Central manipulation of human thermoeffectors during prolonged cold exposure : interaction of thermal and non-thermal stressors

Humans maintain an internal body temperature at ~37℃ through the seamless recruitment of autonomic and behavioural thermoeffectors. In the cold, autonomic thermal responses include cutaneous vasoconstriction, shivering and non-shivering thermogenesis. These responses are orchestrated by feedback- dependent neural networks that detect the cold stimulus, integrate this thermal cue in central regulatory centres, and then initiate the efferent pathways to the thermoeffectors. Behavioural actions, such as a voluntary increase in work rate, are also generally affected by input from thermal receptors. The function of the thermoeffectors can be influenced by the specific characteristics of the thermal stress (i.e., its severity and duration), but also, in an interactive manner, by various non-thermal factors. For instance, nitrous oxide (N2O) and cognitive loading typically act on the central neural circuits of the thermoregulatory system. Thereby, they can impinge on the integrative control function and, thus, alter the onset thresholds for and/or sensitivity of thermoeffector activity. Therefore, this thesis aimed to examine the interaction of thermal and specific non-thermal stressors on human thermoregulatory effector responses during prolonged exposure to cold.

After approval by the Swedish Ethics Review Authority, four studies were conducted, all involving non-cold acclimatised healthy men and employing a within-subject design. To evoke sufficient degrees of deep-body cooling (i.e., mild hypothermia), studies I, II, and III employed an experimental model wherein subjects participated in three 120-minute cold water immersions within 10-12- hour experimental sessions. In study IV, to induce adequate degrees of peripheral vasoconstriction, subjects participated in a hand cold-water (8℃) immersion trial for 30 minutes.

Study I investigated whether prolonged repeated exposure to cold within a day would provoke centrally mediated thermoregulatory fatigue. Twelve men participated in three experimental sessions. In each session, they were repeatedly submersed in either severely (15℃), moderately (20℃), or slightly (28℃) cold water. These water temperatures were selected to induce discrete amounts of heat-producing thermoeffector output, presumptively leading to distinct fatigue levels during each session. The results demonstrated that the function of autonomic thermoeffector responses was preserved over prolonged, repeated whole-body cold exposure, regardless of the severity of the cold stressor. Notably, repeated whole-body exposure to slight cold stress, evoked by 28℃ water, seemed to sensitise the heat-producing thermoeffector responses.

Studies II and III, which were performed within the same experimental project, examined thermoregulatory plasticity and cognitive performance in response to prolonged repeated exposure to 30% N2O and cold. Fourteen men participated in two experimental sessions, during which they performed cold-water immersions in 20°C water, while breathing either normal air or a normoxic gas mixture containing 30% N2O. In study II, it was found that narcosis induced by N2O persistently blunted shivering thermogenesis and thermoperceptual responsiveness. In addition, it was observed in study III that N2O invariably compromised finger dexterity, attention, concentration, working memory, and spatial processing. Thus, a subanesthetic dose of N2O jeopardises human thermoregulatory functions, and, therefore, precipitates hypothermia.

Study IV examined whether finger vasoreactivity and thermosensitivity to localised cooling would be modulated by cognitive loading associated with prolonged performance of a mentally demanding task. Twelve men performed immersion of a hand either immediately after a 60-minute cognitive task battery, during the simultaneous performance of the cognitive task, or without any cognitive task. Based on the findings of this study, it appears that the mode of stressors' application determines the impact of cognitive loading. Notably, the repeated execution of a cognitive task appeared to provoke moderate mental fatigue and transiently attenuated cold-induced vasoconstriction and perceived discomfort. Concurrent sustained cognitive and cold stress did not affect finger vasoreactivity during cooling but facilitated digit reperfusion after cooling.

List of scientific papers

This thesis is based on the following papers, which are referred to by their Roman numerals (I-IV).

I. Moes, M. I., Elia, A., Eiken, O., & Keramidas, M. E. (2025a). Heat- producing thermoeffector plasticity in response to prolonged iterative exposure to a high-heat loss environment: no indication of thermoregulatory fatigue. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 328(4), R433- R446. https://doi.org/10.1152/ajpregu.00310.2024

II. Moes, M. I., Elia, A., Gennser, M., Eiken, O., & Keramidas, M. E. (2023). Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans. Journal of Applied Physiology, 135(3), 631-641. https://doi.org/10.1152/japplphysiol.00309.2023

III. Moes, M. I., Elia, A., Gennser, M., & Keramidas, M. E. (2024). Combined effects of mild hypothermia and nitrous-oxide-induced narcosis on manual and cognitive performance. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 326(3), R197- 209. https://doi.org/10.1152/ajpregu.00246.2023

IV. Moes, M. I., Elia, A., Eiken, O., & Keramidas, M. E. (2025b). Influence of sustained cognitive loading on finger circulatory and thermoperceptual responsiveness to localized cooling. BioRxiv, 2025-02. [Manuscript Preprint] https://doi.org/10.1101/2025.02.15.638420