Hypobaric hypoxia results in a a number of neurophysiological adaptations. The Caudwell Xtreme Everest project involves a series of experiments designed to investigate these changes and elucidate any underlying relationship with concurrent neurocognitive (functional) changes. 224 subjects will be studied at altitudes of up to 5300m during a standardised ascent to Everest Base Camp. More in-depth studies will be performed on 24 researchers and the summit team of 10 at altitudes up to 8848 metres. Brain Oxygenation at Altitude (measured using Near Infra Red Spectroscopy) – Our pilot work from Tibet has demonstrated that some subjects have an ability to maintain brain oxygenation during exercise to a greater extent than others. The hypothesis that this ability would correlate to a smaller rise in neural markers (S100) and an ability to maintain neurocognitive function will be investigated. Brain Blood flow and Inferred Intracranial Pressure (measured using Transcranial Doppler) – It has been hypothesised that high altitude headache and acute mountain sickness are related to the formation of cerebral oedema resulting in a rise in intracranial pressure. To investigate this, transcranial Doppler of the middle cerebral artery is being used to calculate blood flow velocity, vessel calibre and to infer intracranial pressure using the calculated value of pulsitility index. Reflex and Neurocognitive Changes at Altitude: Hypoxia causes a deterioration in neural function. This is being been investigated on a number of levels. At the basic reflex level, the velocity of the papillary light reaction will be studied in all 224 subjects. At the next level, saccadic eye movements will be studied in the 24 researchers. On a more global functional level, neurocognitive and coordination tests are being carried out on all 224 subjects. These results will be related to headache scores and physiological changes. Neural Markers and MRI evidence of hypoxic brain injury Clinically, episodes of brain hypoxia are known to result in the release of S100 and other neuronal markers. Plasma S100 levels are being measured in all 224 subjects. The summiteers are also having MRI scans to investigate microanatomical changes in hippocampal and basal ganglia structure. All of these facets will be correlated with AMS symptoms and neurocognitive changes. Anthropermororphic Predispotision to Acute Mountain Sickness: The “Tight Fit” Hypothesis was proposed by Ross in the 70’s to account for individual predisposition to AMS. He suggests that those with a large brain in a small skull are more susceptible. Skull size and volume has been measured in all 224 subjects to assess cranial size and symptoms scores will be recorded during the ascent. Subjects with the highest and lowest symptom scores will undergo MRI scans to calculate the ratio brain:skull volume. Retinal Imaging and Intraoccular Pressure: It is known that many people ascending to altitude develop retinal haemorrhages. Retinal photography will be used to investigate the nature and incidence of retinal haemmorhages in all 224 subjects. The development of retinal haemorrhages will be correlated with headache, cerebral oxygenation and cerebral blood flow. In the research group intraocular pressure will be correlated with the presence of haemorrhages. Many aspects of neurophysiology and neurocognitive changes are being investigated during the Xtreme Everest expedition. A summary of the preliminary findings will be presented here.