Migraine is the most common neurological disease, with about 1 billion sufferers across the world, out of which there are twice as many women than men (Stovner et al., 2018). It’s also the 2nd biggest cause of disability in the world and 1st among young women (Steiner et al., 2020). While its pathophysiology is not clear, hypoglycemia has been associated with migraine for almost a century (Gray & Burtness, 1935) and its symptoms (such as dizziness, pale skin, nausea, low blood pressure, tiredness, sugar cravings, cognitive difficulties) bear striking resemblance to those associated with migraine, particularly in the premonitory phase (Binder & Bendtson, 1992). A large number of studies in migraine point towards a variety of different metabolic abnormalities, and in fact, one of the most consistently reported changes in migraine is energy metabolism, including mitochondrial dysfunction (S. Ashina et al., 2021) and higher fasting glucose levels (Cavestro et al., 2007; Gross, Lisicki, et al., 2019; Siva et al., 2018). Hypothalamus (controlling homeostasis) is known to be activated early on during migraine attacks (Denuelle et al., 2007; Maniyar et al., 2014; Schulte et al., 2016). Moreover, dysfunctional metabolic responses have been observed after GTT in several studies of sufferers with migraine (Shaw et al., 1997), as have been interictal impairments of glucose tolerance (Cavestro et al., 2007; Dexter et al., 1978). These various abnormalities in combination with unfavourable environmental factors can lead to a higher energy expenditure than supply and might determine disease severity.
Changes in energy availability are usually examined with 31P-MRS (magnetic resonance spectroscopy), which can measure the amount of ATP and ADP, i.e. free energy levels suggestive of the bioenergetic condition (Lodi et al., 2001). Using 31P-MRS, one study found significant reduction of free energy, but also of free magnesium levels which is key for oxidative phosphorylation (Lodi et al., 2001), and other studies using the same methodology have found similar impairments in mitochondrial oxidative phosphorylation during and between migraine attacks (Barbiroli et al., 1992; Kim et al., 2010; Lodi et al., 1997; Lodi et al., 2001; Montagna et al., 1994; Reyngoudt et al., 2012; Schulz et al., 2007; Welch et al., 1989). One hypothesis is that defective production of ATP by mitochondria decreases the cells’ ability to deal with metabolic stress (Lodi et al., 2001). There are also reports of increased ketone bodies during and before an attack which could be suggestive of the brain trying to counterbalance the lack of available energy (Del Moro et al., 2022; Hockaday et al., 1971). A recent systematic review has strengthened this conclusion, stating that the result of decreased neuronal energy in migraine, which suggests mitochondrial dysfunction, is consistent and reproducible (Younis et al., 2017).
Studies have shown that hypoglycemia can prolong CSD in contrast to hyperglycemia which was found to have a protective effect (Hoffmann et al., 2013). Interestingly, migraine with aura is very prevalent in populations living in high altitude which could also suggest an association with hypoxia (Arregui et al., 1991; Linde et al., 2017). Another metabolic feature is an increase in lactate levels which could suggest impairments in oxygenation (as it’s a signal of the brain turning to the alternative energy sources; Di Lorenzo et al., 2016; Okada et al., 1998; Sandor et al., 2005; Watanabe et al., 1996), although strong conclusions cannot be drawn due to variabilities in methodologies and sufferer selection criteria. Yet another interesting finding is that of increased ADP concentrations and decreased phosphocreatine, which normally regenerates ATP from ADP in times of rapidly changing energy demands (Barbiroli et al., 1992; Lodi, Kemp, et al., 1997; Schulz et al., 2007). Examining other markers of mitochondrial function and oxidative stress in high frequency migraineurs showed that many of them are abnormal, most significantly lowered ALA (alpha-lipoic acid) (Gross et al., 2021) which is important for the citric acid cycle (specifically pyruvate dehydrogenase, a step crucial for metabolizing glucose) and is a known antioxidant (Packer et al., 1995). While this was a study of sufferer population only and needs to be further validated in comparisons with a control group, alpha-lipoic acid also contains thiol-groups which were found to be decreased in migraineurs separately from ALA itself (Eren et al., 2015). Metabolic changes were also found to modulate the activity of the pain receptors in the trigeminal nerve in a rat model (Martins-Oliveira et al., 2017).
Other mitochondrial enzymes, such as succinate dehydrogenase, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase, citrate synthetase, cyclooxygenase and monoamine oxidase have also been found to have reduced activity in the platelets of migraine sufferers, further suggesting a generalized metabolic dysfunction (Littlewood et al., 1984; Sangiorgi et al., 1994).
Neuronal hyperexcitability, which is one of the most consistent findings in migraineurs, is intrinsically related to Cortical Spreading Depression (CSD; the underlying pathophysiological mechanism behind aura), as it could increase its likelihood of occurrence by lowering the “trigger” threshold. In support of that, there are reports of increased excitatory activity in e.g. the occipital (visual) cortex which is also linked to a visually triggered migraine (Aurora et al., 1999). More generally, hyperexcitability in migraineurs was measured experimentally as lack of habituation to repetitive stimuli (Brighina et al., 2009), which was confirmed in a recent study (Di Lorenzo et al., 2016). This hyperexcitability feature of the migraineur’s brain means that the it needs huge amounts of additional energy as under normal conditions, most of the glucose is normally used on the action potentials and postsynaptic potentials (Mergenthaler et al., 2013). CSD also disturbs the metabolism in the brain as a lot of additional energy is needed to restore the ion homeostasis, which can result in temporary hypoxia (Takano et al., 2007). Further, using a PET scanner which allows for monitoring glucose with a radioactive tracer, the neuronal activation evoked by visual stimuli was found to exceed glucose uptake in migraine sufferers but not healthy controls (Lisicki et al., 2018).
Oxidative stress and inflammation are also characteristics of dysfunctional metabolic state, as it makes the body less capable of dealing with those factors. Interestingly, all common migraine triggers are likely to increase the levels of oxidative stress. One study in mice showed that if there is insufficient energy or O2 present, it can cause synaptic metabolic stress and lower the threshold or even prolong CSD (Kilic et al., 2018; Takano et al., 2007). The disturbances in energy and the subsequent oxidative stress could also potentially account for activation of nociceptive ion channels which are sensitive to oxidants (Fila et al., 2021). Many of the common triggers can be connected to dysfunctional metabolism and supplements of key co-factors of metabolic pathways such as riboflavin or CoQ10 have been shown to be helpful in migraine management. In cases of disturbed metabolism, the pain signaling would still originate from the trigeminovascular activation and CGRP release, potentially caused by activation of pannexin channels, opening when neurons are stressed and which could mediate the CSD-CGRP connection (Karatas et al., 2013). Interestingly, they also open in response to metabolic changes which could provide a link between the metabolic dysfunction and pain signaling of the trigeminal nerve (Kilic et al., 2018).
Finally, not everyone will be showing the same metabolic dysfunctions – in a recent review it was suggested that there might in fact be a metabolic subgroup of sufferers which has dysfunctional energy metabolism as the root cause of their migraine, but which would not be the case for everybody (Gross, Lisicki, et al., 2019). Further, this might be a result of an adaptive mechanism of a “hyperexcitable” brain which becomes overactive in reaction to any number of stimuli (migraine triggers), experiences CSD and as a consequence, the depletion of its energy resources. As a response, pain signaling is activated which forces energy-preserving mechanisms, such as rest, avoidance of intense stimuli, lack of movement etc. Several recent reviews have discussed extensively the possibility of mitochondrial dysfunction and impaired brain glucose metabolism as the underlying cause of migraine (Bohra et al., 2022; Del Moro et al., 2022; Islam & Nyholt, 2022).
In summary, migraine seems to be characterized by a mismatch between increased energy demand and decreased energy availability. For a comprehensive review of metabolic abnormalities in migraine, please refer to the tables linked below:
