, Volume 55, Issue 8, pp 1039–1047 | Cite as

Spinal cord stimulation modulates cerebral neurobiology: a proton magnetic resonance spectroscopy study

  • Maarten MoensEmail author
  • Peter Mariën
  • Raf Brouns
  • Jan Poelaert
  • Ann De Smedt
  • Ronald Buyl
  • Steven Droogmans
  • Peter Van Schuerbeek
  • Stefan Sunaert
  • Bart Nuttin
Functional Neuroradiology



Although spinal cord stimulation (SCS) is a widely used treatment for chronic neuropathic pain secondary to spinal surgery, little is known about the underlying physiological mechanisms.


The primary aim of this study is to investigate the neural substrate underlying short-term SCS by means of 1H MR spectroscopy with short echo time, in 20 patients with failed back surgery syndrome.


Marked increase of γ-aminobutyric acid (GABA) and decrease in glucose in the ipsilateral thalamus were found between baseline situation without SCS and after 9′ of SCS, indicating the key role of the ipsilateral thalamus as a mediator of chronic neuropathic pain. In addition, this study also showed a progressive decrease in glucose in the ipsilateral thalamus over time, which is in line with the findings of previous studies reporting deactivation in the ipsilateral thalamic region.


The observation of GABA increase and glucose decrease over time in the ipsilateral thalamus may be the causal mechanism of the pain relief due to SCS or an epiphenomenon.


Spinal cord stimulator Proton magnetic resonance spectroscopy GABA Thalamus 



We thank Ursule Van de Velde and Cindy Tettelin for their help in data management.

Conflict of interest

MM is a clinical investigator of The Research Foundation Flanders (FWO) and received the Lyrica Independent Investigator Research Award (LIIRA); he has received consultancy or speaker honoraria from Medtronic and Pfizer. RB has received consultancy or speaker honoraria from Pfizer, Medtronic, Shire Human Genetics Therapies, Sanofi-Aventis and Bayer. BN has received grants for research, education, and travel from Medtronic Inc, and holds a Chair for Neurosurgery for Psychiatric Disorders, funded by a donation from Medtronic Inc.; he has received grants from OT, FWO, IWT-3WIN, and SBO.


  1. 1.
    Kelly GA, Blake C, Power CK, O’Keeffe D, Fullen BM (2012) The impact of spinal cord stimulation on physical function and sleep quality in individuals with failed back surgery syndrome: a systematic review. Eur J Pain 16(6):793–802. doi: 10.1002/j.1532-2149.2011.00092.x PubMedCrossRefGoogle Scholar
  2. 2.
    Sears NC, Machado AG, Nagel SJ, Deogaonkar M, Stanton-Hicks M, Rezai AR, Henderson JM (2011) Long-term outcomes of spinal cord stimulation with paddle leads in the treatment of complex regional pain syndrome and failed back surgery syndrome. Neuromodulation 14(4):312–318. doi: 10.1111/j.1525-1403.2011.00372.x, discussion 318PubMedCrossRefGoogle Scholar
  3. 3.
    Abeloos L, De Witte O, Riquet R, Tuna T, Mathieu N (2011) [Long-term outcome of patients treated with spinal cord stimulation for therapeutically refractory failed back surgery syndrome: a retrospective study]. Neurochirurgie 57(3):114–119. doi: 10.1016/j.neuchi.2011.07.001 PubMedCrossRefGoogle Scholar
  4. 4.
    Mekhail N, Wentzel DL, Freeman R, Quadri H (2011) Counting the costs: case management implications of spinal cord stimulation treatment for failed back surgery syndrome. Prof Case Manag 16(1):27–36. doi: 10.1097/NCM.0b013e3181e9263c PubMedGoogle Scholar
  5. 5.
    Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB (2008) The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery 63(4):762–770. doi: 10.1227/01.NEU.0000325731.46702.D9, discussion 770PubMedCrossRefGoogle Scholar
  6. 6.
    Kemler MA, Barendse GA, van Kleef M, de Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA (2000) Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 343(9):618–624. doi: 10.1056/NEJM200008313430904 PubMedCrossRefGoogle Scholar
  7. 7.
    Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB (2007) Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 132(1–2):179–188. doi: 10.1016/j.pain.2007.07.028 PubMedCrossRefGoogle Scholar
  8. 8.
    North RB, Kumar K, Wallace MS, Henderson JM, Shipley J, Hernandez J, Mekel-Bobrov N, Jaax KN (2011) Spinal cord stimulation versus re-operation in patients with failed back surgery syndrome: an international multicenter randomized controlled trial (EVIDENCE study). Neuromodulation 14(4):330–335. doi: 10.1111/j.1525-1403.2011.00371.x, discussion 335-336PubMedCrossRefGoogle Scholar
  9. 9.
    Schechtmann G, Song Z, Ultenius C, Meyerson BA, Linderoth B (2008) Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy. Pain 139(1):136–145. doi: 10.1016/j.pain.2008.03.023 PubMedCrossRefGoogle Scholar
  10. 10.
    Barchini J, Tchagchagian S, Shamaa F, Jabbur SJ, Meyerson BA, Song Z, Linderoth B, Saade NE (2012) Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy. Neuroscience. doi: 10.1016/j.neuroscience.2012.04.057 PubMedGoogle Scholar
  11. 11.
    Grachev ID, Ramachandran TS, Thomas PS, Szeverenyi NM, Fredrickson BE (2003) Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. J Neural Transm 110(3):287–312. doi: 10.1007/s00702-002-0781-9 PubMedCrossRefGoogle Scholar
  12. 12.
    Grachev ID, Fredrickson BE, Apkarian AV (2000) Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain 89(1):7–18PubMedCrossRefGoogle Scholar
  13. 13.
    Gussew A, Rzanny R, Gullmar D, Scholle HC, Reichenbach JR (2011) 1H-MR spectroscopic detection of metabolic changes in pain processing brain regions in the presence of non-specific chronic low back pain. NeuroImage 54(2):1315–1323. doi: 10.1016/j.neuroimage.2010.09.039 PubMedCrossRefGoogle Scholar
  14. 14.
    Grachev ID, Thomas PS, Ramachandran TS (2002) Decreased levels of N-acetylaspartate in dorsolateral prefrontal cortex in a case of intractable severe sympathetically mediated chronic pain (complex regional pain syndrome, type I). Brain Cogn 49(1):102–113. doi: 10.1006/brcg.2001 PubMedCrossRefGoogle Scholar
  15. 15.
    Foerster BR, Petrou M, Edden RA, Sundgren PC, Schmidt-Wilcke T, Lowe SE, Harte SE, Clauw DJ, Harris RE (2012) Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum 64(2):579–583. doi: 10.1002/art.33339 PubMedCrossRefGoogle Scholar
  16. 16.
    Grachev ID, Fredrickson BE, Apkarian AV (2002) Brain chemistry reflects dual states of pain and anxiety in chronic low back pain. J Neural Transm 109(10):1309–1334. doi: 10.1007/s00702-002-0722-7 PubMedCrossRefGoogle Scholar
  17. 17.
    Feraco P, Bacci A, Pedrabissi F, Passamonti L, Zampogna G, Malavolta N, Leonardi M (2011) Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3T MR spectroscopy study. AJNR Am J Neuroradiol 32(9):1585–1590. doi: 10.3174/ajnr.A2550 PubMedCrossRefGoogle Scholar
  18. 18.
    Harris RE, Clauw DJ (2012) Imaging central neurochemical alterations in chronic pain with proton magnetic resonance spectroscopy. Neurosci Lett. doi: 10.1016/j.neulet.2012.03.042 PubMedGoogle Scholar
  19. 19.
    Pattany PM, Yezierski RP, Widerstrom-Noga EG, Bowen BC, Martinez-Arizala A, Garcia BR, Quencer RM (2002) Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am J Neuroradiol 23(6):901–905PubMedGoogle Scholar
  20. 20.
    Van Seventer R, Vos C, Meerding W, Mear I, Le Gal M, Bouhassira D, Huygen FJ (2010) Linguistic validation of the DN4 for use in international studies. Eur J Pain 14(1):58–63. doi: 10.1016/j.ejpain.2009.01.005 PubMedCrossRefGoogle Scholar
  21. 21.
    van Seventer R, Vos C, Giezeman M, Meerding WJ, Arnould B, Regnault A, van Eerd M, Martin C, Huygen F (2012) Validation of the Dutch Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain. Pain Pract. doi: 10.1111/papr.12006 PubMedGoogle Scholar
  22. 22.
    Moens M, Droogmans S, Spapen H, De Smedt A, Brouns R, Van Schuerbeek P, Luypaert R, Poelaert J, Nuttin B (2012) Feasibility of cerebral magnetic resonance imaging in patients with externalised spinal cord stimulator. Clin Neurol Neurosurg 114(2):135–141. doi: 10.1016/j.clineuro.2011.09.013 PubMedCrossRefGoogle Scholar
  23. 23.
    Moens M, Sunaert S, Marien P, Brouns R, De Smedt A, Droogmans S, Van Schuerbeek P, Peeters R, Poelaert J, Nuttin B (2012) Spinal cord stimulation modulates cerebral function: an fMRI study. Neuroradiology. doi: 10.1007/s00234-012-1087-8 PubMedGoogle Scholar
  24. 24.
    Cui JG, O’Connor WT, Ungerstedt U, Linderoth B, Meyerson BA (1997) Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain 73(1):87–95PubMedCrossRefGoogle Scholar
  25. 25.
    Cui JG, Meyerson BA, Sollevi A, Linderoth B (1998) Effect of spinal cord stimulation on tactile hypersensitivity in mononeuropathic rats is potentiated by simultaneous GABA(B) and adenosine receptor activation. Neurosci Lett 247(2–3):183–186PubMedCrossRefGoogle Scholar
  26. 26.
    Guan Y, Wacnik PW, Yang F, Carteret AF, Chung CY, Meyer RA, Raja SN (2010) Spinal cord stimulation-induced analgesia: electrical stimulation of dorsal column and dorsal roots attenuates dorsal horn neuronal excitability in neuropathic rats. Anesthesiology 113(6):1392–1405. doi: 10.1097/ALN.0b013e3181fcd95c PubMedCrossRefGoogle Scholar
  27. 27.
    Smits H, Ultenius C, Deumens R, Koopmans GC, Honig WM, van Kleef M, Linderoth B, Joosten EA (2006) Effect of spinal cord stimulation in an animal model of neuropathic pain relates to degree of tactile "allodynia". Neuroscience 143(2):541–546. doi: 10.1016/j.neuroscience.2006.08.007 PubMedCrossRefGoogle Scholar
  28. 28.
    Smits H, Kleef MV, Honig W, Gerver J, Gobrecht P, Joosten EA (2009) Spinal cord stimulation induces c-Fos expression in the dorsal horn in rats with neuropathic pain after partial sciatic nerve injury. Neurosci Lett 450(1):70–73. doi: 10.1016/j.neulet.2008.11.013 PubMedCrossRefGoogle Scholar
  29. 29.
    Song Z, Ultenius C, Meyerson BA, Linderoth B (2009) Pain relief by spinal cord stimulation involves serotonergic mechanisms: an experimental study in a rat model of mononeuropathy. Pain 147(1-3):241–248. doi: 10.1016/j.pain.2009.09.020 PubMedCrossRefGoogle Scholar
  30. 30.
    Song Z, Meyerson BA, Linderoth B (2011) Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy. Pain 152(7):1666–1673. doi: 10.1016/j.pain.2011.03.012 PubMedCrossRefGoogle Scholar
  31. 31.
    Barchini J, Tchachaghian S, Shamaa F, Jabbur SJ, Meyerson BA, Song Z, Linderoth B, Saade NE (2012) Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy. Neuroscience 215:196–208. doi: 10.1016/j.neuroscience.2012.04.057 PubMedCrossRefGoogle Scholar
  32. 32.
    Nagamachi S, Fujita S, Nishii R, Futami S, Wakamatsu H, Yano T, Kodama T, Tamura S, Kunitake A, Uno T, Takasaki M (2006) Alteration of regional cerebral blood flow in patients with chronic pain—evaluation before and after epidural spinal cord stimulation. Ann Nucl Med 20(4):303–310PubMedCrossRefGoogle Scholar
  33. 33.
    Kishima H, Saitoh Y, Oshino S, Hosomi K, Ali M, Maruo T, Hirata M, Goto T, Yanagisawa T, Sumitani M, Osaki Y, Hatazawa J, Yoshimine T (2010) Modulation of neuronal activity after spinal cord stimulation for neuropathic pain; H(2)15O PET study. NeuroImage 49(3):2564–2569. doi: 10.1016/j.neuroimage.2009.10.054 PubMedCrossRefGoogle Scholar
  34. 34.
    Clavo B, Robaina F, Montz R, Carames MA, Otermin E, Carreras JL (2008) Effect of cervical spinal cord stimulation on cerebral glucose metabolism. Neurol Res 30(6):652–654. doi: 10.1179/174313208X305373 PubMedCrossRefGoogle Scholar
  35. 35.
    Stancak A, Kozak J, Vrba I, Tintera J, Vrana J, Polacek H, Stancak M (2008) Functional magnetic resonance imaging of cerebral activation during spinal cord stimulation in failed back surgery syndrome patients. Eur J Pain 12(2):137–148. doi: 10.1016/j.ejpain.2007.03.003 PubMedCrossRefGoogle Scholar
  36. 36.
    Kiriakopoulos ET, Tasker RR, Nicosia S, Wood ML, Mikulis DJ (1997) Functional magnetic resonance imaging: a potential tool for the evaluation of spinal cord stimulation: technical case report. Neurosurgery 41(2):501–504PubMedCrossRefGoogle Scholar
  37. 37.
    Rasche D, Siebert S, Stippich C, Kress B, Nennig E, Sartor K, Tronnier VM (2005) Spinal cord stimulation in failed-back-surgery-syndrome. Preliminary study for the evaluation of therapy by functional magnetic resonance imaging (fMRI). Schmerz 19(6):497–500. doi: 10.1007/s00482-005-0388-9, 502-495PubMedCrossRefGoogle Scholar
  38. 38.
    Noback CR (2005) The human nervous system : structure and function, 6th edn. Humana, TotowaGoogle Scholar
  39. 39.
    Lippincott Williams & Wilkins (2011) Professional guide to pathophysiology, 3rd edn. Wolters Kluwer/Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  40. 40.
    Young PA, Young PH, Tolbert DL (2008) Basic clinical neuroscience, 2nd edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  41. 41.
    Wall PD, McMahon SB, Koltzenburg M (2006) Wall and Melzack’s textbook of pain, 5th edn. Elsevier/Churchill Livingstone, PhiladelphiaGoogle Scholar
  42. 42.
    Chen Z, Silva AC, Yang J, Shen J (2005) Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase. J Neurosci Res 79(3):383–391. doi: 10.1002/jnr.20364 PubMedCrossRefGoogle Scholar
  43. 43.
    Muthukumaraswamy SD, Edden RA, Jones DK, Swettenham JB, Singh KD (2009) Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc Natl Acad Sci U S A 106(20):8356–8361. doi: 10.1073/pnas.0900728106 PubMedCrossRefGoogle Scholar
  44. 44.
    Northoff G, Walter M, Schulte RF, Beck J, Dydak U, Henning A, Boeker H, Grimm S, Boesiger P (2007) GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci 10(12):1515–1517. doi: 10.1038/nn2001 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Maarten Moens
    • 1
    Email author
  • Peter Mariën
    • 2
    • 3
  • Raf Brouns
    • 4
  • Jan Poelaert
    • 5
  • Ann De Smedt
    • 4
  • Ronald Buyl
    • 6
  • Steven Droogmans
    • 7
  • Peter Van Schuerbeek
    • 8
  • Stefan Sunaert
    • 9
  • Bart Nuttin
    • 10
  1. 1.Department of Neurosurgery and Center for NeuroscienceUniversitair Ziekenhuis BrusselBrusselsBelgium
  2. 2.Department of NeurologyZNA Middelheim General HospitalAntwerpBelgium
  3. 3.Department of Clinical and Experimental NeurolinguisticsVrije Universiteit BrusselBrusselsBelgium
  4. 4.Neurology and Center for NeuroscienceUniversitair Ziekenhuis BrusselBrusselsBelgium
  5. 5.AnesthesiologyUniversitair Ziekenhuis BrusselBrusselsBelgium
  6. 6.Department of Biostatistics and Medical InformaticsVrije Universiteit BrusselBrusselsBelgium
  7. 7.CardiologyUniversitair Ziekenhuis BrusselBrusselsBelgium
  8. 8.RadiologyUniversitair Ziekenhuis BrusselBrusselsBelgium
  9. 9.Department of Radiology, UZ LeuvenKatholieke Universiteit LeuvenLeuvenBelgium
  10. 10.Neurosurgery, UZ LeuvenKatholieke Universiteit LeuvenLeuvenBelgium

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