Current Pain and Headache Reports

, Volume 14, Issue 2, pp 151–159 | Cite as

Deep Brain Stimulation in Cluster Headache: Hypothalamus or Midbrain Tegmentum?

  • Manjit S. MatharuEmail author
  • Ludvic Zrinzo


Functional and structural neuroimaging studies have provided pivotal insights into the pathophysiology of trigeminal autonomic cephalalgias (TACs), particularly cluster headache (CH). Functional imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in TACs have reported activation of the posterior hypothalamus. A structural neuroimaging study using voxel-based morphometry in CH reported increased volume of the hypothalamic gray, although another larger study failed to reproduce this finding. These studies in CH prompted the use of stereotactic stimulation of the target point identified by functional and structural neuroimaging. The precise anatomical localization of the deep brain stimulation (DBS) target places it at the midbrain tegmentum rather than the posterior hypothalamus. A comparison of the PET and fMRI studies in TACs reveals that the diencephalic/mesencephalic activation is more posteroinferior in the PET studies, straddling the hypothalamus and midbrain tegmentum, whereas the activation is centered on the hypothalamus in the higher spatial resolution fMRI studies. To optimize the outcomes from DBS, it is likely that patients will need to be studied individually using functional imaging techniques that have high spatial and temporal resolution to enable targeting of the appropriate locus with stereotactic stimulation.


Cluster headache Functional imaging Neuromodulation Deep brain stimulation 



Dr. Ludvic Zrinzo has delivered educational talks at meetings sponsored by industry. No other potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd edn. Cephalalgia 2004, 24 (Suppl 1):1–195.Google Scholar
  2. 2.
    Sanchez del Rio M, Linera JA: Functional neuroimaging of headaches. Lancet Neurol 2004, 3:645–651.CrossRefPubMedGoogle Scholar
  3. 3.
    Fontaine D, Lanteri-Minet M, Lazorthes Y, et al.: Anatomical location of effective contacts in patients with chronic cluster headache treated by deep brain stimulation [abstract]. Acta Neurochir (Wien) 2008, 150:933–1012.CrossRefGoogle Scholar
  4. 4.
    Moore-Ede MC: The circadian timing system in mammals: two pacemakers preside over many secondary oscillators. Fed Proc 1983, 42:2802–2808.PubMedGoogle Scholar
  5. 5.
    Kudrow L: Plasma testosterone levels in cluster headache preliminary results. Headache 1976, 16:28–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Leone M, Bussone G: A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 1993, 13:309–317.CrossRefPubMedGoogle Scholar
  7. 7.
    Rainero I, Gallone S, Valfre W, et al.: A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 2004, 63:1286–1288.PubMedGoogle Scholar
  8. 8.
    Schurks M, Kurth T, Geissler I, et al.: Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 2006, 66:1917–1919.CrossRefPubMedGoogle Scholar
  9. 9.
    Bartsch T, Levy MJ, Knight YE, Goadsby PJ: Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004, 109:367–378.CrossRefPubMedGoogle Scholar
  10. 10.
    Holland PR, Akerman S, Goadsby PJ: Hypothalamic neuropeptides orexin A and B modulation of central and peripheral pathways in the pathophysiology of migraine. Cephalalgia 2005, 25:857.Google Scholar
  11. 11.
    May A, Bahra A, Buchel C, et al.: Hypothalamic activation in cluster headache attacks. Lancet 1998, 352:275–278.CrossRefPubMedGoogle Scholar
  12. 12.
    May A, Kaube H, Buchel C, et al.: Experimental cranial pain elicited by capsaicin: a PET study. Pain 1998, 74:61–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Sprenger T, Boecker H, Tolle TR, et al.: Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004, 62:516–517.PubMedGoogle Scholar
  14. 14.
    Morelli N, Pesaresi I, Cafforio G, et al.: Functional magnetic resonance imaging in episodic cluster headache. J Headache Pain 2009, 10:11–14.CrossRefPubMedGoogle Scholar
  15. 15.
    Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ: Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol 2006, 59:535–545.CrossRefPubMedGoogle Scholar
  16. 16.
    Matharu MS, Cohen AS, McGonigle DJ, et al.: Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004, 44:747–761.CrossRefPubMedGoogle Scholar
  17. 17.
    May A, Bahra A, Buchel C, et al.: Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999, 46:791–794.CrossRefPubMedGoogle Scholar
  18. 18.
    Sprenger T, Valet M, Platzer S, et al.: SUNCT: bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression. Pain 2005, 113:422–426.CrossRefPubMedGoogle Scholar
  19. 19.
    Sprenger T, Valet M, Hammes M, et al.: Hypothalamic activation in trigeminal autonomic cephalgia: functional imaging of an atypical case. Cephalalgia 2004, 24:753–757.CrossRefPubMedGoogle Scholar
  20. 20.
    Cohen AS: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Cephalalgia 2007, 27:824–832.CrossRefPubMedGoogle Scholar
  21. 21.
    May A, Ashburner J, Buchel C, et al.: Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999, 5:836–838. (Comment in Nat Med 1999, 5:732–733.CrossRefPubMedGoogle Scholar
  22. 22.
    Matharu MS: Functional and structural neuroimaging in primary headache disorders [PhD thesis]. London: Institute of Neurology, University of London; 2006.Google Scholar
  23. 23.
    Lodi R, Pierangeli G, Tonon C, et al.: Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 2006, 66:1264–1266.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang SJ, Lirng JF, Fuh JL, Chen JJ: Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J Neurol Neurosurg Psychiatry 2006, 77:622–625.CrossRefPubMedGoogle Scholar
  25. 25.
    Goadsby PJ, Lipton RB: A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 1997, 120:193–209.CrossRefPubMedGoogle Scholar
  26. 26.
    May A, Goadsby PJ: The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999, 19:115–127.CrossRefPubMedGoogle Scholar
  27. 27.
    Wang Q, Mao LM, Han JS: Naloxone-reversible analgesia produced by microstimulation of the arcuate nucleus of the hypothalamus in pentobarbital-anesthetized rats. Exp Brain Res 1990, 80:201–204.CrossRefPubMedGoogle Scholar
  28. 28.
    Dafny N, Dong WQ, Prieto-Gomez C, et al.: Lateral hypothalamus: site involved in pain modulation. Neuroscience 1996, 70:449–460.CrossRefPubMedGoogle Scholar
  29. 29.
    Lumb BM, Lovick TA: The rostral hypothalamus: an area for the integration of autonomic and sensory responsiveness. J Neurophysiol 1993, 70:1570–1577.PubMedGoogle Scholar
  30. 30.
    Benjamin L, Levy MJ, Lasalandra MP, et al.: Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis 2004, 16:500–505.CrossRefPubMedGoogle Scholar
  31. 31.
    Goadsby PJ, Matharu MS, Boes CJ: SUNCT syndrome or trigeminal neuralgia with lacrimation. Cephalalgia 2001, 21:82–83.CrossRefPubMedGoogle Scholar
  32. 32.
    Goadsby PJ: Trigeminal autonomic cephalalgias: fancy term or constructive change to the IHS classification? J Neurol Neurosurg Psychiatry 2005, 76:301–305.CrossRefPubMedGoogle Scholar
  33. 33.
    Malick A, Burstein R: Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998, 400:125–144.CrossRefPubMedGoogle Scholar
  34. 34.
    DeArmond SJ, Fusco MM, Dewey MM: Structure of the Human Brain: A Photographic Atlas, edn 3. Oxford: Oxford University Press; 1989.Google Scholar
  35. 35.
    Cohen AS: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Cephalalgia 2007, 27:824–832.CrossRefPubMedGoogle Scholar
  36. 36.
    •• Leone M, Proietti Cecchini A, Franzini A, et al.: Lessons from 8 years’ experience of hypothalamic stimulation in cluster headache. Cephalalgia 2008, 28:787–797; discussion 798. This detailed review discusses the use of deep brain stimulation in cluster headache. CrossRefPubMedGoogle Scholar
  37. 37.
    Fontaine D, Lazorthes Y, Mertens P, et al.: Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. J Headache Pain 2010, 11:23–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Walcott BP, Bamber NI, Anderson DE: Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case report. Neurosurgery 2009, 65:E997; discussion E997.CrossRefPubMedGoogle Scholar
  39. 39.
    Lyons MK, Dodick DW, Evidente VG: Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to hypothalamic deep brain stimulation. J Neurosurg 2009, 110:279–281.CrossRefPubMedGoogle Scholar
  40. 40.
    Leone M, Franzini A, D’Amico D, et al.: Hypothalamic deep brain stimulation to relieve intractable chronic SUNCT: the first case S43.003. Neurology 2004, 62(Suppl S5):A356.Google Scholar
  41. 41.
    Schoenen J, Di Clemente L, Vandenheede M, et al.: Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 2005, 128:940–947.CrossRefPubMedGoogle Scholar
  42. 42.
    Franzini A, Ferroli P, Leone M, Broggi G: Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery 2003, 52:1095–1099; discussion 1099–1101.CrossRefPubMedGoogle Scholar
  43. 43.
    D’Andrea G, Nordera GP, Piacentino M: Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster headache [abstract]. Neurology 2006, 5(Suppl 2):140.Google Scholar
  44. 44.
    Bartsch T, Pinsker MO, Rasche D, et al.: Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia 2008, 28:285–295.CrossRefPubMedGoogle Scholar
  45. 45.
    • May A: Morphing voxels: the hype around structural imaging of headache patients. Brain 2009, 132:1419–1425. This excellent review discusses structural imaging in primary headache syndromes. CrossRefPubMedGoogle Scholar
  46. 46.
    Weiller C, May A, Limmroth V, et al.: Brain stem activation in spontaneous human migraine attacks. Nat Med 1995, 1:658–660.CrossRefPubMedGoogle Scholar
  47. 47.
    Bahra A, Matharu MS, Buchel C, et al.: Brainstem activation specific to migraine headache. Lancet 2001, 357:1016–1017.CrossRefPubMedGoogle Scholar
  48. 48.
    Afridi S, Giffin NJ, Kaube H, et al.: A positron emission tomographic study in spontaneous migraine. Arch Neurol 2005, 62:1270–1275.CrossRefPubMedGoogle Scholar
  49. 49.
    Afridi SK, Matharu MS, Lee L, et al.: A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005, 128:932–939.CrossRefPubMedGoogle Scholar
  50. 50.
    Denuelle M, Fabre N, Payoux P, et al.: Hypothalamic activation in spontaneous migraine attacks. Headache 2007, 47:1418–1426.PubMedGoogle Scholar
  51. 51.
    Welch KM, Cao Y, Aurora S, et al.: MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine. Neurology 1998, 51:1465–1469.PubMedGoogle Scholar
  52. 52.
    Cao Y, Welch KM, Aurora S, Vikingstad EM: Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 1999, 56:548–554.CrossRefPubMedGoogle Scholar
  53. 53.
    Cao Y, Aurora SK, Nagesh V, et al.: Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 2002, 59:72–78.PubMedGoogle Scholar
  54. 54.
    Matharu MS, Bartsch T, Ward N, et al.: Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 2004, 127:220–230.CrossRefPubMedGoogle Scholar
  55. 55.
    Hsieh JC, Hannerz J, Ingvar M: Right-lateralised central processing for pain of cluster headache. Pain 1996, 67:59–68.CrossRefPubMedGoogle Scholar
  56. 56.
    May A, Bahra A, Buchel C, et al.: PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000, 55:1328–1335.PubMedGoogle Scholar
  57. 57.
    Kupers RC, Svensson P, Jensen TS: Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study. Pain 2004, 108:284–293.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Headache GroupInstitute of NeurologyLondonUK
  2. 2.Unit of Functional NeurosurgeryInstitute of Neurology and the National Hospital for Neurology and NeurosurgeryLondonUK

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