Increased neural connectivity between the hypothalamus and cortical resting-state functional networks in chronic migraine

  • Gianluca Coppola
  • Antonio Di Renzo
  • Barbara Petolicchio
  • Emanuele Tinelli
  • Cherubino Di Lorenzo
  • Mariano Serrao
  • Valentina Calistri
  • Stefano Tardioli
  • Gaia Cartocci
  • Vincenzo ParisiEmail author
  • Francesca Caramia
  • Vittorio Di Piero
  • Francesco Pierelli
Original Communication



The findings of resting-state functional MRI studies have suggested that abnormal functional integration between interconnected cortical networks characterises the brain of patients with migraine. The aim of this study was to investigate the functional connectivity between the hypothalamus, brainstem, considered as the migraine generator, and the following areas/networks that are reportedly involved in the pathophysiology of migraine: default mode network (DMN), executive control network, dorsal attention system, and primary and dorsoventral visual networks.


Twenty patients with chronic migraine (CM) without medication overuse and 20 healthy controls (HCs) were prospectively recruited. All study participants underwent 3-T MRI scans using a 7.5-min resting-state protocol. Using a seed-based approach, we performed a ROI-to-ROI analysis selecting the hypothalamus as the seed.


Compared to HCs, patients with CM showed significantly increased neural connectivity between the hypothalamus and brain areas belonging to the DMN and dorsal visual network. We did not detect any connectivity abnormalities between the hypothalamus and the brainstem. The correlation analysis showed that the severity of the migraine headache was positively correlated with the connectivity strength of the hypothalamus and negatively with the connectivity strength of the medial prefrontal cortex, which belongs to the DMN.


These data provide evidence for hypothalamic involvement in large-scale reorganisation at the functional-network level in CM and in proportion with the perceived severity of the migraine pain.


Chronic migraine Resting state fMRI Default mode network Dorsal visual network 



The contribution of the G.B. Bietti Foundation in this paper was supported by the Italian Ministry of Health and the Fondazione Roma.

Compliance with ethical standards

Conflicts of interest

The authors declare no financial or other conflicts of interest.

Ethical standard

The study was approved by ethical review board of the Faculty of Medicine, University of Rome, Italy. Written informed consent was obtained from all participants in this study.


  1. 1.
    Haanes KA, Edvinsson L (2019) Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs. CrossRefPubMedGoogle Scholar
  2. 2.
    Coppola G, Di Lorenzo C, Serrao M et al (2016) Pathophysiological targets for non-pharmacological treatment of migraine. Cephalalgia 36:1103–1111. CrossRefPubMedGoogle Scholar
  3. 3.
    ICHD (2018) Headache classification committee of the international headache society (IHS) The International Classification of Headache disorders, 3rd edition. Cephalalgia 38:1–211. CrossRefGoogle Scholar
  4. 4.
    May A (2017) Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci 38:125–130. CrossRefPubMedGoogle Scholar
  5. 5.
    Schulte LH, Allers A, May A (2017) Hypothalamus as a mediator of chronic migraine. Neurology 88:2011–2016. CrossRefPubMedGoogle Scholar
  6. 6.
    Lerebours F, Boulanouar K, Barège M et al (2019) Functional connectivity of hypothalamus in chronic migraine with medication overuse. Cephalalgia. CrossRefPubMedGoogle Scholar
  7. 7.
    Lee MJ, Park BY, Cho S et al (2019) Increased connectivity of pain matrix in chronic migraine: a resting-state functional MRI study. J Headache Pain 20:29. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Coppola G, Di Renzo A, Petolicchio B et al (2019) Aberrant interactions of cortical networks in chronic migraine. Neurology 92:e2550–e2558. CrossRefPubMedGoogle Scholar
  9. 9.
    Weiller C, May A, Limmroth V et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660CrossRefGoogle Scholar
  10. 10.
    Bahra A, Matharu MS, Buchel C et al (2001) Brainstem activation specific to migraine headache. Lancet 357:1016–1017CrossRefGoogle Scholar
  11. 11.
    Stankewitz A, May A (2011) Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology 77:476–482CrossRefGoogle Scholar
  12. 12.
    Olesen J, Bes A, Kunkel R, Lance JW, Nappi G, Pfaffenrath V, Rose FC, Schoenberg BS, Soyka D, Tfelt-Hansen P, Welch KMA (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629–808. doi: 10.1177/0333102413485658.Google Scholar
  13. 13.
    Coppola G, Petolicchio B, Di Renzo A et al (2017) Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features. J Headache Pain 18:115. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Georg Thieme, ThiemeGoogle Scholar
  15. 15.
    Whitfield-Gabrieli S, Nieto-Castanon A (2012) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2:125–141. CrossRefPubMedGoogle Scholar
  16. 16.
    Pujol J, Macià D, Garcia-Fontanals A et al (2014) The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. PAIN® 155:1492–1503. CrossRefGoogle Scholar
  17. 17.
    Shen W, Tu Y, Gollub RL et al (2019) Visual network alterations in brain functional connectivity in chronic low back pain: a resting state functional connectivity and machine learning study. NeuroImage Clin 22:101775. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Messina R, Rocca MA, Colombo B et al (2018) Gray matter volume modifications in migraine. Neurology 91:e280–e292. CrossRefPubMedGoogle Scholar
  19. 19.
    Baroncini M, Jissendi P, Balland E et al (2012) MRI atlas of the human hypothalamus. Neuroimage 59:168–180. CrossRefPubMedGoogle Scholar
  20. 20.
    Sakai Y, Dobson C, Diksic M et al (2008) Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 70:431–439. CrossRefPubMedGoogle Scholar
  21. 21.
    Matharu MS, Bartsch T, Ward N et al (2004) Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 127:220–230. CrossRefPubMedGoogle Scholar
  22. 22.
    Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A (2007) Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache 47:996–1003CrossRefGoogle Scholar
  23. 23.
    Denuelle M, Fabre N, Payoux P et al (2007) Hypothalamic activation in spontaneous migraine attacks. Headache 47:1418–1426PubMedGoogle Scholar
  24. 24.
    Maniyar F, Sprenger T, Monteith T et al (2014) Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137:232–241CrossRefGoogle Scholar
  25. 25.
    Schulte LH, May A (2016) The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139:1987–1993. CrossRefPubMedGoogle Scholar
  26. 26.
    Raichle M, MacLeod AM, Snyder AZ et al (2001) A default mode of brain function. Proc Natl Acad Sci USA 98:676–682CrossRefGoogle Scholar
  27. 27.
    Gazzaley A, Nobre AC (2012) Top-down modulation: bridging selective attention and working memory. Trends Cogn Sci 16:129–135. CrossRefPubMedGoogle Scholar
  28. 28.
    Heinzel S, Lorenz RC, Duong Q-L et al (2017) Prefrontal-parietal effective connectivity during working memory in older adults. Neurobiol Aging 57:18–27. CrossRefPubMedGoogle Scholar
  29. 29.
    Galletti C, Fattori P (2018) The dorsal visual stream revisited: Stable circuits or dynamic pathways? Cortex 98:203–217. CrossRefPubMedGoogle Scholar
  30. 30.
    Corbetta M, Shulman GL (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev 3:201–215CrossRefGoogle Scholar
  31. 31.
    Vossel S, Geng JJ, Fink GR (2014) Dorsal and ventral attention systems. Neuroscientist 20:150–159. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mishkin M, Ungerleider LG, Macko KA (1983) Object vision and spatial vision: two cortical pathways. Trends Neurosci 6:414–417. CrossRefGoogle Scholar
  33. 33.
    Bekrater-Bodmann R, Foell J, Diers M et al (2014) The importance of synchrony and temporal order of visual and tactile input for illusory limb ownership experiences—an fMRI study applying virtual reality. PLoS ONE 9:e87013. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Boulloche N, Denuelle M, Payoux P et al (2010) Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry 81:978–984CrossRefGoogle Scholar
  35. 35.
    Mehnert J, Bader D, Nolte G, May A (2019) Visual input drives increased occipital responsiveness and harmonized oscillations in multiple cortical areas in migraineurs. NeuroImage Clin 23:101815. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Razavi BM, Hosseinzadeh H (2017) A review of the role of orexin system in pain modulation. Biomed Pharmacother 90:187–193. CrossRefPubMedGoogle Scholar
  37. 37.
    Roohbakhsh A, Alavi MS, Azhdari-Zarmehri H (2018) The orexinergic (hypocretin) system and nociception: an update to supraspinal mechanisms. Curr Med Chem 25:3917–3929. CrossRefPubMedGoogle Scholar
  38. 38.
    Jin J, Chen Q, Qiao Q et al (2016) Orexin neurons in the lateral hypothalamus project to the medial prefrontal cortex with a rostro-caudal gradient. Neurosci Lett 621:9–14. CrossRefPubMedGoogle Scholar
  39. 39.
    Wiech K, Ploner M, Tracey I (2008) Neurocognitive aspects of pain perception. Trends Cogn Sci 12:306–313. CrossRefPubMedGoogle Scholar
  40. 40.
    Tu Y, Jung M, Gollub RL et al (2019) Abnormal medial prefrontal cortex functional connectivity and its association with clinical symptoms in chronic low back pain. Pain 160:1308–1318. CrossRefPubMedGoogle Scholar
  41. 41.
    Schreiber KL, Loggia ML, Kim J et al (2017) Painful after-sensations in fibromyalgia are linked to catastrophizing and differences in brain response in the medial temporal lobe. J Pain 18:855–867. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    James MH, Campbell EJ, Dayas CV (2017) Role of the orexin/hypocretin system in stress-related psychiatric disorders. Current topics in behavioral neurosciences. Springer, Cham, pp 197–219Google Scholar
  43. 43.
    Grafe LA, Eacret D, Luz S et al (2017) Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress. Neuroscience 348:313–323. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sarchielli P, Rainero I, Coppola F et al (2008) Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid. Cephalalgia 28:714–722. CrossRefPubMedGoogle Scholar
  45. 45.
    Rainero I, Ferrero M, Rubino E et al (2006) Endocrine function is altered in chronic migraine patients with medication-overuse. Headache J Head Face Pain 46:597–603. CrossRefGoogle Scholar
  46. 46.
    Siva ZO, Uluduz D, Keskin FE et al (2018) Determinants of glucose metabolism and the role of NPY in the progression of insulin resistance in chronic migraine. Cephalalgia 38:1773–1781. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gianluca Coppola
    • 1
  • Antonio Di Renzo
    • 2
  • Barbara Petolicchio
    • 3
  • Emanuele Tinelli
    • 3
  • Cherubino Di Lorenzo
    • 4
  • Mariano Serrao
    • 1
  • Valentina Calistri
    • 3
  • Stefano Tardioli
    • 3
  • Gaia Cartocci
    • 3
  • Vincenzo Parisi
    • 2
    Email author
  • Francesca Caramia
    • 3
  • Vittorio Di Piero
    • 3
  • Francesco Pierelli
    • 1
    • 5
  1. 1.Department of Medico-Surgical Sciences and BiotechnologiesSapienza University of Rome Polo PontinoLatinaItaly
  2. 2.Research Unit of Neurophysiology of Vision and NeurophthalmologyIRCCS-Fondazione BiettiRomeItaly
  3. 3.Department of Human NeurosciencesSapienza University of RomeRomeItaly
  4. 4.Don Carlo Gnocchi Onlus FoundationMilanItaly
  5. 5.IRCCS-NeuromedPozzilliItaly

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