Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.

Habituation deficits in various sensory modalities have been observed in migraine patients in several experimental designs. The underlying neuronal mechanisms are, however, still unknown. Past studies have used electrophysiological measures and focussed on habituation behaviour during one single session. We were interested in how repeated painful stimulation over several days is processed, perceived and modulated in migraineurs. Fifteen migraine patients and 15 healthy controls were stimulated daily with a 20 min trigeminal pain paradigm for eight consecutive days, using functional MRI performed on days one and eight and one follow-up measurement three months later. The results demonstrate that migraine patients did not differ in behavioural pain ratings compared to the controls at any time. However, functional imaging data revealed a significant difference in several brain areas over time. The activity level in the prefrontal cortex (PFC) and the rostral anterior cingulate cortex (rACC) increased in healthy control subjects from day one to day eight, whereas it decreased in migraine patients. These data suggest that several brain areas known to be involved in endogenous pain control show a completely opposite behaviour in migraine patients compared to healthy controls. These brain networks seem not to be disrupted per se in migraine patients but changed activity over time responding to repetitive nociceptive input. The alteration of pain inhibitory circuits may be the underlying mechanism responsible for the dys-functional neuronal filters of sensory input.