Trigeminal Nociceptive Transmission in Migraineurs Predicts Migraine Attacks

Abstract

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.

Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine

“…Our study found significant activation in response to trigeminal nerve somatosensory stimulation in bilateral Sp5 (oralis subnucleus). Interestingly, Stankweitz et al (20) demonstrated a positive correlation between Sp5 activity and time to next ictal event, suggesting that Sp5 response to nociceptive stimulation may be an important predictor of an upcoming migraine attack. In our study, we similarly observed a positive correlation between Sp5 activation and the interictal phase, though not specifically with time to subsequent attack (r ¼ À0.33, p ¼ 0.21).…”

Structural and Functional Neuroimaging in Migraine: Insights From 3 Decades of Research

“…52 Decreased activation of trigeminal nuclei with nociceptive stimulation. 45 Magnetic resonance angiography Dilation of extracranial middle meningeal artery and intracranial middle cerebral artery; sumatriptan-induced contraction. 35 Positron emission tomography Increased blood flow in the brainstem (midbrain and dorsal pons), cerebellum, hypothalamus, thalamus, insula, cingulate cortex, prefrontal cortex, auditory cortex, and visual association cortex (brainstem and hypothalamus activation persisting after sumatriptan injection).…”

“…Functional MRI studies also compared brain responses during trigeminal pain processing in migraine patients with those of healthy control (HC) subjects. 45 The activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Interictal patients exhibited lower activations in the spinal trigeminal nuclei compared with controls, however, preictal (shortly before attack) subjects showed activity similar to controls, indicating that the trigeminal activation level increases over the pain-free migraine interval.…”

The role of BOLD-fMRI in elucidating migraine pathophysiology

“…The hypothesis of a compensatory reorganization of anti-nociceptive network in migraine is supported by another BOLD-fMRI study, using repetitive trigeminal-nociceptive stimulation, which showed significant increased ACC and decreased SSC responses in MwoA patients [31]. The same authors reported a cycling behavior of the spinal trigeminal nuclei activity in response to nociceptive stimulation, demonstrating that the trigeminal activation level increases over the pain-free migraine interval [32]. More recently, Stankewitz and May [33] have investigated neuronal substrates of olfactory stimulation during migraine attack and interictal period and, at a later stage, using both trigeminonociceptive and olfactory stimuli, explored neuronal correlates of habituation in migraine subjects [34].…”