Secondary Logo

The Premonitory Phase of Migraine

Bench to Bedside Insights

Hurley, Dan

doi: 10.1097/01.NT.0000489583.84551.2a
Back to Top | Article Outline




In a plenary lecture at the American Headache Society annual meeting, Peter Goadsby, MD, PhD, of King's College London and University of California, San Francisco, presented an overview of basic and clinical research advances in understanding the premonitory phase of migraine.

SAN DIEGO—The yawning, fatigue, photophobia, hunger, and other symptoms of the premonitory phase of migraine are providing important new clues to the disorder's underlying pathophysiology and potential new drug targets, according to a plenary presentation here at the annual meeting of the American Headache Society.

But rather than think of these premonitory symptoms as being caused by “triggers” in the external environment, the current view is that they are generated internally by changes in the brain state, and they are as much a part of the migraine as is the headache itself, said Peter Goadsby, MD, PhD, professor of neurology at King's College London and the University of California, San Francisco, who presented an overview of basic and clinical research advances in understanding the premonitory phase of migraine.

In recent years, he said, the field has begun to gain a greater understanding of the underlying mechanisms prompting those symptoms. “The beauty of being able to explore the biology of just yawning is that it allows us to dig down into role of dopamine. Asking why people get hungry brings us to the role of the hypothalamus and of neuropeptide Y,” Dr. Goadsby said. “We're in a state of real learning around this. We can now link what the patients are telling us [about their symptoms] with the underlying biology.”

For example, a 2007 study he coauthored in the Annals of Neurology showed that central dopamine-containing neurons play a role in modulating nociception in the trigeminovascular system, the area thought to be involved in headache pain; neuronal firing there was also shown to be reduced by dopamine agonists.

And in a 2011 study in Pain, he and colleagues reported that serotonergic and dopaminergic antinociceptive pathways act simultaneously on neurons in the trigeminocervical complex, and that both need to be functioning for trigeminal sensitization to be reversed.



Functional neuroimaging studies have cast new insights, as well, into the underlying biology of the premonitory phase. Using positron emission tomography scans, Dr. Goadsby and colleagues gave nitroglycerin to patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The nitroglycerin-initiated premonitory symptoms activated the posterolateral hypothalamus, which, he concluded, “can explain many of the premonitory symptoms.”

“What we were able to show is that these changes in the hypothalamus are not a response to pain, but precede it,” Dr. Goadsby said.

Given the previously known effect of neuropeptide Y (NPY) on the autonomic nervous system, Dr. Goadsby was interested in its role in migraine. He and colleagues reported in a paper published online ahead of print in March in the journal Pain that NPY inhibits trigeminovascular nociception in a dose-dependent manner. “Based on the role of NPY in appetite regulation, it is possible that disruption of the NPY system might explain changes of appetite in migraineurs.”

“We think the Y1 receptor is the most important one,” he told the audience. “We're pretty confident that neuropeptide Y in the hypothalamus has a big effect on these premonitory symptoms of craving and changes in hunger.”

Turning to another peptide, he described research into the role of pituitary adenylate cyclase activating peptide (PACAP), a known trigger of migraines that has been shown to rise in migraine without aura and to normalize with sumatriptan.

In an animal study published last year in Science Translational Medicine, he and colleagues reported that PACAP induced a robust increase in ongoing spontaneous firing and hypersensitivity to intra- and extracranial somatosensory stimulation, which did not coincide with meningeal vasodilation. A receptor antagonist to PACAP, however, inhibited that effect.

“It's a very interesting peptide that works [and resides] in the trigeminal system,” Dr. Goadsby said. “The PACAP hypothesis is where the CGRP hypothesis was in the 1990s.”

“So here's another whole system that helps you understand something a patient will tell you about, and that leads to another target,” Dr. Goadsby concluded. “There's so much work to be done. Just pick one of these premonitory symptoms and run down the biology of it.”

Back to Top | Article Outline


Andrew Charles, MD, professor of neurology and director of the University of California, Los Angeles Goldberg Migraine Program at the David Geffen School of Medicine, said he shares Dr. Goadsby's view that headache is only one component of a migraine.

“If we can recognize mechanisms in the premonitory phase, there's a better chance we can shut them off before the train is out of the station,” Dr. Charles said.

The hypothalamus, Dr. Charles added, offers what he called “an exciting new potential therapeutic target. The imaging studies by Dr. Goadsby of the premonitory phase really highlights changes in the hypothalamus. That would explain a number of the symptoms, like fatigue, changes in appetite, excessive urination. The peptides released by the hypothalamus might well be novel targets for therapy.”

Back to Top | Article Outline


•. Bergerot A, Storer RJ, Goadsby PJ. Dopamine inhibits trigeminovascular transmission in the rat Ann Neurol 2007;61(3):251–262.
    •. Charbit AR, Akerman S, Goadsby PJ. Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms Pain 2011; 152 (10): 2365–2376.
      •. Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks Brain 2014; 137 (Pt 1): 232–241.
      •. Martins Oliveira M, Akerman S, Tavares I, Goadsby PJ. Neuropeptide Y inhibits the trigeminovascular pathway through NPY Y1 receptor: Implications for migraine Pain 2016; Epub 2016 Mar 25.
        •. Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine Sci Transl Med 2015;7 (308): 308ra157.
          •. Uddman R, Goadsby PJ, Jansen I, Edvinsson L. PACAP, a VIP-like peptide: immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow J Cereb Blood Flow Metab 1993; 13 (2): 291–7.
            •. Charles A. Migraine: a brain state. Curr Opin Neurol 2013; 26 (3): 235–239.
              © 2016 American Academy of Neurology