Mechanisms underlying adaptations to the hypoxia of high altitude: neurovascular regulation, sleep and cognitive function

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OBJECTIVES OF THE PROPOSED RESEARCH PROGRAM: This program aims to better understand the mechanisms that regulate the physiological adaptations to the hypoxia of high altitude. The overall objective is to conduct human integrative cerebrovascular physiology studies, which aim to elucidate the mechanisms, by which sleep is disrupted during acclimatization to high altitude, and to develop and implement ways of improving sleep and daytime function in high altitude workers. SUMMARY OF SCIENTIFIC APPROACH: The program will be conducted at the University of Calgary and at mine sites of our industrial partner, Teck Resources. The studies in Calgary will investigate the alterations that occur in the brain of volunteers, during wakefulness and during sleep, when the arterial blood gas tensions are altered in a pre-defined and fully controlled manner for a period ranging from minutes to 48 hours. A chamber has been built in which the ambient PO2 can be adjusted by adding either nitrogen or oxygen and in which the ambient PCO2 can be adjusted by adding or removing carbon dioxide to prevent respiratory alkalosis and acidosis, respectively. This chamber is unique in Canada and the first of its kind used to carry out investigations that focus predominantly on long-term cerebrovascular adaptations to hypoxia during sleep in humans. Studies at the mine sites will investigate the adaptive nature of the cerebrovascular responses to prolonged exposure to hypoxia at rest, while awake and during sleep, by studying miners during acclimatization to altitude (> 3,000m above sea level; Quebrada Blanca mine, Chile) and miners who work at low altitude (i.e., control group)(Highland Valley Copper mine, Kamloops BC). As this program unfolds, novel approaches to study the mechanisms of neurovascular coupling (combining techniques to study both blood flow and neuronal activity) will ensue. NOVELTY AND EXPECTED SIGNIFICANCE OF THE WORK: Our laboratory is unique in Canada, and its innovative features include i) sophisticated technique to control arterial PCO2 and PO2 accurately and continuously over short and prolonged periods, ii) the ability to make simultaneous and continuous measurements of the ensuing changes in respiration, cerebral blood flow, blood pressure and heart rate with high temporal resolution (breath-by-breath, beat-by-beat), and iii) dynamic mathematical models that describe the way in which cerebral blood flow, blood pressure, heart rate, and respiration behave in response to hypoxia in humans. Further, we have established important and necessary collaborations with Teck Resources (a mining company that operates copper mines in Canada and Chile). This partnership was initiated as part of an NSERC Interaction grant (2011) to address some of the physiological challenges associated with high altitude mining. This research program will enable the use of sophisticated techniques in arterial gas control to study the mechanisms that regulate cerebrovascular, respiratory, and cardiovascular control in humans. The research environments are unique and ideally suited for studies of high altitude physiology. The proposed program will have a major impact in helping advance our knowledge of human cerebrovascular physiology and the adaptations that ensue with exposure to hypoxia and altitude. It is anticipated that the research will highlight the impact of poor sleep on daytime performance, which can be applied to operators of heavy equipment everywhere regardless of the cause of sleep loss and the geographic location of the workers. Finally, this program will bring together an interdisciplinary team in biomedical research and will provide outstanding training opportunities for HQP both within the university environment and industry in Canada and abroad.