This thesis studies the effect of hypoxia (at rest and during exercise) on the arterial and venous cerebral circulation, investigating the venous system role in high altitude headache. Methods: 1) Hypobaric hypoxic studies investigated 198 trekkers and 24 Investigators to 5300m, 14 to 6400m and 8 to 8848m. 2) Normobaric hypoxic studies used Magnetic Resonance Imaging (MRI)) at sea-level. Four domains were addressed: i. Arterial: Hypobaric hypoxia: (n=24) Transcranial Doppler (TCD) measured middle cerebral artery diameter (MCAD) and blood velocity (MCAv). Sea-Level normobaric hypoxia: (n=7) A hypoxicator (FiO2 = 11%) for 3 hours with a 3Tesla MRI scan measured MCAD and MCAv. ii. Brain Oxygenation: Near Infrared Spectroscopy (NIRS) monitored Regional Brain Oxygenation (rSO2). iii. Venous: Retinal imaging at altitude and MRI at sea-level assessed the venous system. iv. Headache: A daily diary recorded headache burden. Results: Arterial: Hypobaric and normobaric hypoxia induced MCA dilatation. Mean (±(SEM)) MCAD increased in hypoxia (from 5.23(±0.23)mm (at 5300m) to 9.34(±0.88)mm (at 7950m)(p<0.001) (TCD). At sea-level, (after 3 hours FiO2 = 11%) MCAD increased from 3.04(±0.13)mm to 3.27(±0.13)mm (MRI). Brain Oxygenation: rSO2 decreased more than peripheral arterial saturation (SaO2), especially during exercise. The relative percentage reduction in resting SaO2 and rSO2 from 75m to 5300m was -22.23 ±0.56% and -30.61 ±1.28% (p<0.001) respectively. Venous: Hypoxia induced retinal and cerebral venous distension. Twenty-three of 24 subjects exhibited retinal venous distension (range 5 to 44%). Degree of distension correlated with headache (r = 0.553, p=0.005). Possession of a narrow transverse sinus strongly related to retinal and cerebral venous distension and headache. Headache: Headache Severity Index (HSI) (headache score x duration) correlated inversely to both lateral and third ventricular volumes summed (r = -0.5, p = 0.005) and pericerebellar CSF volume (r = -0.56, p = 0.03). Conclusions: Large cerebral arteries dilate and veins distend with hypoxia. This suggests an important influence of cerebral venous anatomy and physiology on headache, with implications for pathophysiological states and their management
