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Biological insights from the premonitory symptoms of migraine

  • Review Article
  • Published:

From Nature Reviews Neurology

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Abstract

Migraine is a common neurological disorder with a diverse clinical phenotype that comprises more than just head pain. Premonitory (prodromal) symptoms can start hours to days before the onset of a migraine headache and can predict its onset in some individuals. Such symptomatology can include lethargy, yawning, light and sound sensitivity, thirst and cravings. This earliest phase of the migraine attack provides valuable insights into the neurobiology of the disorder, furthering our understanding of how and why these phenotypically heterogeneous symptoms are mediated. Improvements in our understanding of migraine could provide novel therapeutic opportunities, with the possibility of closing the therapeutic gap that remains owing to a lack of sufficiently effective and well-tolerated acute and preventive treatments. Improved understanding of disease mechanisms and potential therapeutic targets through bench-to-bedside research into the premonitory phase is an exciting and emerging means of achieving this aim going forward. In this Review, we discuss the current evidence in the literature in relation to the phenotype and mediation of premonitory symptoms in migraine, and discuss the neurobiological insights gained from these studies.

Key points

  • The premonitory stage of migraine occurs before the onset of migraine headache in adults and children and can predict headache onset.

  • The prevalence of premonitory symptoms is probably underreported owing to a lack of patient and physician recognition and to misinterpretation of the symptoms as migraine triggers.

  • Symptoms that can manifest during the premonitory phase can be broadly grouped as cognitive and mood changes, fatigue and changes in alertness, homeostatic and hormonal changes, and migrainous or sensory sensitivities.

  • Correlation of premonitory symptoms with functional neuroimaging changes during this phase suggests vital involvement of subcortical and cortical areas, namely the hypothalamus, midbrain and limbic areas.

  • Linking the clinical phenotype and neuroanatomy to the neurochemical systems in these brain areas has revealed neurotransmitters and neuropeptides that might mediate premonitory symptoms and contribute to migraine pathophysiology.

  • Further research looking at agents that target the identified receptors could lead to novel targeted treatment options for migraine.

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Fig. 1: A summary of the timeline of a migraine attack.
Fig. 2: Changes in sensory perception and brain function in one patient with migraine over 30 days.
Fig. 3: The current understanding of the pathophysiology of migraine.

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Acknowledgements

The authors would like to thank the Association of British Neurologists and Guarantors of Brain for funding N.K., and to thank the Migraine Trust for providing funding and support for studies within the team. No specific funding was granted for this work. The authors’ work is supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre.

Reviewer information

Nature Reviews Neurology thanks W. Becker, R. Evans and J. Pascual for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Nazia Karsan & Peter J. Goadsby

  2. NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK

    Nazia Karsan & Peter J. Goadsby

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  1. Nazia Karsan
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N.K. was responsible for the literature search, design of the manuscript and the main composition of the manuscript. P.J.G. edited the manuscript and provided additional text and citations. Both authors proofread the final manuscript prior to submission.

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Correspondence to Peter J. Goadsby.

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N.K. has received speaker honoraria from Teva Pharmaceuticals. P.J.G. reports grants and personal fees from Amgen and Eli-Lilly and personal fees from Alder Biopharmaceuticals, Allergan, Autonomic Technologies, Dr Reddy’s Laboratories, Electrocore LLC, eNeura, Novartis, Scion, Teva Pharmaceuticals and Trigemina. He also reports personal fees from Journal Watch, Massachusetts Medical Society, MedicoLegal work, Oxford University Press, Up-to-Date and Wolters Kluwer. He also declares a patent for magnetic stimulation for headache assigned to eNeura without fee.

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Glossary

P3 interval

A neurophysiological event-related potential component that appears at ~300 ms after a specific task is completed and reflects cognitive decision making; also known as the P300 interval.

Cognitive habituation

The progressive decrease of amplitude or frequency of a response to cognitive stimulation that is not related to receptor adaptation or fatigue.

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Karsan, N., Goadsby, P.J. Biological insights from the premonitory symptoms of migraine. Nat Rev Neurol 14, 699–710 (2018). https://doi.org/10.1038/s41582-018-0098-4

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