https://www.nature.com/articles/s41582-019-0255-4 Skip to main content Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Advertisement Advertisement Nature Reviews Neurology * View all journals * Search * My Account Login * Explore content * Journal information * Publish with us Subscribe * Sign up for alerts * RSS feed 1. nature 2. nature reviews neurology 3. review articles 4. article * Review Article * Published: 04 October 2019 The metabolic face of migraine -- from pathophysiology to treatment * Elena C. Gross ORCID: orcid.org/0000-0003-3868-6506^1, * Marco Lisicki ORCID: orcid.org/0000-0001-9765-6759^2, * Dirk Fischer ORCID: orcid.org/0000-0003-0707-9201^1, * Peter S. Sandor^3 & * Jean Schoenen ORCID: orcid.org/0000-0002-6506-6460^2 Nature Reviews Neurology volume 15, pages627-643(2019)Cite this article * 9329 Accesses * 24 Citations * 147 Altmetric * Metrics details Subjects * Mechanisms of disease * Metabolism * Migraine * Pathogenesis Abstract Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain's energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. Technological advances have enabled the examination of different aspects of cerebral metabolism in patients with migraine, and complementary animal research has highlighted possible metabolic mechanisms in migraine pathophysiology. An increasing amount of evidence -- much of it clinical -- suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. Greater understanding of metabolism in migraine offers novel therapeutic opportunities. In this Review, we describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data (including neuroimaging, biochemical, genetic and therapeutic studies), and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. We discuss experimental data to consider potential mechanisms by which metabolic abnormalities could generate attacks. Finally, we highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions. Key points * Prevalent triggers of migraine attacks can all be linked to unbalanced cerebral energy metabolism and/or oxidative stress. * Magnetic resonance spectroscopy studies have shown that mitochondrial phosphorylation potential and ATP are decreased in the brains of people with migraine between attacks. Glucose (and lipid) metabolism and mitochondrial functions are abnormal in the peripheral blood. * Among patients with migraine, various single nucleotide polymorphisms are present in non-coding mitochondrial DNA and nuclear-encoded mitochondrial proteins; common variants associated with migraine are functionally involved in mitochondrial metabolism. * Metabolic enhancers, such as riboflavin and coenzyme Q10, and dietary or pharmacological ketogenesis improve migraine but novel, more efficient metabolic strategies are needed. * Experimental studies indicate a link between cerebral energy disequilibrium and cortical spreading depression and/or trigeminovascular system activation; calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide could also help restore energy homeostasis. * Migraine can be regarded as a conserved, adaptive response that occurs in individuals with a genetic predisposition and a mismatch between the brain's energy reserve and workload. Access through your institution Buy or subscribe Access through your institution Change institution Buy or subscribe Access options Subscribe to Journal Get full journal access for 1 year $59.00 only $4.92 per issue Subscribe All prices are NET prices. VAT will be added later in the checkout. Tax calculation will be finalised during checkout. Rent or Buy article Get time limited or full article access on ReadCube. from$8.99 Rent or Buy All prices are NET prices. Additional access options: * Log in * Access through your institution * Learn about institutional subscriptions Fig. 1: Cerebral metabolomics that might be involved in migraine pathogenesis and therapeutic targets. [41582_2019_255_Fig1_HTML] Fig. 2: Metabolic face of migraine attack generation and resolution. [41582_2019_255_Fig2_HTML] References 1. 1. Gray, P. A. & Burtness, H. I. Hypoglycemic headache. Endocrinology 19, 549-560 (1935). Google Scholar 2. 2. Amery, W. K. 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PubMed Google Scholar Download references Author information Affiliations 1. Division of Paediatric Neurology, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland Elena C. Gross & Dirk Fischer 2. Headache Research Unit, University of Liege, Department of Neurology, Citadelle Hospital, Liege, Belgium Marco Lisicki & Jean Schoenen 3. RehaClinic group, Bad Zurzach, University of Zurich, Zurich, Switzerland Peter S. Sandor Authors 1. Elena C. Gross View author publications You can also search for this author in PubMed Google Scholar 2. Marco Lisicki View author publications You can also search for this author in PubMed Google Scholar 3. Dirk Fischer View author publications You can also search for this author in PubMed Google Scholar 4. Peter S. Sandor View author publications You can also search for this author in PubMed Google Scholar 5. Jean Schoenen View author publications You can also search for this author in PubMed Google Scholar Contributions E.C.G. was responsible for the literature search and the main composition of the manuscript, including the majority of display items. M.L. edited the manuscript and provided additional text and display items. D.F. and P.S.S. edited the manuscript. J.S. was responsible for the design of the manuscript, edited in depth the manuscript and display items and provided additional text and citations. All authors proofread the final manuscript prior to submission. Corresponding author Correspondence to Jean Schoenen. Ethics declarations Competing interests E.C.G. is the founder of KetoSwiss. E.C.G. and D.F. are the inventors of patent WO/2018/115158 held by the University Children's Hospital Basel (UKBB) and the University of Basel for the use of b-hydroxybutyrate in migraine prevention. M.L., P.S.S. and J.S. declare no competing interests. Additional information Peer review information Nature Reviews Neurology thanks A. Carolei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Supplementary material Rights and permissions Reprints and Permissions About this article Verify currency and authenticity via CrossMark Cite this article Gross, E.C., Lisicki, M., Fischer, D. et al. The metabolic face of migraine -- from pathophysiology to treatment. Nat Rev Neurol 15, 627-643 (2019). https://doi.org/10.1038/s41582-019-0255-4 Download citation * Accepted: 12 August 2019 * Published: 04 October 2019 * Issue Date: November 2019 * DOI: https://doi.org/10.1038/s41582-019-0255-4 Further reading * Migraine in transient global amnesia: a meta-analysis of observational studies + Ioannis Liampas + , Athanasios S. Siouras + , Vasileios Siokas + , Zisis Tsouris + , Dimitrios Rikos + , Alexandros Brotis + , Athina-Maria Aloizou + , Metaxia Dastamani + & Efthimios Dardiotis Journal of Neurology (2021) * Retrospective Observational Study on Riboflavin Prophylaxis in Child and Adolescent Migraine + Rakhi Das + & William Qubty Pediatric Neurology (2021) * A Bidirectional View of Migraine and Diet Relationship + Parisa Gazerani Neuropsychiatric Disease and Treatment (2021) * Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine + Elena C. Gross + , Niveditha Putananickal + , Anna-Lena Orsini + , Deborah R. Vogt + , Peter S. Sandor + , Jean Schoenen + & Dirk Fischer Scientific Reports (2021) * Brain glycogen metabolism: A possible link between sleep disturbances, headache and depression + J-M. Petit + , E. Eren-Kocak + , H. Karatas + , P. Magistretti + & T. 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