The metabolic face of migraine — from pathophysiology to treatment

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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.

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Fig. 1: Cerebral metabolomics that might be involved in migraine pathogenesis and therapeutic targets.
Fig. 2: Metabolic face of migraine attack generation and resolution.


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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.

Correspondence to Jean Schoenen.

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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 β-hydroxybutyrate in migraine prevention. M.L., P.S.S. and J.S. declare no competing interests.

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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) doi:10.1038/s41582-019-0255-4

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