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

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, 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

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).

Keywords: Habituation; Ketogenesis; Ketogenic diet; Migraine; Nociceptive blink reflex; Pain-related evoked potentials.

Conflict of interest statement

Gianluca Coppola is an Editorial Board Member of BMC Neurology. The authors declare that they have no other competing interests.

Figures

Fig. 1
Fig. 1
Explicative block recordings of nociceptive blink reflex (nBR) elicited homolaterally and contralaterally to the stimulated side, and pain-related evoked potentials (PREP) in a patient with migraine recorded before [upper panel] and after a 1-month ketogenic diet, during metabolic ketosis [lower panel]
Fig. 2
Fig. 2
Habituation of the nociceptive blink reflex (nBR) R2 component area-under-the-curve (AUC) [a homolateral; b contralateral to the stimulated side] and pain-related evoked potentials (PREP) N-P amplitude [c] slopes in healthy controls and migraine patients before and after a 1-month ketogenic diet, during metabolic ketosis, in two blocks of five averaged responses expressed as a percentage of the first block

References

    1. Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17:104. doi: 10.1186/s10194-016-0699-5.
    1. Diener H-C, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol. 2015;14:1010–1022. doi: 10.1016/S1474-4422(15)00198-2.
    1. Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache J Head Face Pain. 2018;58:238–275. doi: 10.1111/head.13379.
    1. 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. doi: 10.1111/j.1468-2982.2005.00898.x.
    1. 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;16:220–227. doi: 10.1016/j.ctim.2007.05.002.
    1. Coppola G, Di Lorenzo C, Serrao M, Parisi V, Schoenen J, Pierelli F. Pathophysiological targets for non-pharmacological treatment of migraine. Cephalalgia. 2016;36:1103–1111. doi: 10.1177/0333102415620908.
    1. McDonald, McDonald L. The ketogenic diet. Lyle McDonald. 1998.
    1. Strahlman RS. Can ketosis help migraine sufferers? A case report. Headache. 2006;46:182. doi: 10.1111/j.1526-4610.2006.00321_5.x.
    1. 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;28:305–308.
    1. 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;22:170–177. doi: 10.1111/ene.12550.
    1. 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. doi: 10.3389/FNEUR.2018.00064.
    1. Bigal ME, Lipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology. 2006;67:252–257. doi: 10.1212/01.wnl.0000225052.35019.f9.
    1. 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;54:219–234. doi: 10.1111/head.12296.
    1. Rainero I, Limone P, Ferrero M, Valfrè W, Pelissetto C, Rubino E, Gentile S, Lo Giudice R, Pinessi L. Insulin Sensitivity is Impaired in Patients with Migraine. Cephalalgia. 2005;25(8):593–597. doi: 10.1111/j.1468-2982.2005.00928.x.
    1. 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;47:1436–1442. doi: 10.1111/j.1526-4610.2007.00719.x.
    1. Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy. Continuum (Minneap Minn) 2013;19(3 Epilepsy):756–766. doi: 10.1212/01.CON.0000431396.23852.56.
    1. 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;48:1756–1763. doi: 10.1111/j.1528-1167.2007.01156.x.
    1. 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. doi: 10.14814/phy2.12411.
    1. 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. doi: 10.1186/s10194-016-0650-9.
    1. Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization in primary headaches. J Headache Pain. 2013;14:65. doi: 10.1186/1129-2377-14-65.
    1. 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;26:1106–1114. doi: 10.1111/j.1468-2982.2006.01183.x.
    1. 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;69:835–841. doi: 10.1212/01.wnl.0000269670.30045.6b.
    1. 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. doi: 10.1016/j.neucli.2011.12.003.
    1. 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;130:765–770. doi: 10.1093/brain/awl351.
    1. 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;35:600–607. doi: 10.1177/0333102414550418.
    1. Harris JD. Habituatory response decrement in the intact organism. Psychol Bull. 1943;40:385–422. doi: 10.1037/h0053918.
    1. 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;32:1189–1197. doi: 10.1177/0333102412461890.
    1. 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;13:866–873. doi: 10.1016/j.jpain.2012.05.014.
    1. 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;39:501–507. doi: 10.1111/ejn.12458.
    1. 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. doi: 10.1016/j.neuroimage.2009.01.038.
    1. Ring C, Kavussanu M, Willoughby AR. Emotional modulation of pain-related evoked potentials. Biol Psychol. 2013;93:373–376. doi: 10.1016/j.biopsycho.2013.04.006.
    1. 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;12:357–370. doi: 10.1017/S1461145708009334.
    1. Koppel SJ, Swerdlow RH. Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem Int. 2018;117:114–125. doi: 10.1016/j.neuint.2017.05.019.
    1. Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002;277:30409–30412. doi: 10.1074/jbc.R200006200.
    1. 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;49:615–619. doi: 10.1002/mrm.10429.
    1. Melø TM, Nehlig A, Sonnewald U. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem Int. 2006;48:498–507. doi: 10.1016/j.neuint.2005.12.037.
    1. Dienel GA. Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int. 2013;63:244–258. doi: 10.1016/j.neuint.2013.06.015.
    1. Fisler JS, Shimizu H, Bray GA. Brain 3-hydroxybutyrate, glutamate, and GABA in a rat model of dietary obesity. Physiol Behav. 1989;45:571–577. doi: 10.1016/0031-9384(89)90075-9.
    1. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–658. doi: 10.1096/fasebj.9.8.7768357.
    1. 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. doi: 10.1016/j.brainres.2009.02.074.
    1. 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;67:2325–2334. doi: 10.1046/j.1471-4159.1996.67062325.x.
    1. Kawamura M, Ruskin DN, Geiger JD, Boison D, Masino SA. Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res. 2014;55:2254–2260. doi: 10.1194/jlr.M046755.
    1. 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;210:449–457. doi: 10.1016/j.expneurol.2007.11.015.
    1. 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–e49. doi: 10.1111/epi.12603.
    1. 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;105:673–679. doi: 10.1213/01.ane.0000278127.68312.dc.
    1. 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;42:1209–1214. doi: 10.1212/WNL.42.6.1209.
    1. 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;25:507–518. doi: 10.1111/j.1468-2982.2005.00900.x.
    1. 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;72:1588–1594. doi: 10.1212/WNL.0b013e3181a41269.
    1. 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;60:223–235. doi: 10.1002/ana.20899.
    1. 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;145:256–264. doi: 10.1016/j.neuroscience.2006.11.065.
    1. Bough K. Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. Epilepsia. 2008;8:91–93. doi: 10.1111/j.1528-1167.2008.01846.x.
    1. do K, Vallejo J, Rho JM. Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem. 2010;114:130–141.
    1. Holstege G. No title. In: Paxinos G, editor. The human nervous system. 1990th -ed. London: Academic; 1990. pp. 287–296.
    1. Esteban A. A neurophysiological approach to brainstem reflexes. Blink reflex. Neurophysiol Clin. 1999;29:7–38. doi: 10.1016/S0987-7053(99)80039-2.
    1. Di Lorenzo C, Coppola G, Pierelli F. A case of cluster headache treated with rotigotine: clinical and neurophysiological correlates. Cephalalgia. 2013;33:1272–1276. doi: 10.1177/0333102413490346.
    1. 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;36:587–597. doi: 10.1016/j.tins.2013.07.001.
    1. Kossoff EH, Hartman AL. Ketogenic diets: new advances for metabolism-based therapies. Curr Opin Neurol. 2012;25:173–178. doi: 10.1097/WCO.0b013e3283515e4a.
    1. 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. doi: 10.1186/1129-2377-14-25.
    1. 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. doi: 10.1186/s10194-017-0827-x.
    1. Hebestreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One. 2017;12:e0184406. doi: 10.1371/journal.pone.0184406.
    1. 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. doi: 10.1111/j.1600-0404.1984.tb07773.x.
    1. 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;20:525–532. doi: 10.1046/j.1468-2982.2000.00075.x.
    1. 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;40:30–35. doi: 10.1046/j.1526-4610.2000.00005.x.
    1. Schoenen J. Beta blockers and the central nervous system. Cephalalgia. 1986;6(Suppl 5):47–54. doi: 10.1177/03331024860060S506.
    1. Schoenen J, De NAM, Timsit-berthier M, Timsit MJ. Contingent negative variation and efficacy of beta-blocking agents. In migraine. Cephalalgia. 1986;6:229–233. doi: 10.1046/j.1468-2982.1986.0604229.x.
    1. 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;11:505–512. doi: 10.1007/s10194-010-0247-7.
    1. 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;442:81–85. doi: 10.1016/j.neulet.2008.06.076.
    1. 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;626:149–157. doi: 10.1016/j.neulet.2016.05.034.
    1. 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;6:195–198. doi: 10.1007/s10194-005-0183-0.
    1. 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;122:2482–2487. doi: 10.1016/j.clinph.2011.05.006.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe