The metabolic face of migraine—from pathophysiology to treatment

DOI: https://doi.org/10.1038/s41582- 019- 0255- 4

Abstract-Summary Technological advances have enabled the examination of different aspects of cere- bral 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 homeo- stasis 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 rela- tionship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine.

Extended: In this Review, we describe the abnormalities of energy metabolism observed in migraine with a particular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies.

Introduction Early connection between migraine and energy metabolism, clinical and basic research in migraine largely focused on the vasculature, neurovasculature and neu- rotransmission until Willem Amery revived the idea that metabolism is involved in the pathogenesis of migraine in his hypothesis-generating review in 1982 (ref [176]). Evidence that cortical responsivity and sensory processing are abnormal in patients with migraine between attacks (reviewed elsewhere [177]) led to the sug- gestion that a combination of sensory overload and lowered energy reserve ignites the major pain-signalling system of the brain, the trigeminovascular system, leading to the migraine attack [178].

In this Review, we describe the abnormalities of energy metabolism observed in migraine with a particular focus on clinical data, including phenotypic, biochemi- cal, genetic and therapeutic studies.

We also discuss experimental data to elaborate on the potential role of such meta-

bolic abnormalities in migraine attack generation.

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Triggers and Metabolic Dysfunction Two systematic reviews [179, 180] and a study of 1,207 patients with migraine [181] have identified that the most common migraine trigger factors are stress or subsequent relaxation, fasting or skipping a meal, sleep changes (too much or too little), ovarian hormone changes (including 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 misinter- preted [182].

Some triggers—such as skipping a meal or fasting, exercise, dehydration,

hypoxia and lack of sleep—have a clear link to metabolism.

Many other triggers, including hormonal changes, also have a potential common metabolic denominator: changes in mitochondrial metabolism and/or oxidative stress [183].

In combination, these observations show that most migraine triggers or aggravat-

ing factors have a link to energy metabolism and oxidative stress.

Biochemical Studies The absence of a stimulus-induced increase in lactate levels in patients with migraine could be considered pathological, as it might render them vulnerable to an energy crisis, particularly because neuronal activation is likely to have a higher energy demand in patients with migraine than in healthy individuals because their sensory information processing is abnormal [184].

Comparison of responses to an intravenous GTT during and outside attacks in patients with migraine with aura [185] showed that, during an attack, glucose toler- ance was impaired, levels of free fatty acid, ketone bodies, glycerol and cortisol were increased, and the ratio of β-hydroxybutyrate to acetoacetate (both ketone bodies) was increased.

In one study, increases in blood glucose levels in response to glucagon injection

were less pronounced in patients with migraine than in healthy controls [186].

Genetic Studies Mitochondrial function could be impaired in migraine as a result of single nucleo- tide polymorphisms (SNPs) in the non-coding portion of mtDNA, which could influence mitochondrial metabolism.

A high prevalence of specific SNPs in non-coding mtDNA has been seen in patients with migraine and occipital stroke associated with haplogroup U [187], as well as in migraine without aura and in cyclic vomiting, a childhood equivalent of migraine [188].

A polymorphism (the rs4880 TT (Val/Val) genotype) in the gene that encodes superoxide dismutase 2 (SOD2), a crucial enzyme in the clearance of mitochondrial ROS, has been associated with unilateral cranial autonomic symptoms in patients with migraine with aura [189].

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2 Mechanisms

Further genetic findings that indicate alterations in metabolism in migraine include associations of the condition with polymorphisms in insulin-related genes [190–193].

Genes associated with mitochondrial function were enriched in migraine- associated loci identified by GWAS, a finding that establishes a genetic link between mitochondrial function and migraine [194].

Therapeutic Studies A systematic review published in 2017 showed that high-dose riboflavin (400 mg daily) is well tolerated, inexpensive and effectively reduces migraine headache fre- quency [195].

In four placebo-controlled double-blind trials and two open-label studies, CoQ10 treatment (400 mg capsules or 300 mg liquid suspension daily) reduced migraine frequency in adults [196–199].

In double-blind randomized placebo-controlled trials, a 2 mg daily dose of folic acid (vitamin B9) combined with 25 mg pyridoxine (vitamin B6) and 400 μg cobala- min (vitamin B12) reduced migraine-related disability and the frequency and sever- ity of migraine with aura [200, 201].

A randomized controlled trial published in 2019 showed that 500 mg magnesium oxide daily had a similar preventive effect in migraine as 400 mg sodium valproate daily [202].

In a randomized controlled trial published in 2019, a combination of 500  mg l-carnitine and 30 mg CoQ10 daily was significantly more effective than placebo in reducing headache severity, frequency and duration during an 8-week treatment period [199].

Metabolism and Migraine Pathophysiology We consider these changes in relation to three hallmarks of the pathophysiological migraine cascade: hypothalamic and brainstem activation (which is thought to initi- ate and modulate the attack), CSD (which is responsible for the aura) and trigemi- novascular activation (which causes the headache and associated symptoms).

Limited evidence from animal experiments suggests that the migraine attack

itself can affect mitochondrial energy metabolism in the trigeminal ganglion.

Some evidence suggests that CGRP release is a response to oxidative stress or cerebral energy disequilibrium and might be part of an adaptive response, thereby challenging the perception that CGRP is the pathophysiological trigger of migraine. Cerebral energy deficiency and/or increased oxidative stress decrease the thresh- old for CSD and activate TRP channels and ASICs, thereby stimulating CGRP and PACAP release.

The downstream molecular events activated by pannexin channel opening could be the missing link between energy disequilibrium at the cortical level and the migraine attack.

Future Research Studies to examine the role of specific alterations in mitochondrial function and/or energy metabolism in migraine subgroups are needed.

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More data are also needed to determine whether therapeutic interventions that improve mitochondrial function lead to changes in sensory processing and cerebral energy availability that correlate with treatment responses.

To ensure that all micronutrients needed for mitochondrial function are available, laboratory tests can be used to individualize supplementation with minerals, hydro- phobic and lipophilic vitamins and trace minerals that are deficient [203].

Measurement of oxidative and/or nitrosative stress levels and antioxidant status in individuals could detect a potential mismatch between oxidative stress levels and antioxidant capacity and enable therapeutic adjustments to be made, although stud- ies are needed to prove that such an approach improves migraine management.

For patients with compromised energy metabolism, an alternative source of fuel

for the brain, in addition to glucose and lactate, might be beneficial.

Conclusion The evidence discussed in this Review indicates that, from a metabolic perspective, migraine is a conserved adaptive response [204] that helps to reduce harmful oxida- tive stress levels and restore brain energy homeostasis, a concept that was proposed by Edward Liveing as early as 1873 (ref [205]).

Reported migraine trigger factors can be linked to energy disequilibrium and oxidative stress, and numerous biochemical and genetic studies point towards a variety of different metabolic abnormalities in migraine.

Most preventive migraine treatments can improve metabolic functioning in addi-

tion to their effects on brain responsiveness and excitability.

These neuropeptide pathways are the likely culprits for the migraine headache and associated symptoms, but they could also participate in an antioxidant response and various metabolic changes that help restore energy homeostasis.

More research is needed on different metabolic subtypes, the association between metabolic phenotypes and genotypes and treatment responses to metabolic agents, interactions between the sensory system and metabolism, and metabolic nutraceuti- cal treatments for migraine.

Acknowledgement A machine generated summary based on the work of Gross, Elena C.; Lisicki, Marco; Fischer, Dirk; Sándor, Peter S.; Schoenen, Jean. 2019 in Nature Reviews Neurology.

From transformation to chronification of migraine: pathophysiological and clinical aspects