Interictal dysfunction of a brainstem descending modulatory center in migraine patients

Abstract

Background: The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks, either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an attack (i.e. the interictal phase).

Methods and findings: Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41 degrees C and noxious heat (pain threshold+1 degrees C). Stimuli were either applied to the forehead on the affected side (as reported during an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed significantly greater NCF activation in control subjects than the migraine patients.

Conclusions: Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the evaluation of therapies for migraine.

Figure 1. Functional differences in the brainstem and the brain of migraine vs. healthy control subjects.

(A) Pain ratings: No significant effects of group or stimulation site for 41°C (2-Way repeated measures ANOVA [group, site], group F = 0·3646, p = 0·5521, df = 1, site F = 2·7355, p = 0·1123, df = 1) and Thr+1°C (2-Way repeated measures ANOVA [group, site], group F = 0·2918, p = 0·5950, df = 1, site F = 0·4060, p = 0·5312, df = 1). Mig = migraine subject; HC = healthy control. (B) Activation contrast: Interictal migraine subjects show decreased nucleus cuneiformis (NCF) responses to stimuli relative to controls. The exception is Thr+1°C on the face. The green area in the reference images highlight NCF (adapted from Duvernoy[46]). C = contralateral to stimulus site; I = ipsilateral. p<0·05 (uncorrected). (C) Single trial averages: Responses recorded from anatomically defined NCF region of interest. Y-axis = normalized % signal change. Gray shade represents stimulus application. N = 12 in each condition, except for Thr+1°C for Face (N = 11). One patient was excluded because of stimulus-correlated motion; the corresponding control was also excluded.