and support, including energy, nutrient, and fluid requirements as well as physical and cognitive performance.