Brain Structure and Function

, Volume 221, Issue 5, pp 2541–2551 | Cite as

Neurotransmitter changes during interference task in anterior cingulate cortex: evidence from fMRI-guided functional MRS at 3 T

  • Simone Kühn
  • Florian Schubert
  • Ralf Mekle
  • Elisabeth Wenger
  • Bernd Ittermann
  • Ulman Lindenberger
  • Jürgen Gallinat
Original Article


Neural activity as indirectly observed in blood oxygenation level-dependent (BOLD) response is thought to reflect changes in neurotransmitter flux. In this study, we used fMRI-guided functional magnetic resonance spectroscopy (MRS) to measure metabolite/BOLD associations during a cognitive task at 3 T. GABA and glutamate concentration in anterior cingulate cortex (ACC) were determined by means of MRS using the SPECIAL pulse sequence before, during and after the performance of a manual Stroop task. MRS voxel positions were centred around individuals’ BOLD activity during Stroop performance. Levels of GABA and glutamate showed inverted U-shape patterns across measurement time points (before, during, and after task), glutamine increased linearly and total creatine did not change. The GABA increase during task performance was associated with ACC BOLD signal changes in both congruent and incongruent Stroop conditions. Using an fMRI-guided MRS approach, an association between induced inhibitory neurotransmitter increase and BOLD changes was observed. The proposed procedure might allow the in vivo investigation of normal and dysfunctional associations between neurotransmitters and BOLD signal crucial for cerebral functioning.


Spectroscopy GABA glutamate MRS fMRI Stroop 


  1. Arrubla J, Tse DH, Amkreutz C, Neuner I, Shah NJ (2014) GABA concentration in posterior cingulate cortex predicts putamen response during resting state fMRI. PLoS One 9(9):e106609. doi:10.1371/journal.pone.0106609 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews MP, Cowen JP (2008) Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol Off Sci J Coll Int Neuropsychopharmacol 11(2):255–260. doi:10.1017/S1461145707007924 Google Scholar
  3. Botvinick MM, Cohen JD, Carter CS (2004) Conflict monitoring and anterior cingulate cortex: an update. Trends Cogn Sci 8(12):539–546. doi:10.1016/j.tics.2004.10.003 CrossRefPubMedGoogle Scholar
  4. Carter CS, van Veen V (2007) Anterior cingulate cortex and conflict detection: an update of theory and data. Cogn Aff Behav Neurosci 7(4):367–379CrossRefGoogle Scholar
  5. Carter CS, Braver TS, Barch DM, Botvinick MM, Noll D, Cohen JD (1998) Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 280(5364):747–749CrossRefPubMedGoogle Scholar
  6. Donahue MJ, Near J, Blicher JU, Jezzard P (2010) Baseline GABA concentration and fMRI response. Neuro Image 53(2):392–398. doi:10.1016/j.neuroimage.2010.07.017 PubMedGoogle Scholar
  7. Duncan NW, Wiebking C, Northoff G (2014) Associations of regional GABA and glutamate with intrinsic and extrinsic neural activity in humans—a review of multimodal imaging studies. Neurosci Biobehav Rev 47:36–52. doi:10.1016/j.neubiorev.2014.07.016 CrossRefPubMedGoogle Scholar
  8. Edden RA, Intrapiromkul J, Zhu H, Cheng Y, Barker PB (2012) Measuring T2 in vivo with J-difference editing: application to GABA at 3 Tesla. J Magnet Res Imag JMRI 35(1):229–234. doi:10.1002/jmri.22865 CrossRefGoogle Scholar
  9. Epp AM, Dobson KS, Dozois DJ, Frewen PA (2012) A systematic meta-analysis of the Stroop task in depression. Clin Psychol Rev 32(4):316–328. doi:10.1016/j.cpr.2012.02.005 CrossRefPubMedGoogle Scholar
  10. Floyer-Lea A, Wylezinska M, Kincses T, Matthews PM (2006) Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning. J Neurophysiol 95(3):1639–1644. doi:10.1152/jn.00346.2005 CrossRefPubMedGoogle Scholar
  11. Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A, Umene-Nakano W, Hayashi K, Oonari N, Korogi Y, Nakamura J (2009) Reduction of brain gamma-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3 T Proton MRS study. Schizophr Res 112(1–3):192–193. doi:10.1016/j.schres.2009.04.026 CrossRefPubMedGoogle Scholar
  12. Govindaraju V, Young K, Maudsley AA (2000) Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13(3):129–153CrossRefPubMedGoogle Scholar
  13. Guitart-Masip M, Economides M, Huys QJ, Frank MJ, Chowdhury R, Duzel E, Dayan P, Dolan RJ (2014) Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment. Psychopharmacology 231(5):955–966. doi:10.1007/s00213-013-3313-4 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64(2):193–200. doi:10.1001/archpsyc.64.2.193 CrossRefPubMedGoogle Scholar
  15. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, Gil R, Slifstein M, Abi-Dargham A, Lisanby SH, Shungu DC (2012) Elevated prefrontal cortex gamma-aminobutyric acid and glutamate–glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 69(5):449–459. doi:10.1001/archgenpsychiatry.2011.1519 CrossRefPubMedGoogle Scholar
  16. Laird AR, McMillan KM, Lancaster JL, Kochunov P, Turkeltaub PE, Pardo JV, Fox PT (2005) A comparison of label-based review and ALE meta-analysis in the Stroop task. Hum Brain Mapp 25(1):6–21. doi:10.1002/hbm.20129 CrossRefPubMedGoogle Scholar
  17. Lin Y, Stephenson MC, Xin L, Napolitano A, Morris PG (2012) Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T. J Cerebral Blood Flow Metabol Off J Int Soc Cerebral Blood Flow Metabol 32(8):1484–1495. doi:10.1038/jcbfm.2012.33 CrossRefGoogle Scholar
  18. Luykx JJ, Laban KG, van den Heuvel MP, Boks MP, Mandl RC, Kahn RS, Bakker SC (2012) Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of (1)H-MRS findings. Neurosci Biobehav Rev 36(1):198–205. doi:10.1016/j.neubiorev.2011.05.014 CrossRefPubMedGoogle Scholar
  19. Mangia S, Tkac I, Gruetter R, Van de Moortele PF, Maraviglia B, Ugurbil K (2007) Sustained neuronal activation raises oxidative metabolism to a new steady-state level: evidence from 1H NMR spectroscopy in the human visual cortex. J Cerebral Blood Flow Metabol Off J Int Soc Cerebral Blood Flow Metabol 27(5):1055–1063. doi:10.1038/sj.jcbfm.9600401 Google Scholar
  20. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C (2004) Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5(10):793–807. doi:10.1038/nrn1519 CrossRefPubMedGoogle Scholar
  21. Mekle R, Mlynarik V, Gambarota G, Hergt M, Krueger G, Gruetter R (2009) MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T. Magnet Reson Med Off J Soc Magnet Reson Med/Soc Magnet Reson Med 61(6):1279–1285. doi:10.1002/mrm.21961 CrossRefGoogle Scholar
  22. Mekle RKS, Pfeiffer H, Schubert F, Ittermann B (2014) Detection of metabolite changes in response to a varying visual stimulation paradigm using short TE 1H MRS at 7 T. Proceedings of the 22nd Annual Meeting ISMRM, Milan, ItalyGoogle Scholar
  23. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R (1998) Simultaneous in vivo spectral editing and water suppression. NMR Biomed 11(6):266–272CrossRefPubMedGoogle Scholar
  24. Meyerhoff DJ, Mon A, Metzler T, Neylan TC (2014) Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep 37:893–900PubMedPubMedCentralGoogle Scholar
  25. Michels L, Martin E, Klaver P, Edden R, Zelaya F, Lythgoe DJ, Luchinger R, Brandeis D, O’Gorman RL (2012) Frontal GABA levels change during working memory. PLoS One 7(4):e31933. doi:10.1371/journal.pone.0031933 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Michels L, Schulte-Vels T, Schick M, O’Gorman RL, Zeffiro T, Hasler G, Mueller-Pfeiffer C (2014) Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: preliminary findings. Psychiatry Res 224(3):288–295. doi:10.1016/j.pscychresns.2014.09.007 CrossRefPubMedGoogle Scholar
  27. Mlynarik V, Gambarota G, Frenkel H, Gruetter R (2006) Localized short-echo-time proton MR spectroscopy with full signal-intensity acquisition. Magnet Reson Med Off J Soc Magnet Reson Med/Soc Magnet Reson Med 56(5):965–970. doi:10.1002/mrm.21043 CrossRefGoogle Scholar
  28. Moeller SJ, Honorio J, Tomasi D, Parvaz MA, Woicik PA, Volkow ND, Goldstein RZ (2014) Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction. Cereb Cortex 24(3):643–653. doi:10.1093/cercor/bhs345 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Morgan PT, Pace-Schott EF, Mason GF, Forselius E, Fasula M, Valentine GW, Sanacora G (2012) Cortical GABA levels in primary insomnia. Sleep 35:806–814CrossRefGoogle Scholar
  30. 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 USA 106(20):8356–8361. doi:10.1073/pnas.0900728106 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Near J, Andersson J, Maron E, Mekle R, Gruetter R, Cowen P, Jezzard P (2013) Unedited in vivo detection and quantification of gamma-aminobutyric acid in the occipital cortex using short-TE MRS at 3 T. NMR Biomed 26(11):1353–1362. doi:10.1002/nbm.2960 CrossRefPubMedGoogle Scholar
  32. Nee DE, Wager TD, Jonides J (2007) Interference resolution: insights from a meta-analysis of neuroimaging tasks. Cognit Aff Behav Neurosci 7(1):1–17CrossRefGoogle Scholar
  33. 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 CrossRefPubMedGoogle Scholar
  34. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9(1):97–113CrossRefPubMedGoogle Scholar
  35. Onur OA, Piefke M, Lie CH, Thiel CM, Fink GR (2011) Modulatory effects of levodopa on cognitive control in young but not in older subjects: a pharmacological fMRI study. J Cogn Neurosci 23(10):2797–2810. doi:10.1162/jocn.2011.21603 CrossRefPubMedGoogle Scholar
  36. Ordidge RJCA, Lohman JAB (1986) Image-selected in vivo spectroscopy (ISIS). A new technique for spatially selective NMR spectroscopy. J Magn Reson 66:283–294Google Scholar
  37. Patel AB, de Graaf RA, Mason GF, Rothman DL, Shulman RG, Behar KL (2005) The contribution of GABA to glutamate/glutamine cycling and energy metabolism in the rat cortex in vivo. Proc Natl Acad Sci USA 102(15):5588–5593. doi:10.1073/pnas.0501703102 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Plante DT, Jensen JE, Schoerning L, Winkelman JW (2012) Reduced gamma-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: a link to major depressive disorder? Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 37(6):1548–1557. doi:10.1038/npp.2012.4 CrossRefGoogle Scholar
  39. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnet Reson Med Off J Soc Magnet Reson Med/Soc Magnet Reson Med 30(6):672–679CrossRefGoogle Scholar
  40. Rosso IM, Weiner MR, Crowley DJ, Silveri MM, Rauch SL, Jensen JE (2014) Insula and anterior cingulate GABA levels in posttraumatic stress disorder: preliminary findings using magnetic resonance spectroscopy. Depress Anxiety 31:115–123CrossRefPubMedPubMedCentralGoogle Scholar
  41. Rothman DL, Petroff OA, Behar KL, Mattson RH (1993) Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proc Natl Acad Sci USA 90(12):5662–5666CrossRefPubMedPubMedCentralGoogle Scholar
  42. Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA, Holcomb HH, Barker PB (2013) In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 39(5):1096–1104. doi:10.1093/schbul/sbs092 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, Berman RM, Charney DS, Krystal JH (1999) Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56(11):1043–1047CrossRefPubMedGoogle Scholar
  44. Sanacora G, Mason GF, Krystal JH (2000) Impairment of GABAergic transmission in depression: new insights from neuroimaging studies. Crit Rev Neurobiol 14(1):23–45CrossRefPubMedGoogle Scholar
  45. Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4):663–665CrossRefPubMedGoogle Scholar
  46. Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB, Berman RM, Krystal JH (2003) Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 160(3):577–579CrossRefPubMedGoogle Scholar
  47. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61(7):705–713. doi:10.1001/archpsyc.61.7.705 CrossRefPubMedGoogle Scholar
  48. Schaller B, Mekle R, Xin L, Kunz N, Gruetter R (2013) Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 tesla. J Neurosci Res 91(8):1076–1083. doi:10.1002/jnr.23194 CrossRefPubMedGoogle Scholar
  49. Schaller B, Xin L, O’Brien K, Magill AW, Gruetter R (2014) Are glutamate and lactate increases ubiquitous to physiological activation? A (1)H functional MR spectroscopy study during motor activation in human brain at 7Tesla. NeuroImage 93(Pt 1):138–145. doi:10.1016/j.neuroimage.2014.02.016 CrossRefPubMedGoogle Scholar
  50. Schousboe A, Westergaard N, Hertz L (1993) Neuronal-astrocytic interactions in glutamate metabolism. Biochem Soc Trans 21(1):49–53CrossRefPubMedGoogle Scholar
  51. Schubert F, Gallinat J, Seifert F, Rinneberg H (2004) Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. NeuroImage 21(4):1762–1771. doi:10.1016/j.neuroimage.2003.11.014 CrossRefPubMedGoogle Scholar
  52. Song X-W, Dong Z-Y, Long X-Y, Li S-F, Zuo X-N, Zhu C-Z, He Y, Yan C-G, Zang Y-F (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS One 6(9):e25031. doi:10.1371/journal.pone.0025031 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Stagg CJ, Best JG, Stephenson MC, O’Shea J, Wylezinska M, Kincses ZT, Morris PG, Matthews PM, Johansen-Berg H (2009a) Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci Off J Soc Neurosci 29(16):5202–5206. doi:10.1523/JNEUROSCI.4432-08.2009 CrossRefGoogle Scholar
  54. Stagg CJ, Wylezinska M, Matthews PM, Johansen-Berg H, Jezzard P, Rothwell JC, Bestmann S (2009b) Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. J Neurophysiol 101(6):2872–2877. doi:10.1152/jn.91060.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Stagg CJ, Bachtiar V, Johansen-Berg H (2011) The role of GABA in human motor learning. Curr Biol CB 21(6):480–484. doi:10.1016/j.cub.2011.01.069 CrossRefPubMedGoogle Scholar
  56. Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–662CrossRefGoogle Scholar
  57. Tkac I, Oz G, Adriany G, Ugurbil K, Gruetter R (2009) In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7 T. Magnet Reson Med Off J Soc Magnet Reson Med/Soc Magn Reson Med 62(4):868–879. doi:10.1002/mrm.22086 CrossRefGoogle Scholar
  58. Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M, Ekanayake V, Fernandez H, Potenza MN, Dolan RJ, Hallett M (2010) Impulsive choice and response in dopamine agonist-related impulse control behaviors. Psychopharmacology 207(4):645–659. doi:10.1007/s00213-009-1697-y CrossRefPubMedPubMedCentralGoogle Scholar
  59. Wang XJ (2010) Neurophysiological and computational principles of cortical rhythms in cognition. Physiol Rev 90(3):1195–1268. doi:10.1152/physrev.00035.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Winterer G, Weinberger DR (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 27(11):683–690. doi:10.1016/j.tins.2004.08.002 CrossRefPubMedGoogle Scholar
  61. Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, Carter CS (2010) GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci Off J Soc Neurosci 30(10):3777–3781. doi:10.1523/JNEUROSCI.6158-09.2010 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Simone Kühn
    • 1
    • 4
  • Florian Schubert
    • 2
  • Ralf Mekle
    • 2
  • Elisabeth Wenger
    • 1
  • Bernd Ittermann
    • 2
  • Ulman Lindenberger
    • 1
  • Jürgen Gallinat
    • 3
    • 4
  1. 1.Max Planck Institute for Human DevelopmentCenter for Lifespan PsychologyBerlinGermany
  2. 2.Physikalisch-Technische Bundesanstalt (PTB)BerlinGermany
  3. 3.St. Hedwig-Krankenhaus, Clinic for Psychiatry and PsychotherapyCharité University MedicineBerlinGermany
  4. 4.University Clinic Hamburg-Eppendorf, Clinic and Policlinic for Psychiatry and PsychotherapyHamburgGermany

Personalised recommendations