Top

Published in:

Open Access 01-12-2019 | Migraine | Research article

A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs

Authors: Cherubino Di Lorenzo, Gianluca Coppola, Martina Bracaglia, Davide Di Lenola, Giulio Sirianni, Paolo Rossi, Giorgio Di Lorenzo, Vincenzo Parisi, Mariano Serrao, Mackenzie C. Cervenka, Francesco Pierelli

Published in: BMC Neurology | Issue 1/2019

Abstract

Background

A short ketogenic diet (KD) treatment can prevent migraine attacks and correct excessive cortical response. Here, we aim to prove if the KD-related changes of cortical excitability are primarily due to cerebral cortex activity or are modulated by the brainstem.

Methods

Through the stimulation of the right supraorbital division of the trigeminal nerve, we concurrently interictally recorded the nociceptive blink reflex (nBR) and the pain-related evoked potentials (PREP) in 18 migraineurs patients without aura before and after 1-month on KD, while in metabolic ketosis. nBR and PREP reflect distinct brain structures activation: the brainstem and the cerebral cortex respectively. We estimated nBR R2 component area-under-the-curve as well as PREP amplitude habituation as the slope pof the linear regression between the 1st and the 2nd block of 5 averaged responses.

Results

Following 1-month on KD, the mean number of attacks and headache duration reduced significantly. Moreover, KD significantly normalized the interictal PREP habituation (pre: + 1.8, post: − 9.1, p = 0.012), while nBR deficit of habituation did not change.

Conclusions

The positive clinical effects we observed in a population of migraineurs by a 1-month KD treatment coexists with a normalization at the cortical level, not in the brainstem, of the typical interictal deficit of habituation. These findings suggest that the cerebral cortex may be the primary site of KD-related modulation.

Trial registration

ClinicalTrials.gov NCT03775252 (retrospectively registered, December 09, 2018).

Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17:104. https://doi.org/10.1186/s10194-016-0699-5.CrossRefPubMedPubMedCentral

Diener H-C, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol. 2015;14:1010–22. https://doi.org/10.1016/S1474-4422(15)00198-2.CrossRefPubMed

Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache J Head Face Pain. 2018;58:238–75. https://doi.org/10.1111/head.13379.CrossRef

Rossi P, Di Lorenzo G, Malpezzi MG, Faroni J, Cesarino F, Di Lorenzo C, et al. Prevalence, pattern and predictors of use of complementary and alternative medicine (CAM) in migraine patients attending a headache clinic in Italy. Cephalalgia. 2005;25:493–506. https://doi.org/10.1111/j.1468-2982.2005.00898.x.CrossRefPubMed

Rossi P, Torelli P, Di Lorenzo C, Sances G, Manzoni GC, Tassorelli C, et al. Use of complementary and alternative medicine by patients with cluster headache: results of a multi-Centre headache clinic survey. Complement Ther Med. 2008;16:220–7. https://doi.org/10.1016/j.ctim.2007.05.002.CrossRefPubMed

Coppola G, Di Lorenzo C, Serrao M, Parisi V, Schoenen J, Pierelli F. Pathophysiological targets for non-pharmacological treatment of migraine. Cephalalgia. 2016;36:1103–11. https://doi.org/10.1177/0333102415620908.CrossRefPubMed

McDonald, McDonald L. The ketogenic diet. Lyle McDonald; 1998.

Strahlman RS. Can ketosis help migraine sufferers? A case report. Headache. 2006;46:182.CrossRef

Di Lorenzo C, Currà A, Sirianni G, Coppola G, Bracaglia M, Cardillo A, et al. Diet transiently improves migraine in two twin sisters: possible role of ketogenesis? Funct Neurol. 2013;28:305–8.PubMed

10.

Di Lorenzo C, Coppola G, Sirianni G, Di Lorenzo G, Bracaglia M, Di Lenola D, et al. Migraine improvement during short lasting ketogenesis: a proof-of-concept study. Eur J Neurol. 2015;22:170–7. https://doi.org/10.1111/ene.12550.CrossRefPubMed

11.

Di Lorenzo C, Coppola G, Di Lenola D, Evangelista M, Sirianni G, Rossi P, et al. Efficacy of modified Atkins ketogenic diet in chronic cluster headache: an open-label, single-arm, clinical trial. Front Neurol. 2018;9:64. https://doi.org/10.3389/FNEUR.2018.00064.CrossRefPubMedPubMedCentral

12.

Bigal ME, Lipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology. 2006;67:252–7.CrossRef

13.

Chai N, Scher AI, Moghekar A, Bond DS, Peterlin BL. Obesity and headache: part I--a systematic review of the epidemiology of obesity and headache. Headache. 2014;54:219–34.CrossRef

14.

Rainero I, Limone P, Ferrero M, Valfrè W, Pelissetto C, Rubino E, et al. Insulin sensitivity is impaired in patients with migraine. Cephalalgia. 2005;25:593–597. http://www.ncbi.nlm.nih.gov/pubmed/16033384.CrossRef

15.

Cavestro C, Rosatello A, Micca G, Ravotto M, Marino MP, Asteggiano G, et al. Insulin metabolism is altered in migraineurs: a new pathogenic mechanism for migraine? Headache. 2007;47:1436–42.CrossRef

16.

Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy. Continuum (Minneap Minn). 2013;19(3 Epilepsy):756–66. https://doi.org/10.1212/01.CON.0000431396.23852.56.CrossRef

17.

Cantello R, Varrasi C, Tarletti R, Cecchin M, D’Andrea F, Veggiotti P, et al. Ketogenic diet: electrophysiological effects on the normal human cortex. Epilepsia. 2007;48:1756–63.CrossRef

18.

Blaise JH, Ruskin DN, Koranda JL, Masino SA. Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. Physiol Rep. 2015;3:e12411.CrossRef

19.

Di Lorenzo C, Coppola G, Bracaglia M, Di Lenola D, Evangelista M, Sirianni G, et al. Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain. 2016;17:58. https://doi.org/10.1186/s10194-016-0650-9.CrossRefPubMedPubMedCentral

20.

Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization in primary headaches. J Headache Pain. 2013;14:65. https://doi.org/10.1186/1129-2377-14-65.CrossRefPubMedPubMedCentral

21.

Ayzenberg I, Obermann M, Nyhuis P, Gastpar M, Limmroth V, Diener HC, et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia. 2006;26:1106–14. https://doi.org/10.1111/j.1468-2982.2006.01183.x.CrossRefPubMed

22.

Obermann M, Yoon M-S, Ese D, Maschke M, Kaube H, Diener H-C, et al. Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia. Neurology. 2007;69:835–41. https://doi.org/10.1212/01.wnl.0000269670.30045.6b.CrossRefPubMed

23.

Lefaucheur J-P, Ahdab R, Ayache SS, Lefaucheur-Ménard I, Rouie D, Tebbal D, et al. Pain-related evoked potentials: a comparative study between electrical stimulation using a concentric planar electrode and laser stimulation using a CO2 laser. Neurophysiol Clin Neurophysiol. 2012;42:199–206. https://doi.org/10.1016/j.neucli.2011.12.003.CrossRef

24.

Di Clemente L, Coppola G, Magis D, Fumal A, De Pasqua V, Di Piero V, et al. Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine? Brain. 2007;130:765–70.CrossRef

25.

Coppola G, Di Lorenzo C, Bracaglia M, Di Lenola D, Parisi V, Perrotta A, et al. Lateralized nociceptive blink reflex habituation deficit in episodic cluster headache: correlations with clinical features. Cephalalgia. 2015;35:600–7. https://doi.org/10.1177/0333102414550418.CrossRefPubMed

26.

Harris JD. Habituatory response decrement in the intact organism. Psychol Bull. 1943;40:385–422.CrossRef

27.

Di Lorenzo C, Coppola G, Currà A, Grieco G, Santorelli FM, Lepre C, et al. Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism. Cephalalgia. 2012;32:1189–97. https://doi.org/10.1177/0333102412461890.CrossRefPubMed

28.

Di Lorenzo C, Di Lorenzo G, Daverio A, Pasqualetti P, Coppola G, Giannoudas I, et al. The Val66Met polymorphism of the BDNF gene influences trigeminal pain-related evoked responses. J Pain. 2012;13:866–73. https://doi.org/10.1016/j.jpain.2012.05.014.CrossRefPubMed

29.

Di Lorenzo C, Daverio A, Pasqualetti P, Coppola G, Giannoudas I, Barone Y, et al. The upstream variable number tandem repeat polymorphism of the monoamine oxidase type a gene influences trigeminal pain-related evoked responses. Eur J Neurosci. 2014;39:501–7. https://doi.org/10.1111/ejn.12458.CrossRefPubMed

30.

Obermann M, Pleger B, de Greiff A, Stude P, Kaube H, Diener H-C, et al. Temporal summation of trigeminal pain in human anterior cingulate cortex. Neuroimage. 2009;46:193–200. https://doi.org/10.1016/j.neuroimage.2009.01.038.CrossRefPubMed

31.

Ring C, Kavussanu M, Willoughby AR. Emotional modulation of pain-related evoked potentials. Biol Psychol. 2013;93:373–6. https://doi.org/10.1016/j.biopsycho.2013.04.006.CrossRefPubMedPubMedCentral

32.

Watson TD, Petrakis IL, Edgecombe J, Perrino A, Krystal JH, Mathalon DH. Modulation of the cortical processing of novel and target stimuli by drugs affecting glutamate and GABA neurotransmission. Int J Neuropsychopharmacol. 2009;12:357–70. https://doi.org/10.1017/S1461145708009334.CrossRefPubMed

33.

Koppel SJ, Swerdlow RH. Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem Int. 2018;117:114–25. https://doi.org/10.1016/j.neuint.2017.05.019.CrossRefPubMed

34.

Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002;277:30409–12. https://doi.org/10.1074/jbc.R200006200.CrossRefPubMed

35.

Wang ZJ, Bergqvist C, Hunter JV, Jin D, Wang D-J, Wehrli S, et al. In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy--exploration of GABA levels in a ketogenic diet. Magn Reson Med. 2003;49:615–9. https://doi.org/10.1002/mrm.10429.CrossRefPubMed

36.

Melø TM, Nehlig A, Sonnewald U. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem Int. 2006;48:498–507. https://doi.org/10.1016/j.neuint.2005.12.037.CrossRefPubMed

37.

Dienel GA. Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int. 2013;63:244–58. https://doi.org/10.1016/j.neuint.2013.06.015.CrossRefPubMedPubMedCentral

38.

Fisler JS, Shimizu H, Bray GA. Brain 3-hydroxybutyrate, glutamate, and GABA in a rat model of dietary obesity. Physiol Behav. 1989;45:571–7.CrossRef

39.

Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.CrossRef

40.

Suzuki Y, Takahashi H, Fukuda M, Hino H, Kobayashi K, Tanaka J, et al. Beta-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes. Brain Res. 2009;1268:17–23.CrossRef

41.

Erecińska M, Nelson D, Daikhin Y, Yudkoff M. Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J Neurochem. 1996;67:2325–34.CrossRef

42.

Kawamura M, Ruskin DN, Geiger JD, Boison D, Masino SA. Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res. 2014;55:2254–60.CrossRef

43.

Nylen K, Velazquez JL, Likhodii SS, Cortez MA, Shen L, Leshchenko Y, et al. A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exp Neurol. 2008;210:449–57.CrossRef

44.

Simeone TA, Samson KK, Matthews SA, Simeone KA. In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv 1.1α knockout mice. Epilepsia. 2014;55:e44–9.CrossRef

45.

Yang L, Zhao J, Milutinovic PS, Brosnan RJ, Eger EI, Sonner JM. Anesthetic properties of the ketone bodies beta-hydroxybutyric acid and acetone. Anesth Analg. 2007;105:673–9. https://doi.org/10.1213/01.ane.0000278127.68312.dc.CrossRefPubMed

46.

Barbiroli B, Montagna P, Cortelli P, Funicello R, Iotti S, Monari L, et al. Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology. 1992;42:1209–14.CrossRef

47.

Sándor P, Dydak U, Schoenen J, Kollias SS, Hess K, Boesiger P, et al. MR-spectroscopic imaging during visual stimulation in subgroups of migraine with aura. Cephalalgia. 2005;25:507–18.CrossRef

48.

Di Lorenzo C, Pierelli F, Coppola G, Grieco GSS, Rengo C, Ciccolella M, et al. Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs. Neurology. 2009;72:1588–94. https://doi.org/10.1212/WNL.0b013e3181a41269.CrossRefPubMed

49.

Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006;60:223–35.CrossRef

50.

Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 2007;145:256–64.CrossRef

51.

Bough K. Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. Epilepsia. 2008;8:91–3.CrossRef

52.

do K, Vallejo J, Rho JM. Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem. 2010;114:130–41.

53.

Holstege G. No title. In: Paxinos G, editor. The human nervous system. 1990th -ed. ed. London: Academic; 1990. p. 287–96.CrossRef

54.

Esteban A. A neurophysiological approach to brainstem reflexes. Blink reflex. Neurophysiol Clin. 1999;29:7–38. https://doi.org/10.1016/S0987-7053(99)80039-2.CrossRefPubMed

55.

Di Lorenzo C, Coppola G, Pierelli F. A case of cluster headache treated with rotigotine: clinical and neurophysiological correlates. Cephalalgia. 2013;33:1272–6. https://doi.org/10.1177/0333102413490346.CrossRefPubMed

56.

Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36:587–97. https://doi.org/10.1016/j.tins.2013.07.001.CrossRefPubMedPubMedCentral

57.

Kossoff EH, Hartman AL. Ketogenic diets: new advances for metabolism-based therapies. Curr Opin Neurol. 2012;25:173–8. https://doi.org/10.1097/WCO.0b013e3283515e4a.CrossRefPubMedPubMedCentral

58.

Di Clemente L, Puledda F, Biasiotta A, Viganò A, Vicenzini E, Truini A, et al. Topiramate modulates habituation in migraine: evidences from nociceptive responses elicited by laser evoked potentials. J Headache Pain. 2013;14:25. https://doi.org/10.1186/1129-2377-14-25.CrossRefPubMedPubMedCentral

59.

Hebestreit JM, May A. The enigma of site of action of migraine preventives: no effect of metoprolol on trigeminal pain processing in patients and healthy controls. J Headache Pain. 2017;18:116.CrossRef

60.

Hebestreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One. 2017;12:e0184406. https://doi.org/10.1371/journal.pone.0184406.CrossRefPubMedPubMedCentral

61.

Nyrke T, Kangasniemi P, Lang AH, Petersen E. Steady-state visual evoked potentials during migraine prophylaxis by propranolol and femoxetine. Acta Neurol Scand. 1984;69:9–14.CrossRef

62.

Palmer JE, Chronicle EP, Rolan P, Mulleners WM. Cortical hyperexcitability is cortical under-inhibition: evidence from a novel functional test of migraine patients. Cephalalgia. 2000;20:525–32.CrossRef

63.

Sándor PS, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache. 2000;40:30–5.CrossRef

64.

Schoenen J. Beta blockers and the central nervous system. Cephalalgia. 1986;6(Suppl 5):47–54.CrossRef

65.

Schoenen J, De NAM, Timsit-berthier M, Timsit MJ. Contingent negative variation and efficacy of beta-blocking agents. In migraine. Cephalalgia. 1986;6:229–33.CrossRef

66.

de Tommaso M, Brighina F, Fierro B, Francesco VD, Santostasi R, Sciruicchio V, et al. Effects of high-frequency repetitive transcranial magnetic stimulation of primary motor cortex on laser-evoked potentials in migraine. J Headache Pain. 2010;11:505–12. https://doi.org/10.1007/s10194-010-0247-7.CrossRefPubMedPubMedCentral

67.

de Tommaso M, Guido M, Sardaro M, Serpino C, Vecchio E, De S, et al. Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients. Neurosci Lett. 2008;442:81–5.CrossRef

68.

Vecchio E, Ricci K, Montemurno A, Delussi M, Invitto S, de Tommaso M. Effects of left primary motor and dorsolateral prefrontal cortex transcranial direct current stimulation on laser-evoked potentials in migraine patients and normal subjects. Neurosci Lett. 2016;626:149–57. https://doi.org/10.1016/j.neulet.2016.05.034.CrossRefPubMed

69.

de Tommaso M, Libro G, Guido M, Losito L, Lamberti P, Livrea P. Habituation of single CO2 laser-evoked responses during interictal phase of migraine. J Headache Pain. 2005;6:195–8. https://doi.org/10.1007/s10194-005-0183-0.CrossRefPubMedPubMedCentral

70.

de Tommaso M, Santostasi R, Devitofrancesco V, Franco G, Vecchio E, Delussi M, et al. A comparative study of cortical responses evoked by transcutaneous electrical vs CO2 laser stimulation. Clin Neurophysiol. 2011;122:2482–7. https://doi.org/10.1016/j.clinph.2011.05.006.CrossRefPubMed

Title: A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs
Authors: Cherubino Di Lorenzo
Gianluca Coppola
Martina Bracaglia
Davide Di Lenola
Giulio Sirianni
Paolo Rossi
Giorgio Di Lorenzo
Vincenzo Parisi
Mariano Serrao
Mackenzie C. Cervenka
Francesco Pierelli
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Migraine
Evoked Potential
Headache
Evoked Potential
Published in: BMC Neurology / Issue 1/2019
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-019-1351-1

At a glance: The STEP trials

Springer Medicine

A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2019

Inflammatory profiling of patients with familial amyloid polyneuropathy

Differences and diversity of autoimmune encephalitis in 77 cases from a single tertiary care center

Paranasal sinus air suction for immediate pain relief of acute migraine – a randomized, double blind pilot study

Understanding side effects of therapy for myasthenia gravis and their impact on daily life

Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy

Physio4FMD: protocol for a multicentre randomised controlled trial of specialist physiotherapy for functional motor disorder