Disease mechanisms which can be modelled with experimental hypoxia
Symptoms of acute mountain sickness, a disease of the brain which is developed by individuals who ascent to high altitudes to fast, are often migraine-like and include headache, nausea and vomiting [83]. An association between migraine and hypoxia has been suggested for patients with patent foramen ovale (a hole between the left and right atria of the heart). In these patients, who also suffer from migraine, PaO2 was lower than in healthy controls and normobaric oxygen treatment attenuated the frequency and severity of their migraines [84]. Furthermore, hypoxia has been shown to act as a reliable trigger for a complete physiological migraine [85-87]. Frank et al. used normobaric hypoxia at 12.6% oxygen for 6 hours which triggered migraines in 80% of participants with over 16% presenting with aura [85]. Schoonman et al. showed that hypoxia was a more reliable migraine trigger than nitroglycerine, which is the current experimental standard [87]. Hypoxia also offers a major safety advantage over the pharmacological models as it can be easily reversed at any point in the trial, whereas a dose of nitroglycerine cannot be withdrawn and requires the addition of a second medication like triptans to terminate its effects [88]. However, this phenomenon is under investigated as the few existing studies have relatively small population sizes. Migraine research can greatly benefit from a greater emphasis on hypoxia, both as a dependable and physiologically accurate trigger for interventional studies and as a window into the causational mechanism.
Experimental hypoxia models have been utilized to study various disease mechanisms associated with migraine. One such mechanism is cortical spreading depression (CSD), a wave of neuronal depolarization and subsequent depression that spreads across the cerebral cortex [89]. CSD has been implicated in the generation of migraine aura and is hypothesized to contribute to the initiation and propagation of migraine attacks. Hypoxia-induced CSD models have provided insights into the underlying mechanisms and potential therapeutic targets for migraine [90]. Furthermore, experimental hypoxia can be used to investigate the role of oxygen levels in modulating neurovascular function and the release of neurotransmitters, such as serotonin and CGRP, which are involved in migraine pathophysiology [91]. Hypoxia models allow researchers to examine the effects of reduced oxygen levels on cerebral blood flow, vascular reactivity, and neuroinflammatory processes, providing valuable information about the interplay between hypoxia and migraine mechanisms.