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Migraine, Brain Glucose Metabolism and the “Neuroenergetic” Hypothesis: A Scoping Review

Open AccessPublished:March 13, 2022DOI:https://doi.org/10.1016/j.jpain.2022.02.006

      Highlight

      • The role of brain glucose metabolism in the pathophysiology of migraine remains unclear.
      • The rationale for a brain energy deficit in migraine (the “neuroenergetic hypothesis“) is presented.
      • The role of postprandial hypoglycemia and brain insulin resistance in migraine is discussed.
      • Brain insulin resistance may be the pathophysiological link between episodic and chronic migraine.
      • Diet, exercise, and mind-body interventions were discussed as potential treatment regimes.

      Abstract

      Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases.

      Perspective

      Although additional experimental studies are needed to support this novel “neuroenergetic” hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.

      Key words

      Migraine is a common neurovascular disorder, characterized by recurrent headache attacks associated with neurological and gastrointestinal symptoms.
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      This scoping review focuses on cerebral metabolic aspects of migraine, in an attempt to provide a clearer understanding of the disease pathogenesis, the complex pathophysiological interplay between episodic and chronic migraine and those between migraine and its comorbidities, and, hopefully, to highlight mechanisms that could become potential targets for novel preventive interventions.
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      Conversely, we investigated into the “neuroenergetic” hypothesis by collecting and analyzing evidence for this new hypothesis, suggesting that postprandial (or reactive) hypoglycemia may well play a major pathophysiological role in episodic migraine and that brain insulin resistance could be a pivotal factor in migraine chronification.
      In support of this hypothesis, we report some features associated with the pathophysiology and clinical progression of migraine, ie, brain mitochondrial dysfunction, impaired brain glucose metabolism, a decrease in grey matter volume and neuroinflammation, all of which are related to brain insulin resistance. Comorbidities of migraine, where impaired glucose metabolism and, mainly, insulin resistance are common pathophysiological features, were also identified: obesity, depression and cerebrovascular diseases.
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      From Neuronal Cell Stress to Headache

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      Spreading depression triggers headache by activating neuronal Panx1 channels.

      Cerebral Energy Deficiency: How Does it Come About?

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      The Role of Postprandial (or Reactive) Hypoglycemia in Episodic Migraine

      Hypoglycemia: an “old friend”

      Hypoglycemia was considered a precipitating factor in migraine headaches as far back as 1935.
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      In the light of new supportive evidence, particularly studies investigating glucose homeostasis in migraine patients, recent research has brought the hypoglycemic hypothesis back into play.
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      The evidence suggesting that the cerebral energy deficit may characterize people who are particularly susceptible to postprandial (or reactive) hypoglycemia, because of altered insulin sensitivity, will be detailed in the following paragraphs.
      In 1998, Bonora et al. estimated that the prevalence of insulin resistance was of 65.9% for subjects with impaired glucose tolerance, 83.9% for non-insulin-dependent diabetes mellitus sufferers, 53.5% for people with hypercholesterolemia, 84.2% for those with hypertriglyceridemia, 88.1% in subjects with low HDL cholesterol, 62.8% in hyperuricemia and 58.0% in hypertension.
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      and this was later demonstrated with the hyperinsulinemic normoglycemic glucose clamp technique.
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      Postprandial hypoglycemia is not uncommon, both in the general population and in those with diseases that alter the glucose metabolism. Table 1 reports some significant studies on the incidence of postprandial hypoglycemia and shows that a 2-h OGTT does not suffice to fully understand the real prevalence of those suffering from postprandial hypoglycemia, but that a 4- or 5-hour (OGTT) may be required.
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      • Fang K
      • Hao W
      • Han Y
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      • Yu Q
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      ,
      • Murata M
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      ,
      • Parekh S
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      • Khunti K
      • Davies MJ.
      Clinical characteristics of people experiencing biochemical hypoglycaemia during an oral glucose tolerance test: Cross-sectional analyses from a UK multi-ethnic population.
      Table 1Summary of the Studies Investigating Postprandial Hypoglycemia Incidence at Different Oral Glucose Tolerance Test (OGTT) Times and Different Hypoglycemic Threshold.
      First AuthorOGTT (hours)Subject characteristicsPostprandial Hypoglycemia Incidence
      Sørensen M.
      • Sørensen M
      • Johansen OE.
      Idiopathic reactive hypoglycaemia - prevalence and effect of fibre on glucose excursions.
      2Subjects without diagnosis of abnormal glucose metabolism; 59% had a prior CV complication; mean age 71 years; 214 M, 148 F12% had 2 h- glycaemia ≤3.9 mmol/L or 2 h-glucose < fasting glucose
      Parekh S.
      • Parekh S
      • Bodicoat DH
      • Brady E
      • Webb D
      • Mani H
      • Mostafa S
      • Levy MJ
      • Khunti K
      • Davies MJ.
      Clinical characteristics of people experiencing biochemical hypoglycaemia during an oral glucose tolerance test: Cross-sectional analyses from a UK multi-ethnic population.
      2Diabetes-free; mean age ≈ 57 years; 3410 F, 3068 M5.5% had 2 h- glycaemia <3.3 mmol/l
      Cai X.
      • Cai X
      • Han X
      • Zhou X
      • Zhou L
      • Zhang S
      • Ji L
      Associated factors with biochemical hypoglycemia during an oral glucose tolerance test in a Chinese population.
      2Normal glucose tolerance; mean age 40.2 years; 10399 M, 16207 F0.53% had 2 h-glycaemia < 3.0 mmol/l
      Fariss BL.
      • Fariss BL.
      Prevalence of post-glucose-load glycosuria and hypoglycemia in a group of healthy young men.
      2US Army's healthy young men; 17-29 years old; 4928 M24.4% had 2 h-glycaemia < 3.3 mmol/l
      Johnson DD.
      • Johnson DD
      • Dorr KE
      • Swenson WM
      • Service FJ.
      Reactive hypoglycemia.
      5Normal glucose tolerance; 17% obese; mean age 41 years; 98 F, 49 M23.8% had 2 h-glycaemia < 2.8 mmol/l
      Lev-Ran A.
      • Lev-Ran A
      • Anderson RW.
      The diagnosis of postprandial hypoglycemia.
      5Normal glucose tolerance; mean age ≈ 40 years; 14% overweight; 304 M, 346 F10% had 5 h-glycaemia < 2.6 mmol/l
      5Suspected of having hypoglycemia; mean age ≈ 40 years; 13.5% overweight; 83 F, 35 M13.5% had 5 h-glycaemia < 2.2 mmol/l
      Jung Y.
      • Jung Y
      • Khurana RC
      • Corredor DG
      • Hastillo A
      • Lain RF
      • Patrick D
      • Turkeltaub P
      • Danowski TS.
      Reactive hypoglycemia in women: Results of a health survey.
      5Normal weight; 20-45 years old; 122 F18.8% had 5 h-glycaemia < 3.3 mmol/l
      5Normal weight; 46-70 years old; 43 F2.3% had 5 h-glycaemia < 3.3 mmol/l
      5Obese; 20-44 years old; 58 F31% had 5 h-glycaemia < 3.3 mmol/l
      5Obese; 46-70 years old; 62 F11.3% had 5 h-glycaemia < 3.3 mmol/l
      Guiducci L.
      • Guiducci L
      • Iervasi G
      • Quinones-Galvan A.
      On the paradox insulin resistance/insulin hypersensitivity and obesity: Two tales of the same history.
      > 2Obese and obesity-prone individuals
      (normal weight individuals with a strong family history of obesity).
      32% had 2 h- glycaemia < 3.9 mmol/L
      Altuntas Y.
      • Altuntas Y
      • Bilir M
      • Ucak S
      • Gundogdu S.
      Reactive hypoglycemia in lean young women with PCOS and correlations with insulin sensitivity and with beta cell function.
      4Lean and young PCOS subjects50% had 4 h- glycaemia < 3.0 mmol/l
      Kasim-Karakas SE.
      • Kasim-Karakas SE
      • Cunningham WM
      • Tsodikov A
      Relation of nutrients and hormones in polycystic ovary syndrome.
      5Overwheight and obese young PCOS subjects64% had 5 h- glycaemia < 3.9 mmol/l
      Abbreviation. CV, cardiovascular; M, males; F, females; PCOS, Polycystic ovary syndrome.
      low asterisk (normal weight individuals with a strong family history of obesity).
      As described in Table 1, three studies carried out OGTTs and observed that subjects with diseases characterized by insulin resistance, ie, polycystic ovary syndrome and obesity, had high incidence of reactive hypoglycemia: 32%,
      • Guiducci L
      • Iervasi G
      • Quinones-Galvan A.
      On the paradox insulin resistance/insulin hypersensitivity and obesity: Two tales of the same history.
      50%
      • Altuntas Y
      • Bilir M
      • Ucak S
      • Gundogdu S.
      Reactive hypoglycemia in lean young women with PCOS and correlations with insulin sensitivity and with beta cell function.
      and 64%.
      • Kasim-Karakas SE
      • Cunningham WM
      • Tsodikov A
      Relation of nutrients and hormones in polycystic ovary syndrome.
      Noteworthy, was the high incidence of postprandial hypoglycemia reported also in young, normal weight (on average) subjects, without a diagnosis of abnormal glucose metabolism: 24.4%,
      • Fariss BL.
      Prevalence of post-glucose-load glycosuria and hypoglycemia in a group of healthy young men.
      23.8%,
      • Johnson DD
      • Dorr KE
      • Swenson WM
      • Service FJ.
      Reactive hypoglycemia.
      10%
      • Lev-Ran A
      • Anderson RW.
      The diagnosis of postprandial hypoglycemia.
      and 18.8%.
      • Jung Y
      • Khurana RC
      • Corredor DG
      • Hastillo A
      • Lain RF
      • Patrick D
      • Turkeltaub P
      • Danowski TS.
      Reactive hypoglycemia in women: Results of a health survey.
      Other studies reported in Table 1
      • Cai X
      • Han X
      • Zhou X
      • Zhou L
      • Zhang S
      • Ji L
      Associated factors with biochemical hypoglycemia during an oral glucose tolerance test in a Chinese population.
      ,
      • Parekh S
      • Bodicoat DH
      • Brady E
      • Webb D
      • Mani H
      • Mostafa S
      • Levy MJ
      • Khunti K
      • Davies MJ.
      Clinical characteristics of people experiencing biochemical hypoglycaemia during an oral glucose tolerance test: Cross-sectional analyses from a UK multi-ethnic population.
      ,
      • Sørensen M
      • Johansen OE.
      Idiopathic reactive hypoglycaemia - prevalence and effect of fibre on glucose excursions.
      carried out OGTTs to identify reactive hypoglycemia in thousands of diabetes-free subjects or subjects with normal glucose tolerance.
      No association was observed between reactive hypoglycemia at the 2-h OGTT and insulin resistance. Conversely, a glycemia of < 3.3 mmol/l detected at the 2-h OGTT, was associated with a younger age, higher insulin sensitivity and a lower body mass index. This is further evidence supporting that both high insulin sensitivity and insulin resistance may lead to the development of postprandial hypoglycemia. Moreover, high insulin sensitivity appears to be the most frequent cause of postprandial hypoglycemia, being probably implicated in 50 to 70% of all cases.
      • Brun JF
      • Bouix O
      • Monnier JF
      • Blachon C
      • Jourdan N
      • Baccara MT
      • Fédou C
      • Orsetti A
      Increased insulin sensitivity and basal insulin effectiveness in postprandial reactive hypoglycaemia.
      ,
      • Brun JF
      • Fedou C
      • Mercier J.
      Postprandial reactive hypoglycemia.

      Episodic Migraine and Postprandial (or Reactive) Hypoglycemia: Clinical Evidence

      Clinical evidence suggests that migraine can, to a large extent, be generated by postprandial hypoglycemia. Indeed, data from clinical practice has taught us that the most frequent triggering factor reported by migraineurs is fasting and that migraine is more likely to occur in susceptible persons when there is insulin resistance.
      • Masters JB
      • Mortimer MJ
      • Haykm
      Glucose and diet in fasting migraineurs.
      ,
      • Rose FC.
      Trigger factors and natural history of migraine.
      Hockaday et al. carried out a study where 50g of glucose was given to 10 migraineurs whose attacks were associated with fasting, after a 10-hour fast. A total of 6 of 10 of them had a migraine attack within 8 hours of the glucose test,
      • Hockaday J
      • Williamson DH
      • Whitty CWM.
      Blood-glucose levels and fatty-acid metabolism in migraine related to fasting.
      as the hyperglycemic effect of cortisol requires a few hours to appear.
      • Tamburrano G
      • Leonetti F
      • Sbraccia P
      • Giaccari A
      • Locuratolo N
      • Lala A.
      Increased insulin sensitivity in patients with idiopathic reactive hypoglycemia.
      Luyckx et al. observed that 30 of 47 patients who had reactive hypoglycemia had reported signs of a so-called “neuroglycopenia” occurring from 2 to 4 hours after a meal in their everyday life. They had signs and symptoms which included weakness, faintness, headache, irritability, anxiety, nervousness, palpitations, inward trembling, vertigo, hunger, and syncope. In another study, 74 migraineurs who reported that fasting had triggered their attacks, had a 5-h OGTT with 100g of glucose. A curve, consistent with reactive hypoglycemia values, was observed in 56 of 74 (76%) of them.
      • Dexter JD
      • Roberts J
      • Byer JA.
      The five hour glucose tolerance test and effect of low sucrose diet in migraine.
      Wilkinson reported that 11 of 13 (85%) subjects, who seemed to have ‘headaches of a migrainoid nature’ had induced headaches during a 5-hour OGTT. The headache began 3-4 h into the test when the glucose level dropped to its lowest (ie, < 3.3 mmol/L).
      • Wilkinson CF
      Recurrent migrainoid headaches associated with spontaneous hypoglycemia.
      A serum glucose level below 3.3 mmol/L within a few hours of glucose ingestion is considered to be a sign of reactive hypoglycemia.
      • Parekh S
      • Bodicoat DH
      • Brady E
      • Webb D
      • Mani H
      • Mostafa S
      • Levy MJ
      • Khunti K
      • Davies MJ.
      Clinical characteristics of people experiencing biochemical hypoglycaemia during an oral glucose tolerance test: Cross-sectional analyses from a UK multi-ethnic population.
      A review of international literature indicates that, more often than not, there are two main specific dietary factors, ie, fasting and a relatively mild reactive hypoglycemia, which may follow large (ie, 100 g) carbohydrate ingestions, which induce migraine in sufferers and more generalized headaches in the general population.
      • Hufnagl KN
      • Peroutka SJ.
      Glucose regulation in headache: Implications for dietary management.
      The classical signs of hypoglycemia include: blurred vision, headache, confusion, depression, tremors, anxiety, hunger, palpitations, sweating, nausea, dizziness and weakness.
      • Brun JF
      • Bouix O
      • Monnier JF
      • Blachon C
      • Jourdan N
      • Baccara MT
      • Fédou C
      • Orsetti A
      Increased insulin sensitivity and basal insulin effectiveness in postprandial reactive hypoglycaemia.
      ,
      • Johnson DD
      • Dorr KE
      • Swenson WM
      • Service FJ.
      Reactive hypoglycemia.
      ,
      • Tamburrano G
      • Leonetti F
      • Sbraccia P
      • Giaccari A
      • Locuratolo N
      • Lala A.
      Increased insulin sensitivity in patients with idiopathic reactive hypoglycemia.
      Similar symptoms have been observed in subjects with insulinoma,
      • Chammas NK
      • Teale JD
      • Quin JD.
      Insulinoma: How reliable is the biochemical evidence?.
      ,
      • Huai JC
      • Zhang W
      • Niu HO
      • Su ZX
      • McNamara JJ
      • Machi J.
      Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound.
      ,
      • Larijani B
      • Aghakhani S
      • Lor SSM
      • Farzaneh Z
      • Pajouhi M
      • Bastanhagh MH.
      Insulinoma in Iran: A 20-year review.
      ,
      • Richards ML
      • Gauger PG
      • Thompson NW
      • Kloos RG
      • Giordano TJ.
      Pitfalls in the surgical treatment of insulinoma.
      ,
      • Shreenivas AV
      • Leung V.
      A rare case of insulinoma presenting with postprandial hypoglycemia.
      a rare condition that can lead to postprandial hypoglycemia. The patients enrolled into these studies complained of typical hypoglycemia symptoms, such as dizziness, sweating, confusion, irritability and blurred vision, 2 hours after a meal. All the symptoms reported by people with insulinoma may be attributed to an insufficient supply of glucose to the brain. Their comorbidities were epilepsy, anxiety, depression and, interestingly, migraine. The hypoglycemia symptoms match most of the non headache symptoms of migraine, including tiredness and/or weariness, difficulty in concentration, blurred vision, light sensitivity, intolerance and/or irritability, hunger and/or food craving and dizziness.
      • Giffin NJ
      • Ruggiero L
      • Lipton RB
      • Silberstein SD
      • Tvedskov JF
      • Olesen J
      • Altman J
      • Goadsby PJ
      • Macrae A.
      Premonitory symptoms in migraine: An electronic diary study.
      Moreover, estro-progestinic drugs induce hyperinsulinism and hypoglycemia, which might explain the frequent worsening of migraine in patients on these drugs.
      • Kim C
      • Siscovick DS
      • Sidney S
      • Lewis CE
      • Kiefe CI
      • Koepsell TD
      CARDIA Study
      Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA Study. Coronary artery risk development in young adults.
      In line with this, Granella et al. reported a more severe migraine in 25% of patients without aura and in 56% of those with aura on estro-progestinic drugs.
      • Granella F
      • Sances G
      • Pucci E
      • Nappi RE
      • Ghiotto N
      • Napp G.
      Migraine with aura and reproductive life events: A case control study.
      Intriguingly, an experimental study
      • Martins-Oliveira M
      • Akerman S
      • Holland PR
      • Hoffmann JR
      • Tavares I
      • Goadsby PJ.
      Neuroendocrine signaling modulates specific neural networks relevant to migraine.
      demonstrated that administration of insulin as well as glucagon, a peptide hormone produced by alpha cells of the pancreas that counteracts insulin actions, significantly modulate the neuronal firing in the trigeminocervical-complex, a key structure in the pathogenesis of the migraine attack. This suggests that there is a potential neurobiological link between migraine and altered glucose homeostasis.

      Metabolic Similarities Between a Migraine Attack and the Hypoglycemic State

      Biochemical studies highlight similarities in the metabolism observed during a migraine attack and a hypoglycemic state. Indeed, it was observed that the levels of free fatty acid, ketone bodies, glycerol and cortisol, were increased in the venous blood samples of migraineurs during an attack.
      • Shaw SW
      • Johnson RH
      • Keogh HJ.
      Metabolic changes during glucose tolerance tests in migraine attacks.
      The same metabolic pattern was observed during fasting or glucoprivation, in the general population.
      • Allaman I
      • Magistretti PJ.
      Brain energy metabolism.
      Several studies reported a higher frequency of altered insulin sensitivity in both episodic migraine (EM) and chronic migraine (CM).
      • Rainero I
      • Govone F
      • Gai A
      • Vacca A
      • Rubino E.
      Is migraine primarily a metaboloendocrine disorder?.
      Bhoi et al. observed that insulin resistance correlated with the duration of migraine attacks.
      • Bhoi SK
      • Kalita J
      • Misra UK.
      Metabolic syndrome and insulin resistance in migraine.
      A case-control study identified a significant insulin resistance prevalence in CM with a three-fold higher probability of having insulin resistance than the EM group, where an insulin resistance prevalence similar to that of the control group was observed.
      • Fava A
      • Pirritano D
      • Consoli D
      • Plastino M
      • Casalinuovo F
      • Cristofaro S
      • Colica C
      • Ermio C
      • De Bartolo M
      • Opipari C
      • Lanzo R
      • Consoli A
      • Bosco D.
      Chronic migraine in women is associated with insulin resistance: A cross-sectional study.
      This association remained constant also after adjustment for the confounding variables commonly associated with a higher insulin resistance status.

      Glucose-Insulin Metabolism and the Brain

      There is an increasing amount of data on insulin and brain insulin resistance, which evidence important features of migraine, dementia and other neurodegenerative disorders.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Tyagi A
      • Pugazhenthi S.
      Targeting insulin resistance to treat cognitive dysfunction.
      Under physiological conditions, the regulatory mechanisms in the blood-brain barrier, astrocytes and neurons provide an efficient supply of energy during neuronal activation.
      • Kacem K
      • Lacombe P
      • Seylaz J
      • Bonvento G.
      Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: A confocal microscopy study.
      Current literature reports that the human brain is an insulin sensitive organ and, as such, may become insulin resistant.
      • Heni M
      • Kullmann S
      • Preissl H
      • Fritsche A
      • Häring H-U.
      Impaired insulin action in the human brain: Causes and metabolic consequences.
      ,
      • Sripetchwandee J
      • Chattipakorn N
      • Chattipakorn SC.
      Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia.
      Indeed, some researchers suggests that peripheral insulin resistance can extend to the brain, triggering brain insulin resistance.
      • McIntyre RS
      • Soczynska JK
      • Konarski JZ
      • Woldeyohannes HO
      • Law CWY
      • Miranda A
      • Fulgosi D
      • Kennedy SH.
      Should depressive syndromes be reclassified as “metabolic syndrome type II”?.
      ,
      • Sachdeva AK
      • Dharavath RN
      • Chopra K.
      Time-response studies on development of cognitive deficits in an experimental model of insulin resistance.
      ,
      • Sripetchwandee J
      • Chattipakorn N
      • Chattipakorn SC.
      Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia.
      Similarly, to the mechanism that takes place in peripheral insulin resistance, brain insulin resistance occurs when the brain cells fail to respond to insulin. The following paragraphs will focus on the main metabolic pathways involved in brain glucose homeostasis which may be altered by insulin resistance and, consequently, fail to provide an adequate energy supply during neuronal activation (Fig 1).
      Figure 1
      Figure 1Cerebral metabolic abnormalities that might be implicated in migraine pathophysiology. Insulin induces incorporation of GLUT4 from intracellular stores into the plasma membrane in neurons, binding to insulin receptor isoform B (IR-B), during a period of high metabolic demand, especially in brain regions related to cognitive behavior (step 1). The increased abundance of GLUT4 and maybe also GLUT3 in the membrane increases the glucose influx into neurons. The membrane GLUT1 abundance and glycolysis are upregulated in astrocytes during neuronal activation, leading to an interstitial decrease in glucose and an upregulation of GLUT1 in the plasma membranes of capillary endothelial cells. The combined action of insulin and insulin-like growth factor-1 (IGF-1), achieved by the binding to IR-B and IGF-1 receptor (IGF-1R) respectively, lead to the translocation of GLUT1 from intracellular compartments to the cell membrane in astrocytes, stimulating glucose uptake (step 2). Insulin and IGF-1 also stimulate glycogen synthesis in astrocytes (step 3). Glucose crosses the blood-brain barrier (BBB) via glucose transporter 1 (GLUT1), expressed by capillary endothelial cells. Hypoglycemia, which can occur after a glucidic meal (ie, postprandial hypoglycemia), reduces the amount of glucose available for brain metabolism (step 4). In brain insulin resistance, IR-B could be downregulated, triggering an alteration of glucose metabolism in neurons and astrocytes. Lactate is an alternative fuel for the brain and is capable of crossing the BBB through monocarboxylate transporters (MCTs) in endothelial cells, astrocytes and neurons (step 5). Lactate may be also generated by pyruvate, which is generated by astrocytes through a non-oxidative glucose metabolism and shuttled to neurons through monocarboxylate transporters (step 6), as proposed by the astrocyte-lactate-neuron shuttle hypothesis. In neurons and specifically in the mitochondria, glucose and lactate produced pyruvate is converted into acetyl-coenzyme A (Acetyl-CoA), which, via the tricarboxylic acid cycle and oxidative phosphorylation, leads to energy production in the form of ATP (step 7).

      Insulin Resistance and the Brain

      Insulin resistance is generally defined as a reduced sensitivity in body tissues to the action of insulin.
      • Bagdade JD.
      Basal insulin and obesity.
      Therefore, insulin resistance is a state where a normal amount of insulin produces a subnormal physiological response. Similarly, brain insulin resistance can be defined as the failure of brain cells (neurons and glial cells) to respond to insulin.
      • Mielke JG
      • Taghibiglou C
      • Liu L
      • Zhang Y
      • Jia Z
      • Adeli K
      • Wang YT.
      A biochemical and functional characterization of diet-induced brain insulin resistance.
      Systemic and brain insulin resistance may be closely related. In patients with type 2 diabetes (T2DM), systemic insulin resistance may lead to brain insulin resistance and brain dysfunction, whilst abnormal insulin signaling in the brain may have systemic effects, impairing metabolism regulation.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Salkovic-Petrisic M
      • Hoyer S.
      Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: An experimental approach.
      ,
      • Steen E
      • Terry BM
      • Rivera EJ
      • Cannon JL
      • Neely TR
      • Tavares R
      • Xu XJ
      • Wands JR
      • de la Monte SM.
      Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes?.
      Currently, it is not yet clear whether peripheral and brain insulin resistance can exist independently or not.
      The reduced response to insulin could be related to various mechanisms, including a downregulation of insulin receptors, the inability of insulin receptors to bind insulin or an abnormal activation of the insulin signaling cascade.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      At the cellular level, this dysfunction might manifest as an impairment of neurotransmitter release, altered receptor regulation in neurons and glial cells, or dysfunction of processes more directly related to insulin metabolism, such as neuronal glucose uptake in neurons or homeostatic or inflammatory responses to insulin.
      • Koepsell H.
      Glucose transporters in brain in health and disease.
      ,
      • Kullmann S
      • Heni M
      • Hallschmid M
      • Fritsche A
      • Preissl H
      • Häring H-U.
      Brain insulin resistance at the Crossroads of metabolic and cognitive disorders in humans.
      The most efficacious method to measure insulin resistance in humans is considered to be the use of a hyperinsulinemic-euglycemic (HI-EG) clamp, that infuses insulin at a constant rate and a variable infusion of dextrose to maintain euglycemia.
      • Tam CS
      • Xie W
      • Johnson WD
      • Cefalu WT
      • Redman LM
      • Ravussin E.
      Defining insulin resistance from hyperinsulinemic-euglycemic clamps.
      However, HI-EG is demanding and costly. The oral glucose tolerance test (OGTT) is a valid alternative for the evaluation of insulin resistance as it provides information on insulin secretion and action, even if it does not directly yield a measure of insulin sensitivity. Several indexes of insulin resistance have been suggested on the basis of the data derived from OGTTs and some of these had a highly significant correlation with the clamp.
      • Mari A
      • Pacini G
      • Murphy E
      • Ludvik B
      • Nolan JJ
      A modelbased method for assessing insulin sensitivity from the oral glucose tolerance test.
      ,
      • Rabasa-Lhoret R
      • Bastard JP
      • Jan V
      • Ducluzeau PH
      • Andreelli F
      • Guebre F
      • Bruzeau J
      • Louche-Pellissier C
      • MaItrepierre C
      • Peyrat J
      • Chagné J
      • Vidal H
      • Laville M
      Modified quantitative insulin sensitivity check index is better correlated to hyperinsulinemic glucose clamp than other fasting-based index of insulin sensitivity in different insulin-resistant states.
      The study of brain insulin resistance requires intranasal administration of insulin. This approach delivers insulin directly to the CNS, bypassing the BBB, with a minimal insulin increase in the periphery. The direct effects of insulin on CNS activity can be assessed by neuropsychological, neurophysiological and neuroimaging investigations.
      • Novak V
      • Milberg W
      • Hao Y
      • Munshi M
      • Novak P
      • Galica A
      • Manor B
      • Roberson P
      • Craft S
      • Abduljalil A.
      Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes.
      ,
      • Zhang H
      • Hao Y
      • Manor B
      • Novak P
      • Milberg W
      • Zhang J
      • Fang J
      • Novak V.
      Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes.

      Insulin Receptors

      It has been demonstrated that insulin receptors and the related insulin signaling cascade are pivotal factors in brain metabolism, both in neurons and astrocytes.
      • Belfiore A
      • Malaguarnera R
      • Vella V
      • Lawrence MC
      • Sciacca L
      • Frasca F
      • Morrione A
      • Vigneri R.
      Insulin receptor isoforms in physiology and disease: An updated view.
      The insulin receptor (IR) in mammals occurs in two isoforms, IR-A and IR-B, which are expressed in different relative proportions in various organs and tissues. Moreover, it has been observed that their expression varies during development, aging and disease states.
      • Spencer B
      • Rank L
      • Metcalf J
      • Desplats P.
      Identification of insulin receptor splice variant B in neurons by in situ detection in human brain samples.
      On binding to IR-A, insulin triggers the classical mitogenic signaling cascade (non-metabolic effects), whilst if it binds to IR-B it activates the metabolic phenotype pathway.
      • Belfiore A
      • Malaguarnera R
      • Vella V
      • Lawrence MC
      • Sciacca L
      • Frasca F
      • Morrione A
      • Vigneri R.
      Insulin receptor isoforms in physiology and disease: An updated view.
      ,
      • Pomytkin I
      • Costa-Nunes JP
      • Kasatkin V
      • Veniaminova E
      • Demchenko A
      • Lyundup A
      • Lesch KP
      • Ponomarev ED
      • Strekalova T.
      Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment.
      ,
      • Spencer B
      • Rank L
      • Metcalf J
      • Desplats P.
      Identification of insulin receptor splice variant B in neurons by in situ detection in human brain samples.
      The IR‐B/IR‐A mRNA ratio is predominant in human tissues like the liver, adipose tissue, skeletal muscle and kidney and is associated with the metabolic effects of insulin. Conversely, insulin acts as a mitogenic agent in fetal and cancer tissues where, the IR‐A/IR‐B mRNA ratio prevails.
      • Belfiore A
      • Malaguarnera R
      • Vella V
      • Lawrence MC
      • Sciacca L
      • Frasca F
      • Morrione A
      • Vigneri R.
      Insulin receptor isoforms in physiology and disease: An updated view.
      ,
      • Blázquez E
      • Velázquez E
      • Hurtado-Carneiro V
      • Ruiz-Albusac JM.
      Insulin in the brain: Its pathophysiological implications for states related with central insulin resistance, type 2 diabetes and Alzheimer's disease.
      ,
      • Westermeier F
      • Sáez T
      • Arroyo P
      • Toledo F
      • Gutiérrez J
      • Sanhueza C
      • Pardo F
      • Leiva A
      • Sobrevia L.
      Insulin receptor isoforms: An integrated view focused on gestational diabetes mellitus: Insulin receptors and diabetes.
      Although the expression of both IR-A and IR-B in human astrocytes had been previously described,
      • Garwood CJ
      • Ratcliffe LE
      • Morgan SV
      • Simpson JE
      • Owens H
      • Vazquez-Villaseñor I
      • Heath PR
      • Romero IA
      • Ince PG
      • Wharton SB.
      Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors.
      Spencer et al. used an innovative, investigative method (in situ RT-PCR/ FISH assay) and was the first to demonstrate that both IR-A and IR-B are expressed in the neurons of the adult human frontal cortex brain tissue.
      • Spencer B
      • Rank L
      • Metcalf J
      • Desplats P.
      Identification of insulin receptor splice variant B in neurons by in situ detection in human brain samples.
      These IR-A and IR-B receptors have distinct activation and regulation mechanisms. There is a downregulation of IR-B in chronically high levels of insulin, without it affecting the brain IR-A.
      • Garwood CJ
      • Ratcliffe LE
      • Morgan SV
      • Simpson JE
      • Owens H
      • Vazquez-Villaseñor I
      • Heath PR
      • Romero IA
      • Ince PG
      • Wharton SB.
      Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors.
      Indeed, animal studies have demonstrated that an increased IR-A/IR-B ratio is related to insulin resistance
      • Belfiore A
      • Malaguarnera R
      • Vella V
      • Lawrence MC
      • Sciacca L
      • Frasca F
      • Morrione A
      • Vigneri R.
      Insulin receptor isoforms in physiology and disease: An updated view.
      and glucose intolerance in mice.
      • Spencer B
      • Rank L
      • Metcalf J
      • Desplats P.
      Identification of insulin receptor splice variant B in neurons by in situ detection in human brain samples.
      Moreover, IR-A is favored in diabetic or pre-diabetic subjects in a state of peripheral hyperinsulinism, whilst IR-B metabolic processes are reduced.
      • Belfiore A
      • Malaguarnera R
      • Vella V
      • Lawrence MC
      • Sciacca L
      • Frasca F
      • Morrione A
      • Vigneri R.
      Insulin receptor isoforms in physiology and disease: An updated view.
      Alterations in insulin receptor signaling have been associated with dementia
      • Bedse G
      • Di Domenico F
      • Serviddio G
      • Cassano T.
      Aberrant insulin signaling in Alzheimer's disease: Current knowledge.
      and, interestingly, it has been reported that an IR-B analogue, discovered in C. elegans, is involved in learning and memory.
      • Ohno H
      • Kato S
      • Naito Y
      • Kunitomo H
      • Tomioka M
      • Iino Y.
      Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans.
      Therefore, as postulated by Spencer et al., IR-A and IR-B may have distinct functions in neurons.
      • Spencer B
      • Rank L
      • Metcalf J
      • Desplats P.
      Identification of insulin receptor splice variant B in neurons by in situ detection in human brain samples.

      Glucose Transporters in the Brain

      Neurons

      The uptake of glucose by neurons is mainly provided by the insulin-independent high-affinity glucose transporter GLUT3.
      • Koepsell H.
      Glucose transporters in brain in health and disease.
      However, insulin-sensitive GLUT4 is also co-expressed with GLUT3 in some brain regions which are particularly reactive to insulin
      • Kullmann S
      • Heni M
      • Hallschmid M
      • Fritsche A
      • Preissl H
      • Häring H-U.
      Brain insulin resistance at the Crossroads of metabolic and cognitive disorders in humans.
      and related to cognitive behavior and tasks. These regions include the basal forebrain, the hippocampus, the amygdala, the cerebral cortex and the cerebellum.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Jensen VFH
      • Bøgh IB
      • Lykkesfeldt J.
      Effect of insulin-induced hypoglycaemia on the central nervous system: Evidence from experimental studies.
      GLUT4 improves glucose influx into neurons during high metabolic demand tasks, like learning.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Sripetchwandee J
      • Chattipakorn N
      • Chattipakorn SC.
      Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia.
      It has been proven that insulin induces the incorporation of GLUT4 from intracellular stores into the plasma membrane via an AKT-dependent mechanism.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Koepsell H.
      Glucose transporters in brain in health and disease.
      Indeed, Wortmannin, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor (AKT is a significant downstream effecter of PI3K signaling
      • Liu R
      • Chen Y
      • Liu G
      • Li C
      • Song Y
      • Cao Z
      • Li W
      • Hu J
      • Lu C
      • Liu Y.
      PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers.
      ) totally abolishes insulin-dependent GLUT4 translocation and glucose uptake.
      • Benomar Y
      • Naour N
      • Aubourg A
      • Bailleux V
      • Gertler A
      • Djiane J
      • Guerre-Millo M
      • Taouis M.
      Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase-dependent mechanism.
      Benomar et al. observed in an experimental model that cultivated human neuronal cells decreased GLUT4 incorporation into the plasma membrane after chronic insulin treatment.
      • Benomar Y
      • Naour N
      • Aubourg A
      • Bailleux V
      • Gertler A
      • Djiane J
      • Guerre-Millo M
      • Taouis M.
      Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase-dependent mechanism.
      Some authors have hypothesized that protracted changes in glucose and insulin concentrations in the brain and a reduced insulin receptor sensitivity during diabetes, could influence the GLUT4 expression and function in the brain.
      • Koepsell H.
      Glucose transporters in brain in health and disease.
      This was supported by an in vivo experiment on an animal model which demonstrated a reduced GLUT1, GLUT3 and GLUT4 density in mouse brains, after a 3-month diet rich in fat and sugar.
      • Garcia-Serrano AM
      • Duarte JMN.
      Brain metabolism alterations in type 2 diabetes: What did we learn from diet-induced diabetes models?.

      Astrocytes

      Astrocytes are the brain reservoir of glucose storage in the form of glycogen
      • Duran J
      • Gruart A
      • Varea O
      • López-Soldado I
      • Delgado-García JM
      • Guinovart JJ.
      Lack of neuronal glycogen impairs memory formation and learning-dependent synaptic plasticity in mice.
      and inadequate brain glycogen reduces the threshold for CSD in vivo.
      • Kilic K
      • Karatas H
      • Dönmez-Demir B
      • Eren-Kocak E
      • Gursoy-Ozdemir Y
      • Can A
      • Petit JM
      • Magistretti PJ
      • Dalkara T.
      Inadequate brain glycogen or sleep increases spreading depression susceptibility: Brain glycogen, sleep deprivation, and CSD.
      The high affinity glucose transporter GLUT1, the main glucose transporter in astrocytes, is also responsible for glucose transport in the endothelial cells of the blood-brain barrier
      • Gross EC
      • Lisicki M
      • Fischer D
      • Sándor PS
      • Schoenen J.
      The metabolic face of migraine - from pathophysiology to treatment.
      ,
      • Morgello S
      • Uson RR
      • Schwartz EJ
      • Haber RS.
      The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes.
      and is highly expressed in the dendritic end-feet of astrocytes that wrap around brain capillaries.
      • Koepsell H.
      Glucose transporters in brain in health and disease.
      On the basis of the fact that an expression of the insulin-sensitive glucose transporter GLUT4 was observed in astrocytes,
      • Muhič M
      • Vardjan N
      • Chowdhury HH
      • Zorec R
      • Kreft M.
      Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes.
      it was speculated that insulin may stimulate glucose uptake into astrocytes through GLUT4.
      • Muhič M
      • Vardjan N
      • Chowdhury HH
      • Zorec R
      • Kreft M.
      Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes.
      Further experimental studies reported a co-operative mechanism where insulin stimulates glucose uptake through forebrain astrocytes that work in conjunction with insulin-like growth factor-1 (IGF-1), through the synergistic activation of mitogen-activated protein kinases (MAPKs) and protein kinase D (PKD), ie, the MAPK/PKD pathway.
      • Fernandez AM
      • Hernandez-Garzón E
      • Perez-Domper P
      • Perez-Alvarez A
      • Mederos S
      • Matsui T
      • Santi A
      • Trueba-Saiz A
      • García-Guerra L
      • Pose-Utrilla J
      • Fielitz J
      • Olson EN
      • Fernandez de la Rosa R
      • Garcia Garcia L
      • Pozo MA
      • Iglesias T
      • Araque A
      • Soya H
      • Perea G
      • Martin ED
      • Torres Aleman I
      Insulin regulates astrocytic glucose handling through cooperation with IGF-I.
      The combined action of insulin and IGF-1 leads to the translocation of GLUT1 from intracellular compartments to the cell membrane.
      • Fernandez AM
      • Hernandez-Garzón E
      • Perez-Domper P
      • Perez-Alvarez A
      • Mederos S
      • Matsui T
      • Santi A
      • Trueba-Saiz A
      • García-Guerra L
      • Pose-Utrilla J
      • Fielitz J
      • Olson EN
      • Fernandez de la Rosa R
      • Garcia Garcia L
      • Pozo MA
      • Iglesias T
      • Araque A
      • Soya H
      • Perea G
      • Martin ED
      • Torres Aleman I
      Insulin regulates astrocytic glucose handling through cooperation with IGF-I.
      Moreover, Heni et al. demonstrated that insulin stimulates glucose uptake and glycogen synthesis in astrocytes through IR-B.
      • Heni M
      • Hennige AM
      • Peter A
      • Siegel-Axel D
      • Ordelheide A-M
      • Krebs N
      • Machicao F
      • Fritsche A
      • Häring HU
      • Staiger H.
      Insulin promotes glycogen storage and cell proliferation in primary human astrocytes.
      Muhič et al. have demonstrated that insulin and IGF-1 enhance glycogen levels in single isolated astrocytes through the PI3K/AKT pathway.
      • Muhič M
      • Vardjan N
      • Chowdhury HH
      • Zorec R
      • Kreft M.
      Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes.
      This evidence supports the hypothesis that a dysfunction in insulinoid signaling could trigger an inadequate replenishment of glycogen stores.
      Interestingly, the lack of a short-term energy buffer may be pivotal in neurodegenerative and psychiatric disorders.
      • Muhič M
      • Vardjan N
      • Chowdhury HH
      • Zorec R
      • Kreft M.
      Insulin and insulin-like growth factor 1 (IGF-1) modulate cytoplasmic glucose and glycogen levels but not glucose transport across the membrane in astrocytes.

      Migraine Features Potentially Related to Brain Insulin Resistance

      Brain Mitochondrial Dysfunction

      It has been suggested that brain mitochondrial dysfunction takes place in association with brain insulin resistance
      • Sripetchwandee J
      • Chattipakorn N
      • Chattipakorn SC.
      Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia.
      and recent evidence in support of a mitochondrial dysfunction in migraine has also been reported.
      • Gross EC
      • Lisicki M
      • Fischer D
      • Sándor PS
      • Schoenen J.
      The metabolic face of migraine - from pathophysiology to treatment.
      Neuroimaging studies have demonstrated a lower adenosine triphosphate (ATP) and ‘mitochondrial phosphorylation potential’ in the brain of migraineurs without aura during the interictal period, than in controls.
      • Reyngoudt H
      • Paemeleire K
      • Descamps B
      • De Deene Y
      • Achten E.
      31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients.
      Interestingly, the lowest ATP concentrations were observed in the most severely affected migraine patients.
      • Gross EC
      • Lisicki M
      • Fischer D
      • Sándor PS
      • Schoenen J.
      The metabolic face of migraine - from pathophysiology to treatment.
      Several studies have described that the lowest ATP concentrations in the migraineurs’ brains, evaluated by phosphorus magnetic resonance spectroscopy and compared to controls, are associated with a reduced glucose metabolism in the parietal, temporal and frontal lobes, as reported in Table 2.
      • Kim JH
      • Kim S
      • Suh S-I
      • Koh S-B
      • Park K-W
      • Oh K.
      Interictal metabolic changes in episodic migraine: A voxel-based FDG-PET study.
      ,
      • Mathew NT.
      Pathophysiology of chronic migraine and mode of action of preventive medications: July-august 2011.
      ,
      • Ramadan NM
      • Halvorson H
      • Vande-Linde A
      • Levine SR
      • Helpern JA
      • Welch KM.
      Low brain magnesium in migraine.
      ,
      • Schulz UG
      • Blamire AM
      • Corkill RG
      • Davies P
      • Styles P
      • Rothwell PM.
      Association between cortical metabolite levels and clinical manifestations of migrainous aura: An MR-spectroscopy study.
      ,
      • Schulz UG
      • Blamire AM
      • Davies P
      • Styles P
      • Rothwell PM.
      Normal cortical energy metabolism in migrainous stroke: A 31P-MR spectroscopy study.
      ,
      • Welch KM
      • Levine SR
      • D'Andrea G
      • Schultz LR
      • Helpern JA
      Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.
      However, further research is required to elucidate whether brain insulin resistance could be implicated in brain mitochondrial dysfunction.
      Table 2Comparison Between Brain Areas Affected by Reduced Glucose Metabolism, Volume and Energy Metabolism in Insulin Resistance and Migraine.
      Reduced regional cerebral glucose metabolism in subjects with insulin resistanceReduced regional cerebral volume in migraine subjectsReduced regional cerebral energy metabolism in migraine subjects
      According to current literature, most studies have chosen the occipital cortex as the region of interest, as aura, most commonly with visual symptoms, is attributed to this area in patients suffering from this type of migraine.179
      Reduced regional cerebral glucose metabolism in migraine subjects
      The insular lobeInsular cortex (CM)
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      Lai KL et al. enrolled patients with CM without medication overuse headache, major depression or prior preventive treatment.


      Valfrè W, et al.
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      Insular cortex (EM)
      • Kim JH
      • Kim S
      • Suh S-I
      • Koh S-B
      • Park K-W
      • Oh K.
      Interictal metabolic changes in episodic migraine: A voxel-based FDG-PET study.
      .

      Insular cortex (CM)
      • Mathew NT.
      Pathophysiology of chronic migraine and mode of action of preventive medications: July-august 2011.
      The parietal lobeLeft parietal cortex
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      This study30 on young women with Polycystic Ovary Syndrome reported a direct association between mild insulin resistance and brain glucose hypometabolism, which was independent of overweight or obesity.
      .

      Lateral parietal lobe
      • Willette AA
      • Bendlin BB
      • Starks EJ
      • Birdsill AC
      • Johnson SC
      • Christian BT
      • Okonkwo OC
      • La Rue A
      • Hermann BP
      • Koscik RL
      • Jonaitis EM
      • Sager MA
      • Asthana S
      Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease.
      .

      Brodmann areas 7 and 40
      • Baker LD
      • Cross DJ
      • Minoshima S
      • Belongia D
      • Watson GS
      • Craft S.
      Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes.
      Parietal lobe (CM)
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      .

      Left parietal operculum (CM)
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      PCr/Pi ↓, Pi/Tp ↓
      • Welch KM
      • Levine SR
      • D'Andrea G
      • Schultz LR
      • Helpern JA
      Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.
      .

      [Mg+2] ↓
      • Ramadan NM
      • Halvorson H
      • Vande-Linde A
      • Levine SR
      • Helpern JA
      • Welch KM.
      Low brain magnesium in migraine.
      .

      PCr/Pi ↓, Pi/ATP ↑
      • Schulz UG
      • Blamire AM
      • Corkill RG
      • Davies P
      • Styles P
      • Rothwell PM.
      Association between cortical metabolite levels and clinical manifestations of migrainous aura: An MR-spectroscopy study.
      .

      PCr/Pi ↓
      • Schulz UG
      • Blamire AM
      • Davies P
      • Styles P
      • Rothwell PM.
      Normal cortical energy metabolism in migrainous stroke: A 31P-MR spectroscopy study.
      Parietal cortex (CM)
      • Mathew NT.
      Pathophysiology of chronic migraine and mode of action of preventive medications: July-august 2011.
      The anterior cingulate cortexYu Y, et al. (EM, CM)
      • Yu Y
      • Zhao H
      • Dai L
      • Su Y
      • Wang X
      • Chen C
      • Shang Y
      • Ke J
      • Hu C.
      Headache frequency associates with brain microstructure changes in patients with migraine without aura.
      A higher headache frequency was associated with smaller grey matter volume in the anterior cingulate cortex and hippocampus in EM and CM.


      Valfrè W, et al. (CM)
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      Kim JH, et al. (EM)
      • Kim JH
      • Kim S
      • Suh S-I
      • Koh S-B
      • Park K-W
      • Oh K.
      Interictal metabolic changes in episodic migraine: A voxel-based FDG-PET study.


      Mathew NT. (CM)
      • Mathew NT.
      Pathophysiology of chronic migraine and mode of action of preventive medications: July-august 2011.
      The posterior cingulate cortexBaker LD, et al.
      • Baker LD
      • Cross DJ
      • Minoshima S
      • Belongia D
      • Watson GS
      • Craft S.
      Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes.
      Kim JH, et al. (EM)
      • Kim JH
      • Kim S
      • Suh S-I
      • Koh S-B
      • Park K-W
      • Oh K.
      Interictal metabolic changes in episodic migraine: A voxel-based FDG-PET study.
      The temporal lobeLeft middle temporal cortex
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      This study30 on young women with Polycystic Ovary Syndrome reported a direct association between mild insulin resistance and brain glucose hypometabolism, which was independent of overweight or obesity.
      .

      Lateral and medial temporal lobes
      • Willette AA
      • Bendlin BB
      • Starks EJ
      • Birdsill AC
      • Johnson SC
      • Christian BT
      • Okonkwo OC
      • La Rue A
      • Hermann BP
      • Koscik RL
      • Jonaitis EM
      • Sager MA
      • Asthana S
      Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease.
      .

      Temporal/angular gyri (BA 39)
      • Baker LD
      • Cross DJ
      • Minoshima S
      • Belongia D
      • Watson GS
      • Craft S.
      Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes.
      PCr/Pi ↓, Pi/Tp ↓
      • Welch KM
      • Levine SR
      • D'Andrea G
      • Schultz LR
      • Helpern JA
      Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.
      .

      [Mg+2] ↓
      • Ramadan NM
      • Halvorson H
      • Vande-Linde A
      • Levine SR
      • Helpern JA
      • Welch KM.
      Low brain magnesium in migraine.
      .

      PCr/Pi ↓, Pi/ATP ↑
      • Schulz UG
      • Blamire AM
      • Corkill RG
      • Davies P
      • Styles P
      • Rothwell PM.
      Association between cortical metabolite levels and clinical manifestations of migrainous aura: An MR-spectroscopy study.


      PCr/Pi ↓
      • Schulz UG
      • Blamire AM
      • Davies P
      • Styles P
      • Rothwell PM.
      Normal cortical energy metabolism in migrainous stroke: A 31P-MR spectroscopy study.


      The prefrontal cortexAnterior and inferior prefrontal cortices (BA 10, 45, 47)
      • Baker LD
      • Cross DJ
      • Minoshima S
      • Belongia D
      • Watson GS
      • Craft S.
      Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes.
      .

      Bilateral prefrontal cortex
      • Willette AA
      • Bendlin BB
      • Starks EJ
      • Birdsill AC
      • Johnson SC
      • Christian BT
      • Okonkwo OC
      • La Rue A
      • Hermann BP
      • Koscik RL
      • Jonaitis EM
      • Sager MA
      • Asthana S
      Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease.
      Inferior frontal gyrus (BA 44, 45, 47)
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and 47.78


      (CM).
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.


      Lateral orbital gyrus (BA 47)
      The lateral orbital gyrus includes the Brodmann area 47.134
      (CM)
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      Chronic migraine patients had smaller frontal regions than episodic migraine patients.
      Left prefrontal cortex (EM)
      • Kim JH
      • Kim S
      • Suh S-I
      • Koh S-B
      • Park K-W
      • Oh K.
      Interictal metabolic changes in episodic migraine: A voxel-based FDG-PET study.
      .

      Orbitofrontal cortex (BA 10, 11 and 47)
      The orbitofrontal cortex includes the Brodmann areas 10, 11 and 47.113


      (CM)
      • Mathew NT.
      Pathophysiology of chronic migraine and mode of action of preventive medications: July-august 2011.
      The frontal lobeRight superior frontal cortex, right and left middle frontal cortex
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      This study30 on young women with Polycystic Ovary Syndrome reported a direct association between mild insulin resistance and brain glucose hypometabolism, which was independent of overweight or obesity.
      Caudal middle frontal gyrus (CM)
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      .

      Precentral gyrus (CM)
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      .

      Right frontal pole (CM)
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      Chronic migraine patients had smaller frontal regions than episodic migraine patients.


      Medial frontal lobes (CM)
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      Chronic migraine patients had smaller frontal regions than episodic migraine patients.
      PCr/Pi ↓, Pi/Tp ↓
      • Welch KM
      • Levine SR
      • D'Andrea G
      • Schultz LR
      • Helpern JA
      Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.
      .

      [Mg+2] ↓
      • Welch KM
      • Levine SR
      • D'Andrea G
      • Schultz LR
      • Helpern JA
      Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.
      .

      PCr/Pi ↓
      • Schulz UG
      • Blamire AM
      • Davies P
      • Styles P
      • Rothwell PM.
      Normal cortical energy metabolism in migrainous stroke: A 31P-MR spectroscopy study.
      The hippocampusCastellano CA, et al.
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      left hippocampus (CM)
      • Yu Y
      • Zhao H
      • Dai L
      • Su Y
      • Wang X
      • Chen C
      • Shang Y
      • Ke J
      • Hu C.
      Headache frequency associates with brain microstructure changes in patients with migraine without aura.
      The amygdalaCastellano CA, et al.
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      left amygdala
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      Abbreviation. BA, Brodmann area; EM, episodic migraine; CM, chronic migraine; PCr, phosphocreatine; Pi, inorganic phosphate; TP, total phosphorus signal; ATP, adenosine triphosphate.
      low asterisk Lai KL et al. enrolled patients with CM without medication overuse headache, major depression or prior preventive treatment.
      A higher headache frequency was associated with smaller grey matter volume in the anterior cingulate cortex and hippocampus in EM and CM.
      According to current literature, most studies have chosen the occipital cortex as the region of interest, as aura, most commonly with visual symptoms, is attributed to this area in patients suffering from this type of migraine.
      • Reyngoudt H
      • Paemeleire K
      • Descamps B
      • De Deene Y
      • Achten E.
      31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients.
      § The orbitofrontal cortex includes the Brodmann areas 10, 11 and 47.
      • Kringelbach ML.
      The human orbitofrontal cortex: linking reward to hedonic experience.
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and 47.
      • Guenther FH
      • Tourville JA
      • Bohland JW.
      Speech Production.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      low asterisklow asterisk The lateral orbital gyrus includes the Brodmann area 47.

      Mackey S, Petrides M. Chapter 2: The Orbitofrontal Cortex: Sulcal and Gyral Morphology and Architecture". In: Zald DH, Rauch S, editors. New York: Oxford University Press; 2006. p. 34.

      †† Chronic migraine patients had smaller frontal regions than episodic migraine patients.
      ‡‡ This study
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      on young women with Polycystic Ovary Syndrome reported a direct association between mild insulin resistance and brain glucose hypometabolism, which was independent of overweight or obesity.

      Impaired Brain Glucose Metabolism in Migraine

      Specific areas of the brain, like the Brodmann areas 10 and 47, seem to suffer from glucose hypometabolism, both in subjects with insulin resistance and those with chronic migraine (Table 2). This evidence strengthens our hypothesis that brain insulin resistance, stemming from peripheral insulin resistance extending to the brain and impairing a correct astrocytes and/or neurons glucidic metabolism, may well trigger the neuronal cell stress implicated in migraine chronification. This hypothesis is supported by other experimental evidence. Firstly, GLUT4 is mainly expressed by the cerebral areas that regulate memory, learning, emotional and cognitive functions, ie, the hippocampus, the amygdala and the cerebral cortex.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      ,
      • Hamer JA
      • Testani D
      • Mansur RB
      • Lee Y
      • Subramaniapillai M
      • McIntyre RS.
      Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression.
      ,
      • Sankar R
      • Thamotharan S
      • Shin D
      • Moley KH
      • Devaskar SU.
      Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the developing mammalian brain.
      This suggests that the insulin signaling pathway may well play a key role in the utilization of glucose in these areas.
      • Hamer JA
      • Testani D
      • Mansur RB
      • Lee Y
      • Subramaniapillai M
      • McIntyre RS.
      Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression.
      Noteworthy is the fact that all these areas are affected both in subjects with insulin resistance and those with migraine (Table 2). Moreover, it has been observed in rats that insulin activation of GLUT4 improves glucose flux into neurons during periods of high metabolic demand, like during learning or other cognitive tasks.
      • McNay EC
      • Fries TM
      • Gold PE.
      Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task.
      ,
      • McNay EC
      • Gold PE.
      Food for thought: Fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation.
      ,
      • Pearson-Leary J
      • McNay EC.
      Novel roles for the insulin-regulated glucose transporter-4 in hippocampally dependent memory.
      Therefore, we hypothesize that, if this increased glucose demand is not satisfied – in subjects with episodic migraine partly due to postprandial hypoglycemia, and in subjects with chronic migraine partly due to brain insulin resistance – and if the brain is not able to use ketone bodies efficiently,
      • Gross EC
      • Lisicki M
      • Fischer D
      • Sándor PS
      • Schoenen J.
      The metabolic face of migraine - from pathophysiology to treatment.
      as should happen during fasting or carbohydrate restriction
      • Owen OE
      • Morgan AP
      • Kemp HG
      • Sullivan JM
      • Herrera MG
      • Cahill GF
      Brain metabolism during fasting.
      (conditions unlikely in Western countries with a carbohydrate-laden diet
      • Gross EC
      • Lisicki M
      • Fischer D
      • Sándor PS
      • Schoenen J.
      The metabolic face of migraine - from pathophysiology to treatment.
      ), then this would lead to an energy deficit, which would, in turn, trigger a migraine attack.
      Arnold et al. also observed that alterations in insulin levels might affect neuronal glucose uptake and metabolism via GLUT4 translocation in response to insulin-IRS1-AKT signaling in the brain regions involved in cognitive and emotional function.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.
      Moreover, data from a study on normal weight young women with mild insulin resistance (suffering from Polycystic ovary syndrome-PCOS) strengthens the hypothesis that insulin resistance could be a primary cause of cerebral glucose hypometabolism itself. Indeed, a direct association was observed between mild insulin resistance and brain glucose hypometabolism, whether the subjects were overweight and/or obese or not.
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      The same authors studied women with PCOS by fluorodeoxyglucose (FDG)-positron emission tomography (PET) and observed that they had a lower cerebral metabolic glucose rate and volumetric magnetic resonance imaging (MRI) evidenced a reduced volume of the frontal and parietal cortex.
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.

      Brain Morphometric Studies: a Decrease in Grey Matter Volume

      There is increasing evidence supporting an association between grey matter volume and chronic pain conditions.
      • May A.
      Chronic pain may change the structure of the brain.
      Indeed, based on MRI-morphometry, some studies demonstrated grey matter reductions in samples of patients with chronic back pain,
      • Apkarian AV.
      Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.
      ,
      • Fritz HC
      • McAuley JH
      • Wittfeld K
      • Hegenscheid K
      • Schmidt CO
      • Langner S
      • Lotze M.
      Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: Results from a population-based cohort study.
      fibromyalgia
      • Burgmer M
      • Gaubitz M
      • Konrad C
      • Wrenger M
      • Hilgart S
      • Heuft G
      • Pfleiderer B.
      Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia.
      ,
      • Robinson ME
      • Craggs JG
      • Price DD
      • Perlstein WM
      • Staud R.
      Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome.
      or osteoarthritis.
      • Rodriguez-Raecke R
      • Niemeier A
      • Ihle K
      • Ruether W
      • May A
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      Although most of these studies reported that pain is the main cause of grey matter volume reduction, other non-painful conditions do involve the presence of a grey matter reduction, often in the same brain areas, major depression
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      and PCOS
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      (Table 3).
      Table 3The Brain Areas Affected by a Decrease in Grey Matter Volume in Different Pathologies.
      Chronic migraineMajor depressionChronic back painPCOSFibromyalgiaOsteoarthritis
      The insular lobeInsular cortex
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      Lai KL et al. enrolled subjects with CM without medication overuse headache, major depression, or prior preventive treatment.
      Bilateral insula
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      Anterior insula
      • Fritz HC
      • McAuley JH
      • Wittfeld K
      • Hegenscheid K
      • Schmidt CO
      • Langner S
      • Lotze M.
      Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: Results from a population-based cohort study.
      Left mid insula
      • Robinson ME
      • Craggs JG
      • Price DD
      • Perlstein WM
      • Staud R.
      Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome.
      Right insular cortex
      • Rodriguez-Raecke R
      • Niemeier A
      • Ihle K
      • Ruether W
      • May A
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      The parietal lobeLai KL, et al.
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.


      Left parietal operculum
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      Left supramarginal cortex (BA 40)
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      .

      Right superior parietal cortex
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      The anterior cingular cortexYu Y, et al.
      • Yu Y
      • Zhao H
      • Dai L
      • Su Y
      • Wang X
      • Chen C
      • Shang Y
      • Ke J
      • Hu C.
      Headache frequency associates with brain microstructure changes in patients with migraine without aura.
      A higher headache frequency was associated with a smaller grey matter volume in the anterior cingulate cortex and hippocampus in EM and CM.


      Valfrè W, et al.
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      The orbitofrontal cortex includes the Brodmann areas 10, 11 and 47.113
      Wise T, et al.
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      Unlu E, et al.
      • Unlu E
      • Duran AH
      • Balcik C
      • Beker-Acay M
      • Yildiz Y
      • Tulmac OB
      • Unlu BS
      • Yucel A
      Brain diffusion changes in polycystic ovary syndrome.
      Burgmer M, et al.
      • Burgmer M
      • Gaubitz M
      • Konrad C
      • Wrenger M
      • Hilgart S
      • Heuft G
      • Pfleiderer B.
      Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia.


      Robinson ME, et al.
      • Robinson ME
      • Craggs JG
      • Price DD
      • Perlstein WM
      • Staud R.
      Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome.
      Rodriguez-Raecke R, et al.
      • Rodriguez-Raecke R
      • Niemeier A
      • Ihle K
      • Ruether W
      • May A
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      The temporal lobeSuperior temporal gyrus
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      The hippocampusLeft hippocampus
      • Yu Y
      • Zhao H
      • Dai L
      • Su Y
      • Wang X
      • Chen C
      • Shang Y
      • Ke J
      • Hu C.
      Headache frequency associates with brain microstructure changes in patients with migraine without aura.
      Left hippocampus
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      The frontal lobeCaudal middle frontal gyrus
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      .

      Precentral gyrus
      • Lai KL
      • Niddam DM.
      Brain metabolism and structure in chronic migraine.
      .

      Right frontal pole
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      CM patients had smaller frontal regions than episodic migraine patients.
      .

      Medial frontal lobes
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      CM patients had smaller frontal regions than episodic migraine patients.
      Left superior frontal cortex
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      The prefrotal cortexInferior frontal gyrus (BA 44, 45, 47)
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and.78
      • Valfrè W
      • Rainero I
      • Bergui M
      • Pinessi L.
      Voxel-based morphometry reveals gray matter abnormalities in migraine.
      The orbitofrontal cortex includes the Brodmann areas 10, 11 and 47.113
      .

      Lateral orbital gyrus (Brodmann area 47)
      The lateral orbital gyrus includes the Brodmann area 47.134
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      CM patients had smaller frontal regions than episodic migraine patients.
      .
      Medial prefrontal cortex
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      .

      Orbitofrontal cortex
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      .

      Inferior frontal gyrus (BA 44, 45, 47)
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and.78
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      .
      Ventromedial prefrontal cortex (BA 10, 11)
      BA 10 also shows a reduced glucose metabolism in subjects with insulin resistance and migraine.
      • Fritz HC
      • McAuley JH
      • Wittfeld K
      • Hegenscheid K
      • Schmidt CO
      • Langner S
      • Lotze M.
      Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: Results from a population-based cohort study.
      .

      Ventrolateral prefrontal cortex (BA 47)
      • Fritz HC
      • McAuley JH
      • Wittfeld K
      • Hegenscheid K
      • Schmidt CO
      • Langner S
      • Lotze M.
      Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: Results from a population-based cohort study.
      .

      Dorsomedial prefrontal cortex (BA 10)
      • Fritz HC
      • McAuley JH
      • Wittfeld K
      • Hegenscheid K
      • Schmidt CO
      • Langner S
      • Lotze M.
      Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: Results from a population-based cohort study.
      Dorsomedial prefrontal cortex
      • Unlu E
      • Duran AH
      • Balcik C
      • Beker-Acay M
      • Yildiz Y
      • Tulmac OB
      • Unlu BS
      • Yucel A
      Brain diffusion changes in polycystic ovary syndrome.
      .

      Dorsolateral prefrontal cortexes
      • Unlu E
      • Duran AH
      • Balcik C
      • Beker-Acay M
      • Yildiz Y
      • Tulmac OB
      • Unlu BS
      • Yucel A
      Brain diffusion changes in polycystic ovary syndrome.
      Inferior frontal gyrus (BA 44, 45, 47)
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and.78
      • Burgmer M
      • Gaubitz M
      • Konrad C
      • Wrenger M
      • Hilgart S
      • Heuft G
      • Pfleiderer B.
      Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia.
      Dorsolateral prefrontal cortex
      • Rodriguez-Raecke R
      • Niemeier A
      • Ihle K
      • Ruether W
      • May A
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      The amygdalaBurgmer M, et al.
      • Burgmer M
      • Gaubitz M
      • Konrad C
      • Wrenger M
      • Hilgart S
      • Heuft G
      • Pfleiderer B.
      Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia.
      Rodriguez-Raecke R, et al.
      • Rodriguez-Raecke R
      • Niemeier A
      • Ihle K
      • Ruether W
      • May A
      Brain gray matter decrease in chronic pain is the consequence and not the cause of pain.
      Abbreviation. BA, Brodmann area; CM, chronic migraine; EM, episodic migraine.
      low asterisk Lai KL et al. enrolled subjects with CM without medication overuse headache, major depression, or prior preventive treatment.
      A higher headache frequency was associated with a smaller grey matter volume in the anterior cingulate cortex and hippocampus in EM and CM.
      The inferior frontal gyrus includes the Brodmann areas 44, 45 and.
      • Guenther FH
      • Tourville JA
      • Bohland JW.
      Speech Production.
      § Valfrè et al. observed that CM patients had significantly more grey matter reductions in these areas than EM patients.
      The lateral orbital gyrus includes the Brodmann area 47.

      Mackey S, Petrides M. Chapter 2: The Orbitofrontal Cortex: Sulcal and Gyral Morphology and Architecture". In: Zald DH, Rauch S, editors. New York: Oxford University Press; 2006. p. 34.

      low asterisklow asterisk CM patients had smaller frontal regions than episodic migraine patients.
      BA 10 also shows a reduced glucose metabolism in subjects with insulin resistance and migraine.
      Moreover, differently to migraine headache a recent study observed that there is no reduction in grey matter volume in tension-type headache,
      • Chen WT
      • Chou KH
      • Lee PL
      • Hsiao FJ
      • Niddam DM
      • Lai KL
      • Fuh JL
      • Lin CP
      • Wang SJ.
      Comparison of gray matter volume between migraine and "strict-criteria" tension-type headache.
      suggesting that the metabolic alterations typical of migraine may play a role in these morphometric changes.
      Other studies suggest that the reduction in grey matter volume depends mainly on two features shared by chronic migraine, major depression, chronic back pain, polycystic ovary syndrome, fibromyalgia and osteoarthritis, ie, a higher incidence of insulin resistance and systemic inflammation, than what is observed in healthy controls.
      • Castellano CA
      • Baillargeon J-P
      • Nugent S
      • Tremblay S
      • Fortier M
      • Imbeault H
      • Duval J
      • Cunnane SC.
      Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: Possible link to mild insulin resistance.
      ,
      • Courties A
      • Sellam J.
      Osteoarthritis and type 2 diabetes mellitus: What are the links?.
      ,
      • Fava A
      • Plastino M
      • Cristiano D
      • Spanò A
      • Cristofaro S
      • Opipari C
      • Chillà A
      • Casalinuovo F
      • Colica C
      • De Bartolo M
      • Pirritano D
      • Bosco D.
      Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients.
      ,
      • Francisco V
      • Ruiz-Fernández C
      • Pino J
      • Mera A
      • González-Gay MA
      • Gómez R
      • Lago F
      • Mobasheri A
      • Gualillo O.
      Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases.
      ,
      • Hashem LE
      • Roffey DM
      • Alfasi AM
      • Papineau GD
      • Wai DC
      • Phan P
      • Kingwell SP
      • Wai EK.
      Exploration of the inter-relationships between obesity, physical inactivity, inflammation, and low back pain.
      ,
      • Hussain SM
      • Urquhart DM
      • Wang Y
      • Shaw JE
      • Magliano DJ
      • Wluka AE
      • Cicuttini FM.
      Fat mass and fat distribution are associated with low back pain intensity and disability: Results from a cohort study.
      ,
      • Loevinger BL
      • Muller D
      • Alonso C
      • Coe CL
      Metabolic syndrome in women with chronic pain.
      ,
      • Rasgon NL
      • Kenna HA.
      Insulin resistance in depressive disorders and Alzheimer's disease: Revisiting the missing link hypothesis.
      ,
      • Roffey DM
      • Budiansky A
      • Coyle MJ
      • Wai EK.
      Obesity and low back pain: Is there a weight of evidence to support a positive relationship?.
      ,
      • Sharma S
      • Fulton S.
      Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry.
      Interestingly, research data confirmed the efficacy of metformin in obtaining chronic pain relief.
      • Baeza-Flores GDC
      • Guzmán-Priego CG
      • Parra-Flores LI
      • Murbartián J
      • Torres-López JE
      • Granados-Soto V.
      Metformin: A prospective alternative for the treatment of chronic pain.
      This was further supported by evidence showing that a grey matter volume reduction is related to obesity
      • Kullmann S
      • Heni M
      • Hallschmid M
      • Fritsche A
      • Preissl H
      • Häring H-U.
      Brain insulin resistance at the Crossroads of metabolic and cognitive disorders in humans.
      and that hippocampal atrophy can be observed in individuals with impaired glucose tolerance and insulin resistance.
      • Kullmann S
      • Heni M
      • Hallschmid M
      • Fritsche A
      • Preissl H
      • Häring H-U.
      Brain insulin resistance at the Crossroads of metabolic and cognitive disorders in humans.
      Furthermore, a relationship between the metabolic syndrome and chronic pain was also observed.
      • Loevinger BL
      • Muller D
      • Alonso C
      • Coe CL
      Metabolic syndrome in women with chronic pain.
      All brain regions affected by a grey matter volume reduction in the aforementioned pathologies are dedicated to higher cognitive functions (mood regulation, memory, the regulation of affective states, emotion, awareness of bodily states and cognitive processing).
      • Chen XY
      • Chen Z-Y
      • Dong Z
      • Liu M-Q
      • Yu S-Y.
      Regional volume changes of the brain in migraine chronification.
      ,
      • Critchley HD
      • Mathias CJ
      • Dolan RJ.
      Neuroanatomical basis for first- and second-order representations of bodily states.
      ,
      • Rive MM
      • van Rooijen G
      • Veltman DJ
      • Phillips ML
      • Schene AH
      • Ruhé HG.
      Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies.
      ,
      • Strotzer M.
      One century of brain mapping using Brodmann areas.
      ,
      • Uddin LQ.
      Salience processing and insular cortical function and dysfunction.
      ,
      • Wise T
      • Radua J
      • Via E
      • Cardoner N
      • Abe O
      • Adams TM
      • Amico F
      • Cheng Y
      • Cole JH
      • de Azevedo Marques Périco C
      • Dickstein DP
      • Farrow TFD
      • Frodl T
      • Wagner G
      • Gotlib IH
      • Gruber O
      • Ham BJ
      • Job DE
      • Kempton MJ
      • Kim MJ
      • Koolschijn PCMP
      • Malhi GS
      • Mataix-Cols D
      • McIntosh AM
      • Nugent AC
      • O'Brien JT
      • Pezzoli S
      • Phillips ML
      • Sachdev PS
      • Salvadore G
      • Selvaraj S
      • Stanfield AC
      • Thomas AJ
      • van Tol MJ
      • van der Wee NJA
      • Veltman DJ
      • Young AH
      • Fu CH
      • Cleare AJ
      • Arnone D.
      Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
      Interestingly, the Brodmann area 47, part of the prefrontal cortex, is affected by a reduction in grey matter volume in 4/7 diseases listed in Table 3, ie, chronic migraine, major depression, chronic back pain and fibromyalgia. This area is related to memory and emotion
      • Strotzer M.
      One century of brain mapping using Brodmann areas.
      and in particular, to empathy.
      • Ueda K
      • Fujimoto G
      • Ubukata S
      • Murai T.
      Brodmann areas 11, 46, and 47: Emotion, memory, and empathy.
      As aforementioned, GLUT4 is predominantly expressed in the areas of the brain responsible for higher cognitive functions.
      • Arnold SE
      • Arvanitakis Z
      • Macauley-Rambach SL
      • Koenig AM
      • Wang H-Y
      • Ahima RS
      • Craft S
      • Gandy S
      • Buettner C
      • Stoeckel LE
      • Holtzman DM
      • Nathan DM.
      Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums.