The researchers believe there are a number of reasons why space travel could cause headaches, the root cause being microgravity.

Microgravity is known to cause lower oxygen levels in the blood and this may be the trigger for space headache.
—"Space headache a real phenomenon," BBC News, June 2, 2009

The disabling headaches appeared unique described by the crew as "exploding" and were generally unrelated to common space motion sickness.

The Dutch researchers say space headache should be seen as a separate medical condition.
—"Space such a headache," Sydney MX, June 3, 2009

The vast majority of headache episodes (76%) were not associated with symptoms of SMS. We conclude that space flights may trigger headaches without other SMS symptoms in otherwise 'super-healthy' male subjects. We propose to classify space headache as a separate entity among the secondary headaches attributed to disorders of homeostasis.
—AA Vein, H Koppen, J Haan, GM Terwindt, and MD Ferrari, "Space headache: a new secondary headache," Cephalalgia, June 1, 2009