An exploration into the effects of high altitude exposure on the neurovascular coupling response

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Leacy, Jack K.
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University College Cork
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Introduction The neural infrastructure within cerebral tissue is both elaborate and metabolically volatile. Owing to limitations in energy substrate storage capacity, the neural nexus relies upon continuous perfusion for the delivery of essential nutrients. Vital substrates which are transported within the blood help to support energy-dependent metabolic processes throughout the central nervous system at a global and regional level. Despite constituting ≈2% of total body mass, the brain receives a disproportionate ≈20% of total cardiac output. The physiological phenomenon which describes the intimate link between local neuronal activity and regional cerebral blood flow is termed neurovascular coupling (NVC). This phenomenon has been observed across all cerebral structures wherein dynamic changes in local metabolic activity are met with a concomitant increase in local perfusion of the active tissue. A vast body of work has assessed the translational implications of NVC for neurophysiological function and behavioural outcomes across several pathologies (aging, neurodegenerative disease, autoimmune disorders, trauma and metabolic disorders). Thesis Aims Herein, we sought to characterise the effects of high altitude (HA) exposure on NVC in healthy human volunteers encompassing different ascent paradigms (chapters 3 and 4). HA exposure is a pernicious multimodal stressor among habitual lowlanders, which necessitates an integrative physiological acclimatisation to sustain homeostasis and overall health and function. This environmental stressor has pronounced effects on other components of cerebral blood flow control. Prior to this thesis there was a dearth of literature regarding the effects of HA exposure on NVC. In addition, we conducted a complementary laboratory-based investigation which examined the degree of variance within the NVC response attributable to either age and/or sex (chapter 2). This comprehensive study was essential with respect to appreciating the interaction between participant demographics (age, sex) and NVC. Demographic heterogeneity is an inherent component of many HA research expedition. We therefore determined that it was of paramount importance to ascertain the magnitude to which heterogeneity influences our primary physiological measures. Methods Transcranial Doppler ultrasound (TCD) was employed to provide non-invasive measures of cerebral blood velocity. NVC was indexed as the change in posterior cerebral artery velocity (PCAv) during intermittent visual stimulation (30s on/off; 6Hz) in all experiments. This technique is widely used within the literature, as visual stimulation mediates an increase in metabolic activity of the visual cortex, a neural territory perfused by the PCA. Healthy human volunteers were recruited for studies described in chapter 2 (n=125, 41 male), 3 (n=10, 4 male) and 4 (n=12, 7 male). Arterial blood draws were sampled from the radial artery during HA expeditions (chapter 3 and 4), providing and index of ventilatory and acid-base acclimatisation status within each participant. Ascent profiles differed between chapters 3 and 4 relevant to the experimental question. Key results and conclusions Collectively, our results demonstrate that approximately 0-6.1% of the variance across several NVC metrics are attributable to either age and/or sex (chapter 2). Moreover, the magnitude of the haemodynamic response across several NVC metrics was remarkably intact following incremental and acute ascent to 4240m and 3800m respectively (chapters 3 and 4 respectively). Taken in conjunction, this thesis reveals that: (1) Neither age nor sex greatly affect the magnitude of the NVC response in healthy human volunteers (21-66yrs old) and (2) NVC response magnitude remains remarkably intact across multiple HA exposure paradigms in habitual lowlanders.
Neurovascular coupling , High altitude , Cerebral blood flow
Leacy, J. K. 2022. An exploration into the effects of high altitude exposure on the neurovascular coupling response. PhD Thesis, University College Cork.
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