Increased Serotonin Transporter Availability in the Brainstem of Migraineurs – In vivo Evidence for a Serotonergic Dysfunction in Migraineurs

Aim: The serotoninergic system has been supposed to play a major role in migraine pathophysiology for decades. 80% of serotonergic neurons reside within the raphe nuclei in the brainstem. Positron emission tomgraphy (PET) studies on migraineurs show a marked increase of regional cerebral blood flow (rCBF) in the mesopontine brainstem, a region which comprises the rostral raphe nuclei. We hypothesized the mesopontine serotonergic system being involved in the pathophysiology of migraine. Methods: We used I-123 ADAM, a new and highly specific radioligand targeting the serotonin transporter (SERT) and co-registration of MRI and Single Photon Emission Tomography (SPECT) to investigate the brain serotonergic system in migraineurs in vivo. 19 migraine patients (2 patients with migraine with aura, 17 patients with migraine without aura) and 10 healthy, age-and sex-matched controls were enrolled. Patients using migraine prophylaxis were excluded. SPECT-imaging was performed interictally. Region of interst (ROI)-analysis was performed on the basis of coregistered MRI/SPECT-scans. Results: ROI-analysis revealed a highly significant increase of I-123 ADAM uptake in the mesopontine brainstem of migraineurs (p<0.001). Moreover, we found a positive correlation between migraine frequency and brainstem SERT-availability (r=0.5; p=0.027). There was a slight, non-significant increase of I-123-ADAM uptake in the thalamus of migraineurs. Conclusions: We demonstrate a significant increase of brainstem SERT-availability in migraineurs which is correlated to the severity of the disease. Our study provides evidence that migraine is characterized by a chronic disturbance of the brainstem serotonergic system. I-123 ADAM-SPECT may become a valuable tool for the differential diagnosis of headache disorders and for drug monitoring in the future. Moreover, SERT-imaging may have the potential to identify migraineurs at risk for chronification. Finally, SERT-imaging may help to stratify migraine patients for therapeutic algorithms in the future.