The role of the interictal impairment of energy metabolism in migraine has been investigated by the Bologna school [46]. Basing on clinical and biochemical results obtained in muscles and platelets of migraineurs that suggested interictal alterations in oxidative metabolism, authors investigated patients with complicated migraine such as patients with prolonged aura and migraine strokes. Comparing all migraineurs with controls, Pcr/Pi and the ratios of PCr to ATP (PCr/ATP) were reduced, suggesting that a deficit of brain energetic metabolism was present outside attack period, representing therefore an intrinsic feature of the migraineur’s brain. More recently, some authors compared patients with migrainous stroke with those with migraine with persistent aura without infarction and controls finding that the second group showed reduced cortical PCr/Pi while the first one showed values similar to healthy controls [46]. A deficit of brain energy metabolism was detected also in patients with migraine with and without aura [46, 47].

Skeletal muscle mitochondrial ATP production rate, assessed by the rate of post-exercise PCr resynthesis, is considered an almost pure index of mitochondrial functionality. Its analysis revealed a substantial deficit in patients with complicated migraine, migraine with aura, and migraine without aura [46]. Deficit of brain and muscle bioenergetics similar to adults was detected in pediatric patients suffering from migraine with aura [46].

Low magnesium (Mg²⁺) content, indicating bioenergetic metabolism deficit, has been demonstrated in serum, saliva, erythrocytes, and mononuclear cells of migraineurs. Comparing migraineurs with and without aura, a reduction of free Mg²⁺ concentration was found in cerebral cortex during attack but not interictally. Lodi et al. detected an interictal reduction in Mg²⁺ levels in all subtypes of migraine with respect to healthy controls: patients suffering from migraine without aura had higher free Mg²⁺ concentrations than those with migraine stroke or prolonged aura. The Bologna school reported similar findings also in pediatric patients with migraine with aura [46]. Overall, despite the methodological differences and the heterogeneity of migraine patients, brain ³¹P-MRS studies revealed an association between the bioenergetic deficit and the reduced free magnesium concentration both ictally and interictally [46]. Low magnesium is known to lead to neuronal instability and hyperexcitability and so may responsible for predisposing the brain to migraine attack [46]. However, the fundamental mechanisms leading to impaired oxidative phosphorylation and reduced brain Mg²⁺ concentration remain unknown.

Proton MRS ( ¹ H-MRS) is based on the acquisition of signals from excitation of the nucleus of hydrogen. This technique allows an “in vivo” quantification of brain metabolite concentrations providing metabolic information from definite brain areas and systems. N-acetyl-aspartate (NAA), choline (Cho), creatine/phosphocreatine (Cr), myoinositol (mI), and lactate are the metabolites more commonly observed. Lactate represents the end product of glycolysis that typically accumulates when ATP production switches to anaerobic glycolysis. Lactate is normally undetectable in adult human brain and can be detected in diseases associated with an augmented energy request and/or altered cellular capability for oxidative phosphorylation such as malignant tumors, ischemia, and mitochondrial disorders. Some studies evaluated migraineurs with aura by using ¹H-MRS focusing on the occipital lobe both at rest and during stimulation, as visual aura is the most frequent form of aura. The first study on this topic compared metabolite levels in the occipital visual cortex in six normal subjects and five migraine with aura patients and in one with basilar migraine, disclosing high lactate levels in the five patients who had experienced a migraine attack within the previous 2 months [46]. Investigating cortical lactate changes during prolonged visual stimulation in healthy subjects and two groups of migraine with simple visual or complex auras, an increased lactate was observed at baseline in the visual cortex of migraineurs with simple visual aura but not in those with more complex aura, whereas during photic stimulation, lactate in visual cortex increased in migraineurs with more complex aura while remained high in migraineurs with simple visual aura [48]. These results were not confirmed by others authors who showed a greater increase in the lactate peak in migraineurs with aura compared to migraine without aura and healthy subjects.

These differences in results could be explained by different methodology and sampling but a more consistent decrease in NAA in migraine with aura patients compared with those without aura and controls was found. These results were interpreted as indirect evidence of mitochondrial dysfunction because NAA is synthesized in neuronal mitochondria and plays a role in mitochondrial/cytosolic carbon transport [46].

Comparing basal ganglia of migraineurs with aura and controls, no association between any of the metabolite ratios (NAA/Cr, Cho/Cr, and NAA/Cho) and type or duration of aura symptoms was found. Recently, Reyngoudt et al. [47] even when a careful absolute ¹H-MRS quantification was performed and a photic stimulation was carried out, no significant differences in the visual cortex of migraineurs without aura were observed compared to controls.

¹H-MRS study focusing on thalamus found that patients suffering from migraine without aura during interictal period showed a reduced NAA/Cho in the left side when compared to controls. Other brain structures involved in pain processing were investigated, such as anterior cingulate cortex and insular cortex, finding normal metabolic profile in migraineurs without aura. However, glutaminergic changes on linear discriminant analysis were demonstrated [46].