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.

Figure 1.

Experimental design. The stimulation paradigm consisted of three parts: reaction task, stimulation, and rating procedure. Before each of 45 trials (each stimulus was presented 15 times), a reaction time task was implemented. Subjects were instructed to press a button immediately after the fixation cross changed its color from red to yellow. After a jittered time delay, subjects underwent the trigeminal stimulation paradigm in which stimuli (2.5% ammonia, rose odor, air) were administered randomly in the right nostril. Following each stimulus, subjects rated the intensity on a numerical rating scale and a randomized interstimulus interval (ISI) followed.

Figure 2.

Activation pattern during nociceptive input. A conjunction analysis across both groups revealed shared activations of interictal migraineurs (n = 20) and healthy controls (n = 20) during trigeminal nociceptive stimulation of the right nostril. Increased BOLD responses were detected in several pain-processing areas including the insular cortex (IC), midcingulate cortex (MCC), secondary somatosensory cortex (SII), amygdala (AMY), and caudate nuclei (Caudate). Activation maps were plotted at a threshold of p < 0.001 (uncorrected) and were overlaid onto the average structural image of healthy controls and interictal migraine patients. L, Left hemisphere; R, right hemisphere.

Figure 3.

Comparison between interictal migraine patients and healthy controls. During trigemino-nociceptive stimulation of the right nostril, healthy controls (n = 20) showed significantly stronger bilateral activation than interictal migraineurs (n = 20) in a region of the brainstem corresponding to the spinal trigeminal nuclei. The activation is shown at a threshold of p < 0.001 (uncorrected) and overlaid on the average structural image of healthy controls and interictal migraine patients. L, Left hemisphere; R, right hemisphere.

Figure 4.

Relationship between BOLD responses and the time to the next attack. A regression analysis demonstrated that the intensity of the BOLD response in the spinal trigeminal nuclei (independent variable) during nociceptive stimulation predicts the time to the next attack (dependent variable; day 0 on the x axis = headache attack) in the group of interictal migraine patients (n = 20). The diagonal line shows the regression.

Figure 5.

Group-specific BOLD responses in the trigeminal nuclei. The plot shows average trigeminal BOLD responses (mean and SEM) for interictal (n = 20), preictal (n = 10), and ictal (n = 13) migraine patients (circles) and healthy controls (n = 20; square). BOLD responses were obtained from a sphere of 4 mm radius placed around coordinates of the trigeminal nuclei (x = 3, y = −36, z = −45) that originated from a previous study (Stankewitz et al., 2009).

Figure 6.

Increased activation in the pons during an acute headache attack. Migraine patients scanned during head pain (n = 13) showed an increased activation level during trigemino-nociceptive stimulation in the rostral pons compared with their own data outside migraine attacks. For visualization purposes, the activation is shown at a threshold of p < 0.01 (uncorrected) and overlaid on the average structural image of these patients. L, Left hemisphere; R, right hemisphere.