Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging.

Due to the clinical picture and also based on early imaging data (Weiller et al. Nat Med 1:658-660, 1995), the brainstem and midbrain structures have been intensely discussed as possible driving or generating structures in migraine. The fact that the brainstem activation persisted after treatment makes it unlikely that this activation was only due to increased activity of the endogenous anti-nociceptive system. It was consequently (and somewhat simplifying) coined the "migraine generator". Since then several studies have focussed on this region when investigating episodic, but also chronic migraine. Denuelle et al. were the first to not only demonstrate significant activations in the midbrain and pons but also in the hypothalamus, which, just like the brainstem activation in the first study, persisted after headache relief with sumatriptan. Expanding these studies into f-MRI studies, refined the involvement of rostral parts of the pons in acute migraine attacks. However, they also focused on the preictal stage of NO-triggered and native human migraine attacks and suggested a predominant role of the hypothalamus shortly before the beginning of migraine headaches as well as alterations in hypothalamic functional connectivity. Additionally, changes in resting-state functional connectivity of the dorsal pons and the hypothalamus in interictal migraineurs has recently been found. The pathophysiology and genesis of migraine attacks is probably not just the result of one single "brainstem generator". Spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in activity in certain subcortical and brainstem areas, thus changing susceptibility thresholds and not only starting but also terminating headache attacks.