Klinik für Neurologie und Neurophysiologie

Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1(7):658-660.

Weiller C, Kaube H. Posterior hypoperfusion in migraine without aura? Cephalalgia. 2010;30(8):1018-1020. doi:CHA1949_3 [pii] 10.1111/j.1468-2982.2009.01949_3.x

May A, Kaube H, Buchel C, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain. 1998;74(1):61-66.

Reinhard M, Schork J, Allignol A, Weiller C, Kaube H. Cerebellar and cerebral autoregulation in migraine. Stroke. 2012;43(4):987-993. doi:10.1161/STROKEAHA.111.644674

Hosp JA, Reisert M, von Kageneck C, Rijntjes M, Weiller C. Approximation to pain-signaling network in humans by means of migraine. Hum Brain Mapp. 2021;42(3):766-779. doi:10.1002/hbm.25261

In 1987 Neil Raskin and colleagues reported 15 patients, which were previously headache-free, who immediately after implantation of electrodes in the periaqueductal grey of the brain stem developed severe “migrainous“ headaches (Raskin et al., 1987). Despite evidence from animal experiments identifying trigeminal afferents and imbalance in the midbrain endogenous anti-noceptive system and autonomic control regions in the production of headaches, in that time vascular changes (“too much blood in your head“, leading to increased intracranial pressure) were seen as cause of headache in migraine.

Discovery of brain stem activity in the attack independent from symptoms.

The story behind it: A major pharmaceutical company had released sumatriptan as the first 5_HT1d agonist. There was great concern that potential cerebral vasoconstriction induced by the drug might be harmful and thus prevent FDA approval for patients with aura. The company approached our boss, Christoph Diener, about using PET to measure regional cerebral blood flow (rCBF) during acute migraine attacks and after intravenous administration of sumatriptan (at that time, there were no PET facilities in Germany other than the Max Planck Institute in Cologne and the University of Düsseldorf that were involved in neurological diseases). Arne May from Christoph Diener's research group made a huge effort to recruit patients. Patients from the database agreed to let Arne know immediately when a migraine attack might start. We immediately informed the PET team, radiography, people from the cyclotron, radiochemistry, nuclear medicine doctors and ourselves to rush to the unit (as a 'radioactive' unit it was as far away from the rest of the hospital as possible) to scan the patients. Patients were screened and monitored for almost two years, and we managed to scan 9 patients within 60 minutes of the onset of the attack. With arterial cannulation, quantitative measurements of rCBF were possible. The analysis was disappointing, in fact we could not measure any consistent changes in rCBF in any of the post-hoc subgroup definitions we tried. So we could not answer the question we were asked. A few months later, Markus Jüptner, one of our brightest minds in the department (he later decided not to pursue a brilliant academic career but to go into private practice as a psychiatrist), a colleague of mine in the PET group, suggested that we do a "conventional" SPM analysis on the data we had so dearly acquired.

This means a group analysis of the nine patients after stereotactic normalisation in a common space, comparing voxel by voxel in each plane the blood flow during the migraine attack, after relief of the headache by intravenous application of sumatriptan, and again later in a free interval. Holger Kaube, another doctor in Christoph Diener's department, who had been well trained by Peter Goadsby, then in Australia, was well aware of the pathophysiology of migraine and the role of the brainstem. The reconstruction of the images took ages. We all waited anxiously as one brain slice after another was produced and displayed on the screen. At the time, PET studies focused on the cerebral cortex, maybe the cerebellum, but the brainstem? But a small spot appeared in the brainstem, and it was getting bigger with each slice, could it be true?

How it continued/continues: After publication there were some reservations about the validity of the findings and it took the perseverance of Peter Goadsby's group to replicate and refine the findings (Afridi et al, 2005a)(Afridi et al, 2005b). Arne May went on to investigate the role of the hypothalamus in cluster headache and more (May et al., 1998a)(May et al., 1999a)(May et al., 1999b)(May et al., 1998b)(Weiller and Rijntjes, 1999). Serotonin agonists came on the market and became the first-line treatment for acute migraine attacks. There were times when our paper was the most cited in headache or even pain research. The paper is selected in Landmark Papers in Neurology (eds. Turner MR, Kiernan MC, OUP 2015), Chapter 3 (Headache) p. 83: "Again, it is hard to overstate how revolutionary this paper was at the time. Thanks Peter, it really made my day). More importantly, it may have encouraged basic researchers to continue and translate the animal findings into drug development, leading to the approval of the CGRP antibodies that are so successful in migraine prophylaxis today. The discussion on how blood flow changes in the cerebral hemispheres are causally related to headache and other symptoms of migraine as an aura or better seen as an epiphenomenon (Bruyn, 1982) remains open (Weiller and Kaube, 2010)(Reinhard et al., 2012). More recently, we have used advanced tracking methods (global tracking (Reisert et al., 2011) to elucidate the pathophysiology of migraine in a different way (Hosp et al., 2021). Material from the Human Connectome Project was used to describe the connections of the various players involved in migraine pathophysiology in the brainstem and how this is incorporated into the connections to the cerebral hemispheres. We found three interconnected networks centred on the insular cortex: an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain processing and modulatory areas. Direct connections to visual and auditory cortical association fields suggest a possible neural basis for phonophobia, photophobia and aura phenomena. An observation from the original 1995 paper that has received less recognition.

references:

Afridi SK, Giffin NJ, Kaube H, Friston KJ, Ward NS, Frackowiak RSJ, et al. A positron emission tomographic study in spontaneous migraine. Arch Neurol 2005; 62: 1270–5.

Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005

Bruyn GW. Cerebral Cortex and Migraine. In: Critchley M, editor(s). Advances in Neurology. New York: Raven Press; 1982. p. 151–69

Hosp JA, Reisert M, von Kageneck C, Rijntjes M, Weiller C. Approximation to pain-signaling network in humans by means of migraine. Hum Brain Mapp 2021; 42: 766–79.

May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ, Frackowiak RS, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999; 5: 836-8.

May A, Bahra A, Büchel C, Frackowiak RSJ, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet 1998; 352: 275–8.

May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999; 46: 791–4.

May A, Kaube H, Büchel C, Eichten C, Rijntjes M, Jüptner M, et al. Experimental cranial pain elicited by Capsaicin: a PET-study. Pain 1998; 74: 61–6.

Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache 1987; 27: 416–20.

Reinhard M, Schork J, Allignol A, Weiller C, Kaube H. Cerebellar and cerebral autoregulation in migraine. Stroke 2012; 43: 987–93.

Reisert M, Mader I, Anastasopoulos C, Weigel M, Schnell S, Kiselev V. Global fiber reconstruction becomes practical. Neuroimage 2011; 54: 955–62.

Weiller C, Kaube H. Posterior hypoperfusion in migraine without aura? Cephalalgia 2010; 30: 1018–20.

Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658–60.

Weiller C, Rijntjes M. Cluster headache: phrenology revisited? [news; comment]. Nat Med 1999; 5: 732–3.