The metabolic face of migraine-from pathophysiology to treatment Nature reviews | Neurology

As early as 1935, migraine-which now affects \textgreater15% of the population worldwide-was referred to as a 'hypo­ glycaemic headache' 1. Despite this early connection between migraine and energy metabolism, clinical and basic research in migraine largely focused on the vasculature, neurovasculature and neurotransmission until Willem Amery revived the idea that metabolism is involved in the pathogenesis of migraine in his hypothesis­ generating review in 1982 (ref. 2). Since then, accumu­ lating evidence-much of it clinical-indicates that migraine is at least partially an energy deficit syndrome with mitochondrial dysfunction. Technological advances (for example, in neuroimaging and genetics) have enabled examination of different aspects of cerebral metabolism in patients with migraine, and complementary animal research has deciphered possible links between metabolic factors and trigeminovascular activation in migraine pathophysiology. Evidence that cortical responsivity and sensory processing are abnormal in patients with migraine between attacks (reviewed elsewhere 3) led to the suggestion that a combination of sensory overload and lowered energy reserve ignites the major pain­signalling system of the brain, the trigeminovascular system, leading to the migraine attack 4. In this Review, we describe the abnormalities of energy metabolism observed in migraine with a par­ ticular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies. We also discuss experimental data to elaborate on the potential role of such metabolic abnormalities in migraine attack generation. Finally, we highlight therapeutic approaches to targeting of cerebral metabolism (antioxidants, nutraceuticals, pharmaceuticals and dietary ketogenesis). Triggers and metabolic dysfunction Two systematic reviews 5,6 and a study of 1,207 patients with migraine 7 have identified that the most common migraine trigger factors are stress or subsequent relaxa­ tion, fasting or skipping a meal, sleep changes (too much or too little), ovarian hormone changes (includ­ ing menstruation and oral contraception), weather changes (including certain winds, hypoxia and high altitude), physical exercise (including sexual activity), alcohol, strong odours (especially perfume or cigarette smoke), intense light (especially bright or blue light) and loud noises. The distinction between trigger factors and premonitory symptoms of migraine attacks is not always easy, as some premonitory symptoms might be 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.