Beta-blockers such as metoprolol and propranolol are first choice migraine preventive medication. While the clinical efficacy of beta-blockers in reducing migraine attack frequency is certainly established [
1‐
4], it is still poorly understood how they exert their therapeutic effect. So far, no imaging studies investigated the central effects of beta-blockers and our knowledge about the mechanisms derives from preclinical studies. Metoprolol belongs to the group of β-adrenergic blockers and selectively blocks β1 receptors. Beta-blockers attenuate the effects of adrenaline and noradrenaline [
5,
6] and thereby downregulate the stimulating effect of the sympathetic nervous system. This downregulation was examined in several measures of cortical information processing that have been shown to be abnormal in migraineurs, such as visual evoked potentials, auditory evoked potentials and contingent negative variations [
7]. Beta-blockers seem to have a regulatory effect upon all of these. In the visual system of migraineurs, metoprolol decreased the amplitude of visual evoked potentials [
8]. Another study found a decrease of intensity dependence of auditory evoked cortical potentials in migraineurs [
9] and this decrease was related to clinical improvement. It has therefore been proposed that modulating the excitability of the cortex is how beta-blockers reduce the migraine attack frequency. Another neurophysiological approach to observe cortical information processing is the analysis of contingent negative variation (CNV), an event-related, slow cerebral potential following activation in the striato-thalamo-cortical loop. In untreated migraineurs the CNV is significantly increased and lacks habituation. Several studies found that beta-blockers normalize the CNV [
10] and further that normalization of high CNV was positively correlated with treatment response [
10‐
12]. These studies suggest that the effects refer to a general effect of beta-blockers on cortical excitability and abnormal cortical information processing in migraine. Accordingly it has been hypothesized that beta-blockers exert their preventive action in migraine by modulating cortical excitability and processing [
11]. However, the aforementioned studies applied methods with a focus on specific network activity rather than a focus on the location where metoprolol potentially exerts its action in the brain. A plausible explanation for the described abnormalities in sensory processing in migraineurs is a dysfunction of processing in thalamocortical neurons [
13‐
15]. Evidence that preventive action of beta-blockers is effective through β
1-adrenoceptor inhibition in nociceptive neurons in the thalamus comes from electrophysiological animal studies. Shields and Goadsby (2005) reported that thalamocortical activity evoked by superior sagittal sinus stimulation was inhibited after locally applied propranolol [
16].
To address this issue and to achieve a more integrated picture of central effects of metoprolol, we employed pharmacological functional magnetic resonance imaging in combination with a human model of headache attacks. The aim of this study is to assess the effects of metoprolol on brain activation patterns during trigeminal pain in migraine patients, as well as healthy human subjects, determined by fMRI. Based on earlier studies we hypothesize that metoprolol has an inhibiting effect on trigeminal pain processing, especially in the thalamus and/or thalamocortical networks.