Table 3:

Summary of brain molecular and metabolic imaging in migraine.

Authors	Technique	Headache	Participants (N)	Conclusion	References
Aguila et al. (2015)	1H-MRS	Migraine	38	GABA+ increased in MX vs. controls. Suggest altered excitability of cortical neurons during the interictal period. GABA+ included detection of nonspecified macromolecules, which might cause contamination of the results.	Aguila M-ER, et al. NMR Biomed. 2015; 28:890–897.
Arngrim et al. (2016)	1H-MRS	Migraine	29	No differences in MA during hypoxiainduced headaches vs. controls. Suggest no mitochondrial dysfunction.	Arngrim N, et al. Brain. 2106; 139:723–737.
Becerra et al. (2016)	1H-MRS	Migraine	65	No differences in MO+MA vs. controls. Posthoc analysis: Cross-validation test using quadratic discriminant analysis model showed that glutamine, NAA and aspartate as a group differentiate MO+MA from control. Suggest a ‘complex’ of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain, supporting the theory of the hyperexcitable migraine brain.	Becerra L, et al. Neuroimage Clin. 2016; 11:588–594.
Bigal et al. (2008)	1H-MRS	Migraine	28	GABA decreased in MO+MA with severe migraine attacks in the month prior to MRS vs. controls. We suggest that it may indicate reduced inhibition.	Bigal ME, et al. Neurology. 2008; 70:2078–2080.
Bridge et al. (2015)	1H-MRS	Migraine	26	GABA ~10% decreased in MA vs. controls. Suggest reduced inhibition occipitally in MA consistent with occipital hyperexcitability. Positive correlation between glutamate and BOLD activation in the visual cortex during visual stimulation in MA vs. controls. Suggests enhanced glutamate activation. Altogether, the results suggest an abnormal excitation-inhibition coupling in the occipital cortex. The MA cohort reported visual stimuli as a migraine trigger.	Bridge H, et al. Cephalalgia. 2015; 35:1025–1030.
Dichgans et al. (2005)	1H-MRS	Migraine	32	Differences measured in cerebellum for FHM1 vs. controls. Suggest neuronal impairment (NAA), altered glial cell proliferation (myoinositol) and impaired glutamatergic neurotransmission.	Dichgans M, et al. Neurology. 2005; 64:608–613.
Fayed et al. (2014)	1H-MRS	Migraine	216	No differences in MX vs. controls.	Fayed N, et al. Acad Radiol. 2014; 21:1211–1217.
Gonzales de la Aleja et al. (2013)	1H-MRS	Migraine	46	Glutamate increased in MA+MO vs. controls in the anterior paracingulate cortex. Suggests altered excitability and increased susceptibility to migraine triggers. Glutamate/glutamine-ratio abnormal in MO+MA vs. controls in the occipital cortex. Suggests abnormal neuronal–glial coupling of glutamatergic metabolism or increased neuron/astrocyte ratio in the occipital cortex.	Gonzales de la Aleja J, et al. Headache. 2013; 53:365–375.
Grimaldi et al. (2010)	1H-MRS	Migraine	14	No differences in FHM2 vs. controls.	Grimaldi D, et al. Cephalalgia. 2010; 30:522–559.
Gu et al. (2008)	1H-MRS	Migraine	34	NAA/Choline decreased in left thalamus in MO vs. controls. Suggest mitochondrial and neuronal dysfunction due to neuronal deafferentation in the thalamus.	Gu T, et al. Neurol Res 2008; 30:229–233.
Lai et al. (2011)	1H-MRS	Migraine	88	NAA increased in EM in pons bilaterally compared to CM and controls. No differences between CM vs. controls. Suggest neuronal hypertrophy at the dorsal pons in EM. 23/53 CM patients were diagnosed with MOH.	Lai T, et al. J Headache Pain. 2011; 12:295–302.
Lirng et al. (2015)	1H-MRS	Migraine	30	Myo-inositol increased in MX with depression vs. MX without depression. No healthy controls. Suggest glial dysfunction in dorsolateral prefrontal cortex in migraineurs with depression.	Lirng J, et al. Cephalagia. 2015; 35:702–709.
Macri et al. (2003)	1H-MRS	Migraine	15	Choline decreased in MA vs. controls. Suggest membrane composition alterations. Only study to report choline alterations.	Macri M, et al. J Magn Reson Imaging. 2003; 21:1201–1206.
Mohamed et al. (2013)	1H-MRS	Migraine	32	NAA decreased in MO vs. controls. NAA more decreased in right thalamus vs. left thalamus in MO. NAA decreased, lactate and myoinositol increased with increased duration and attack frequency in MO. Suggest altered energy metabolism correlated to severity of disease.	Mohamed RE, et al. Egypt J Radiol Nucl Med. 2013; 44:859–870.
Prescot et al. (2009)	1H-MRS	Migraine	18	No differences in MX vs. controls. Linear discriminant analysis showed a separation between MX and controls based on NAAG and glutamine in anterior cingulate cortex and insula. Suggest glutamatergic abnormalities in anterior cingulate cortex and insula.	Prescot A, et al. Mol Pain. 2009; 5:34.
Reyngoudt et al. (2011)	1H-MRS	Migraine	40	No differences in MO vs. controls before or after visual stimulation. Argue against a significant switch to nonaerobic glucose metabolism during long-lasting photic stimulation of the visual cortex in MO.	Reyngoudt H, et al. J Headache Pain. 2011; 12:295–302.
Sandor et al. (2005)	1H-MRS	Migraine	21	Lactate increased in MA with visual aura vs. FHM/SHM and vs. controls before, during and after visual stimulation in visual cortices. Suggest mitochondrial dysfunction.	Sandor P, et al. Cephalalgia. 2005; 25:507–518.
Sarchielli et al. (2005)	1H-MRS	Migraine	54	NAA decreased at baseline and after visual stimulation in MA vs. MO and vs. controls No differences in MO vs. controls. Suggest less efficient mitochondrial function in MA.	Sarichielli P, et al. Neuroimage. 2005; 24:1025–1031.
Schulz et al. (2007)	1H-MRS	Migraine	37	No difference between MA and SHM+FHM vs. controls. Lactate peaks undetectable.	Schulz UG, et al. Brain. 2007; 130:3102–3110.
Siniatchkin et al. (2012)	1H-MRS	Migraine	20	Glx increased at baseline in MA vs. controls. Suggests excessive glutamate mediated excitation in migraine. Both anodal and cathodal transcranial direct current stimulation caused Glx decrease in MA, which did not increase to baseline after visual stimulation as in controls. Suggest abnormal cortical information processing and excitability in migraineurs mediated by altered glutamatergic neurotransmission.	Siniatchkin M, et al. Cereb Cortex. 2012; 22:2207–2216.
Wang et al. (2006)	1H-MRS	Migraine	37	No differences in CM vs. controls. Suggest that the hypothalamus might not play a pivotal role in chronic migraine.	Wang S, et al. J Neurol Neurosurg Psychiatry. 2006; 77:622–625.
Watanabe et al. (1996)	1H-MRS	Migraine	12	Lactate increased in a small heterogeneous group of patients: migraine with visual aura (N = 3), basilar type migraine (N = 1) and migrainous infarction (N = 2) vs. controls (N = 6). Suggest mitochondrial dysfunction. The participants had last attack within 2 months prior to testing.	Watanabe H, et al. Neurology. 1996; 47:1093–1095.
Zielman et al. (2014)	1H-MRS	Migraine	37	NAA decreased in SHM+FHM1+FHM2 vs. controls in cerebellum. NAA more decreased in FHM1 vs. controls than SHM and FHM2. Suggest neuronal loss or dysfunction in the cerebellum and/or less efficient mitochondrial function. Glx and myo-inositol not measured in pons.	Zielman R, et al. Cephalalgia. 2014; 34:959–967.
Barbiroli et al. (1990)	31P-MRS	Migraine	23	PCr decreased in MpA+MS vs. controls. Suggest mitochondrial abnormalities as apotential cause to defects in oxidative metablosim, making cells not meet energy demand.	Barbiroli B, Montagna P, Cortelli P, et al. Complicated migraine studied by phosphorus magnetic resonance spectroscopy. Cephalalgia 1990: 10:263–272.
Barbiroli et al. (1992)	31P-MRS	Migraine	24	Significant changes in MA vs. controls. Only 31P-MRS study to report decreased pHi. Indicates increased lactate levels. Collectively, the data suggest less freely available energy in the cell and abnormal oxidative metabolism due to mitochondrial dysfunction.	Barbiroli B, et al. Neurology. 1992; 42:1209–1214.
Boska et al. (2002)	31P-MRS	Migraine	86	Magnesium decreased in FHM+SHM vs. controls in the posterior region including the occipital lobe. Suggested to contribute to the cortical hyperexcitability. PDE increased in MO vs. controls in the posterior region including the occipital lobe. Suggested that this might be a compensatory mechanism to maintain membrane stability. Data not shown for ADP.	Boska MD, et al. Neurology. 2002; 58;1227–1233.
Lodi et al. (1997)	31P-MRS	Migraine	27	Significant changes in MA vs. controls. Collectively, these data suggest impaired cerebral oxidative metabolism and abnormal mitochondrial function, unable to meet increased energy demand. Only 31P-MRS study to report increased pHi. Indicates decreased lactate levels. Suggested to be due to ionic abnormalities in the brain causing dysfunction of proton pumps. The cohorts were juvenile.	Lodi R, et al. Pediatr Res. 1997; 42:866–871.
Lodi et al. (2001)	31P-MRS	Migraine	107	Magnesium and deltaGATPhyd decreased in all groups vs. controls. The data suggest reduced release of free energy by ATP hydrolysis due to mitochondrial dysfunction, thus magnesium levels are downregulated to re-equilibrate the rapidly available free energy. deltaGATPhyd is defined as the freely available energy released by ATP hydrolysis in the intact cell, calculated based on ATP, ADP, Pi and magnesium. Data not shown for PCr, Pi, and ADP.	Lodi R, et al. Brain Res Bull. 2001; 54:437–441.
Montagna et al. (1994)	31P-MRS	Migraine	40	Significant changes in MO vs. controls. Collectively, the data suggest a defect and altered energy metabolism.	Montagna P, et al. Neurology. 1994; 44:666–669.
Ramadan et al. (1989)	31P-MRS	Migraine	44	Magnesium decreased ictally in MO þMA (N = 10) vs. controls. Suggest that low magnesium promotes cortical spreading depression, thus initiating the migraine attack. No patient was tested both ictally and interictally. None had aura during testing. Data not shown for PCr, Pi, ADP, and ATP.	Ramadan NM, et al. Headache. 1989; 29:590–593.
Reyngoudt et al. (2010)	31P-MRS	Migraine	44	PCr, PP and ATP decreased in MO vs. controls. Collectively, the data suggest an impaired energy metabolism and the decreased ATP level further suggest presence of a mitochondrial component in migraine. ATP was more decreased in a subgroup with the highest attack frequency. Only 31P-MRS study to determine the absolute [ATP] and not calculate other metabolite concentrations based on assumed [ATP] = 3.0 mmol/L.	Reyngoudt H, et al.Cephalalgia. 2010; 31:1243–1253.
Schulz et al. (2007)	31P-MRS	Migraine	37	Cr/Pi decreased and Pi/ATP increased in sporadic and familiar hemiplegic migraine (N ¼ 9) vs. migraine with nonmotor aura (N ¼ 10) in gray matter. Suggest alterations in the energy metabolism.	Schulz UG, et al. Brain. 2007; 130:3102–3110.
Uncini et al. (1995)	31P-MRS	Migraine	35	Significant changes in family members (N = 5) vs. controls. Suggest abnormal energy metabolism due to mitochondrial dysfunction. Differences reported for 5 family members, whereof 2 have no history of migraine, vs. controls.	Unicini A, et al. J Neurol Sci. 1995; 129:214–222.
Welch et al. (1988)	31P-MRS	Migraine	47	No differences in pHi ictally (N = 11) or interictally (N = 9) in MO+MA vs. controls. Indicates no lactate alteration. Data not shown for ADP and ATP. Data for PCr and Pi are reported in Welch et al. [37]. No ictal vs. interictal state comparison. No patient had aura during testing, and the results were compared to controls who were not age- and gender-matched.	Welch KMA, et al. Cephalalgia. 1988; 8:273–277.
Welch et al. (1989)	31P-MRS	Migraine	47	PCr decreased and Pi increased ictally (N = 11) in MO þMA vs. controls. Pi increased interictally (N = 9) in MO þMA vs. controls. Suggest an altered energy metabolism during migraine attacks. No difference in pHi suggests no lactate alteration. Data not shown for ADP and ATP. No ictal vs. interictal state comparison. No patient had aura during testing, and the results were compared to controls who were not age and gender matched.	Welch KMA, et al. Neurology. 1989; 39:538–541.
Wall et al. (2005)	PET and [carbonyl-11C] zolmitriptan	Migraine	8	Rapid dose-proportional uptake of 11C-zolmitriptan into the brain.	Wall A, Kågedal M, Bergstrom M, et al. Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study. Drugs R.D. 2005; 6(3);139–147.
Da Silva et al. (2014)	PET with 11C-carfentanil	Spontaneous Migraine	12	micro-OR activation in the ictal phase in the medial PFC, strongly associated with the microp-OR availability level during the interictal phase.	Da Silva AF, Nascimento TD, DosSantos MF, et al. Association of micro-opioid activation in the prefrontal cortex with spontaneous migraine attacks-brief report I. Ann Clin Transl Neurol. 2014; 1(6):439–44
Da Silva et al. (2014)	PET with 11C-carfentanil	Spontaneous Migraine	1	Reduction in micro-OR in the pain-modulatory regions of the endogenous micro-opiod system during the migraine attack.	Da Silva AF, Nascimento TD, Love T, et al. 3D-neuronavigation in vivo through a patient’s brain during a spontaneous migraine headache. J Vis Exp. 2014;(88).
Chabriat et al. (1995)	PET with 18F-fuorosetoperone	Migraine	12	No differences of cortical 5-HT2 receptors’ distribution volumes in migraine patients when compared with HC.	Chabriat H, Tehindrazanarivelo A, Vera P, et al. 5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18F-fluorosetoperone. Cephalalgia. 1995; 15(2):104–8.
Demarquay et al. (2011)	PET with a 5HT1A radioligand	Migraine	20	Increased 5-HT1A receptors’ in the pontine raphe during odor-triggered migraine attack.	Demarquay G, Lothe A, Royet JP, et al. Brainstem changes in 5-HT1A receptor availability during migraine attack. Cephalalgia. 2011; 3(1):84–94.
Chugani et al. (1999)	PET with alpha-[11C] methyl-L-tryptophan tracer	Migraine without Aura	19	Increased rate of brain serotonin synthesis in the ictal phase of migraine attack.	Chugani DC, Niimura K, Chaturvedi S, et al. Increased brain serotonin synthesis in migraine. Neurology. 1999; 53(7):1473–9.