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Dynamics of γ-aminobutyric acid concentration in the human brain in response to short visual stimulation

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Abstract

Objective

To find a possible quantitative relation between activation-induced fast (< 10 s) changes in the γ-aminobutyric acid (GABA) level and the amplitude of a blood oxygen level-dependent contrast (BOLD) response (according to magnetic resonance spectroscopy [MRS] and functional magnetic resonance imaging [fMRI]).

Materials and methods

fMRI data and MEGA-PRESS magnetic resonance spectra [echo time (TE)/repetition time (TR) = 68 ms/1500 ms] of an activated area in the visual cortex of 33 subjects were acquired using a 3 T MR scanner. Stimulation was performed by presenting an image of a flickering checkerboard for 3 s, repeated with an interval of 13.5 s. The time course of GABA and creatine (Cr) concentrations and the width and height of resonance lines were obtained with a nominal time resolution of 1.5 s. Changes in the linewidth and height of n-acetylaspartate (NAA) and Cr signals were used to determine the BOLD effect.

Results

In response to the activation, the BOLD-corrected GABA + /Cr ratio increased by 5.0% (q = 0.027) and 3.8% (q = 0.048) at 1.6 and 3.1 s, respectively, after the start of the stimulus. Time courses of Cr and NAA signal width and height reached a maximum change at the 6th second (~ 1.2–1.5%, q < 0.05).

Conclusion

The quick response of the observed GABA concentration to the short stimulus is most likely due to a release of GABA from vesicles followed by its packaging back into vesicles.

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Data availability

Spectroscopy data is available on request.

References

  1. Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 4537197(453):869–878

    Article  ADS  Google Scholar 

  2. Kim SG, Ogawa S (2012) Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals. J Cereb Blood Flow Metab 32:1188–1206

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci 87:9868–9872

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  4. Logothetis NK (2003) The underpinnings of the BOLD functional magnetic resonance imaging signal. J Neurosci 23:3963–3971

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Attwell D, Buchan AM, Charpak S, Lauritzen M, MacVicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  6. Stanley JA, Raz N (2018) Functional magnetic resonance spectroscopy: the “new” MRS for cognitive neuroscience and psychiatry research. Front Psychiatry 9:76

    Article  PubMed  PubMed Central  Google Scholar 

  7. Koush Y, Rothman DL, Behar KL, De Graaf RA, Hyder F (2022) Human brain functional MRS reveals interplay of metabolites implicated in neurotransmission and neuroenergetics. J Cereb Blood Flow Metab 42:911–934

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Pasanta D, He JL, Ford T, Oeltzschner G, Lythgoe DJ, Puts NA (2023) Functional MRS studies of GABA and glutamate/Glx—a systematic review and meta-analysis. Neurosci Biobehav Rev 144:104940

    Article  PubMed  CAS  Google Scholar 

  9. Muthukumaraswamy SD, Edden RAE, 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 106:8356–8361

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mangia S, Tkáč I, Gruetter R, Van De Moortele PF, Giove F, Maraviglia B, Uǧurbil K (2006) Sensitivity of single-voxel 1H-MRS in investigating the metabolism of the activated human visual cortex at 7 T. Magn Reson Imaging. https://doi.org/10.1016/j.mri.2005.12.023

    Article  PubMed  Google Scholar 

  11. Donahue MJ, Near J, Blicher JU, Jezzard P (2010) Baseline GABA concentration and fMRI response. Neuroimage 53:392–398

    Article  PubMed  CAS  Google Scholar 

  12. 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 1012(10):1515–1517

    Article  Google Scholar 

  13. Lipp I, Evans CJ, Lewis C, Murphy K, Wise RG, Caseras X (2015) The relationship between fearfulness, GABA+, and fear-related BOLD responses in the Insula. PLoS ONE 10:e0120101

    Article  PubMed  PubMed Central  Google Scholar 

  14. Michou E, Williams S, Vidyasagar R, Downey D, Mistry S, Edden RAE, Hamdy S (2015) fMRI and MRS measures of neuroplasticity in the pharyngeal motor cortex. Neuroimage 117:1–10

    Article  PubMed  Google Scholar 

  15. Bednařík P, Tkáč I, Giove F, Dinuzzo M, Deelchand DK, Emir UE, Eberly LE, Mangia S (2015) Neurochemical and BOLD responses during neuronal activation measured in the human visual cortex at 7 Tesla. J Cereb Blood Flow Metab 35:601–610

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kiemes A, Davies C, Kempton MJ, Lukow PB, Bennallick C, Stone JM, Modinos G (2021) GABA, glutamate and neural activity: a systematic review with meta-analysis of multimodal 1H-MRS-fMRI studies. Front Psychiatry 12:255

    Article  Google Scholar 

  17. Mangia S, Tkáč I, Gruetter R, Van De Moortele PF, Maraviglia B, Uǧurbil 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 Cereb Blood Flow Metab 27:1055–1063

    Article  PubMed  CAS  Google Scholar 

  18. Chen C, Sigurdsson HP, Pépés SE, Auer DP, Morris PG, Morgan PS, Gowland PA, Jackson SR (2017) Activation induced changes in GABA: functional MRS at 7 T with MEGA-sLASER. Neuroimage 156:207–213

    Article  PubMed  CAS  Google Scholar 

  19. Schaller B, Xin L, O’Brien K, Magill AW, Gruetter R (2014) Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla. Neuroimage. https://doi.org/10.1016/j.neuroimage.2014.02.016

    Article  PubMed  Google Scholar 

  20. Mekle R, Kühn S, Pfeiffer H, Aydin S, Schubert F, Ittermann B (2017) Detection of metabolite changes in response to a varying visual stimulation paradigm using short-TE 1H MRS at 7 T. NMR Biomed. https://doi.org/10.1002/nbm.3672

    Article  PubMed  Google Scholar 

  21. Betina Ip I, Berrington A, Hess AT, Parker AJ, Emir UE, Bridge H (2017) Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. Neuroimage 155:113–119

    Article  PubMed  CAS  Google Scholar 

  22. Kupers R, Danielsen ER, Kehlet H, Christensen R, Thomsen C (2009) Painful tonic heat stimulation induces GABA accumulation in the prefrontal cortex in man. Pain 142:89–93

    Article  PubMed  CAS  Google Scholar 

  23. Cleve M, Gussew A, Reichenbach JR (2015) In vivo detection of acute pain-induced changes of GABA+ and Glx in the human brain by using functional 1H MEGA-PRESS MR spectroscopy. Neuroimage 105:67–75

    Article  PubMed  CAS  Google Scholar 

  24. Floyer-Lea A, Wylezinska M, Kincses T, Matthews PM (2006) Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning. J Neurophysiol 95:1639–1644

    Article  PubMed  CAS  Google Scholar 

  25. Kühn S, Schubert F, Mekle R, Wenger E, Ittermann B, Lindenberger U, Gallinat J (2016) Neurotransmitter changes during interference task in anterior cingulate cortex: evidence from fMRI-guided functional MRS at 3 T. Brain Struct Funct 221:2541–2551

    Article  PubMed  Google Scholar 

  26. 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 91:1076–1083

    Article  PubMed  CAS  Google Scholar 

  27. Boillat Y, Xin L, van der Zwaag W, Gruetter R (2020) Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: a functional MRS study at 7 Tesla. J Cereb Blood Flow Metab 40:488–500

    Article  PubMed  Google Scholar 

  28. 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 Cereb Blood Flow Metab 32:1484–1495

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kurcyus K, Annac E, Hanning NM, Harris AD, Oeltzschner G, Edden R, Riedl V (2018) Opposite dynamics of GABA and glutamate levels in the occipital cortex during visual processing. J Neurosci 38:9967–9976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Yakovlev A, Manzhurtsev A, Menshchikov P, Ublinskiy M, Bozhko O, Akhadov T, Semenova N (2020) The effect of visual stimulation on GABA and macromolecule levels in the human brain in vivo. Biophys Russ Fed 65:51–57

    Article  CAS  Google Scholar 

  31. Koush Y, De Graaf RA, Kupers R, Dricot L, Ptito M, Behar KL, Rothman DL, Hyder F (2021) Metabolic underpinnings of activated and deactivated cortical areas in human brain. J Cereb Blood Flow Metab. https://doi.org/10.1177/0271678X21989186

    Article  PubMed  PubMed Central  Google Scholar 

  32. Apšvalka D, Gadie A, Clemence M, Mullins PG (2015) Event-related dynamics of glutamate and BOLD effects measured using functional magnetic resonance spectroscopy (fMRS) at 3T in a repetition suppression paradigm. Neuroimage 118:292–300

    Article  PubMed  Google Scholar 

  33. Lally N, Mullins PG, Roberts MV, Price D, Gruber T, Haenschel C (2014) Glutamatergic correlates of gamma-band oscillatory activity during cognition: a concurrent ER-MRS and EEG study. Neuroimage 85:823–833

    Article  PubMed  CAS  Google Scholar 

  34. Yakovlev A, Manzhurtsev A, Menshchikov P, Ublinskiy M, Melnikov I, Kupriyanov D, Akhadov T, Semenova N (2022) Functional magnetic resonance spectroscopy study of total glutamate and glutamine in the human visual cortex activated by a short stimulus. Biophysics 67:265–273

    Article  CAS  Google Scholar 

  35. Mullins PG (2018) Towards a theory of functional magnetic resonance spectroscopy (fMRS): a meta-analysis and discussion of using MRS to measure changes in neurotransmitters in real time. Scand J Psychol 59:91–103

    Article  PubMed  Google Scholar 

  36. Kauppinen RA, Pirttila TRM, Auriola SOK, Williams SR (1994) Compartmentation of cerebral glutamate in situ as detected by 1H/13C n.m.r. Biochem J 298:121–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Koolschijn RS, Clarke WT, Ip IB, Emir UE, Barron HC (2023) Event-related functional magnetic resonance spectroscopy. Neuroimage 276:120194

    Article  PubMed  CAS  Google Scholar 

  38. Zhu XH, Chen W (2001) Observed BOLD effects on cerebral metabolite resonances in human visual cortex during visual stimulation: a functional 1H MRS study at 4 T. Magn Reson Med 46:841–847

    Article  PubMed  CAS  Google Scholar 

  39. Ernst T, Hennig J (1994) Observation of a fast response in functional MR. Magn Reson Med 32:146–149

    Article  PubMed  CAS  Google Scholar 

  40. Frahm J, Merboldt KD, Hanicke W (1969) Localized proton spectroscopy using stimulated echoes. J Magn Reson 72:502–508

    ADS  Google Scholar 

  41. Dwyer GE, Craven AR, Bereśniewicz J, Kazimierczak K, Ersland L, Hugdahl K, Grüner R (2021) Simultaneous measurement of the BOLD effect and metabolic changes in response to visual stimulation using the MEGA-PRESS sequence at 3 T. Front Hum Neurosci. https://doi.org/10.3389/fnhum.2021.644079

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R (1998) Simultaneous in vivo spectral editing and water suppression. NMR Biomed 11:266–272

    Article  PubMed  CAS  Google Scholar 

  43. Edden RAE, Puts NAJ, Harris AD, Barker PB, Evans CJ (2014) Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. J Magn Reson Imaging 40:1445–1452

    Article  PubMed  Google Scholar 

  44. Mikkelsen M, Tapper S, Near J, Mostofsky SH, Puts NAJ, Edden RAE (2020) Correcting frequency and phase offsets in MRS data using robust spectral registration. NMR Biomed. https://doi.org/10.1002/nbm.4368

    Article  PubMed  PubMed Central  Google Scholar 

  45. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679

    Article  PubMed  CAS  Google Scholar 

  46. Harris AD, Puts NAJ, Edden RAE (2015) Tissue correction for GABA-edited MRS: considerations of voxel composition, tissue segmentation, and tissue relaxations. J Magn Reson Imaging 42:1431–1440

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mullins PG, McGonigle DJ, O’Gorman RL, Puts NAJ, Vidyasagar R, Evans CJ, Edden RAE (2014) Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage 86:43–52

    Article  PubMed  CAS  Google Scholar 

  48. Friston KJ, Ashburner J, Frith CD, Poline J-B, Heather JD, Frackowiak RSJ (1995) Spatial registration and normalization of images. Hum Brain Mapp 3:165–189

    Article  Google Scholar 

  49. Evans AC, Marrett S, Neelin P, Collins L, Worsley K, Dai W, Milot S, Meyer E, Bub D (1992) Anatomical mapping of functional activation in stereotactic coordinate space. Neuroimage 1:43–53

    Article  PubMed  CAS  Google Scholar 

  50. Penny WD, Friston KJ, Ashburner JT, Kiebel SJ, Nichols TE (eds) (2007) Statistical parametric mapping. Elsevier. https://doi.org/10.1016/B978-0-12-372560-8.X5000-1

    Book  Google Scholar 

  51. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300

    MathSciNet  Google Scholar 

  52. Choi IY, Andronesi OC, Barker P, Bogner W, Edden RAE, Kaiser LG, Lee P, Marjańska M, Terpstra M, de Graaf RA (2021) Spectral editing in 1H magnetic resonance spectroscopy: experts’ consensus recommendations. NMR Biomed 34:e4411

    Article  PubMed  CAS  Google Scholar 

  53. Duarte JMN, Gruetter R (2013) Glutamatergic and GABAergic energy metabolism measured in the rat brain by 13C NMR spectroscopy at 14.1 T. J Neurochem 126:579–590

    Article  PubMed  CAS  Google Scholar 

  54. Bruns D, Jahn R (1995) Real-time measurement of transmitter release from single synaptic vesicles. Nature 377:62–65

    Article  ADS  PubMed  CAS  Google Scholar 

  55. Cheng H, Wang A, Newman S, Dydak U (2021) An investigation of glutamate quantification with PRESS and MEGA-PRESS. NMR Biomed. https://doi.org/10.1002/nbm.4453

    Article  PubMed  PubMed Central  Google Scholar 

  56. Egashira Y, Takase M, Watanabe S, Ishida J, Fukamizu A, Kaneko R, Yanagawa Y, Takamori S (2016) Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading. Proc Natl Acad Sci U S A 113:10702–10707

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  57. Betina Ip I, Emir UE, Parker AJ, Campbell J, Bridge H (2019) Comparison of neurochemical and BOLD signal contrast response functions in the human visual cortex. J Neurosci 39:7968–7975

    Article  PubMed  Google Scholar 

  58. Elliott M, Knodt A, Ireland D, Morris M, Poulton R, Ramrakha S, Sison M, Moffitt T, Caspi A, Hariri A (2020) What is the test-retest reliability of common Task-fMRI measures? New empirical evidence and a meta-analysis. Biol Psychiatry 87:S132–S133

    Article  Google Scholar 

  59. Lu H, Van Zijl PCM (2005) Experimental measurement of extravascular parenchymal BOLD effects and tissue oxygen extraction fractions using multi-echo VASO fMRI at 1.5 and 3.0 T. Magn Reson Med. https://doi.org/10.1002/mrm.20379

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by the Russian Foundation for Basic Research (grant/award No. 19-29-10040) and the Russian Science Foundation (grant/award No 23-13-00011).

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Authors and Affiliations

  1. Clinical and Research Institute of Emergency Paediatric Surgery and Traumatology, Bol’shaya Polyanka St. 22, Moscow, 119180, Russian Federation

    Alexey Yakovlev, Andrei Manzhurtsev, Maxim Ublinskiy, Tolib Akhadov & Natalia Semenova

  2. N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, Kosygina St. 4, Moscow, 119334, Russian Federation

    Alexey Yakovlev, Anatoly Vanin & Natalia Semenova

  3. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina St. 4, Moscow, 119334, Russian Federation

    Alexey Yakovlev, Andrei Manzhurtsev, Maxim Ublinskiy, Petr Menshchikov & Natalia Semenova

  4. Moscow State University, Leninskie Gory Str. 1, Moscow, 119991, Russian Federation

    Alexandra Gritskova, Andrei Manzhurtsev, Maxim Ublinskiy, Tolib Akhadov & Natalia Semenova

  5. LLC Philips Healthcare, 13 Sergeya Makeeva Str., Moscow, 123022, Russian Federation

    Petr Menshchikov & Dmitriy Kupriyanov

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  1. Alexey Yakovlev
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Contributions

Study conception and design: AY and NS; acquisition of the data: AY and AG; analysis and interpretation of the data: AY, AG, AM, and NS; drafting of the manuscript: AY, AG, AV, AM, and NS; critical revision: AM, DK, AV, PM, MU, TA, and NS; funding acquisition: PM and DK.

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Correspondence to Alexey Yakovlev.

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Yakovlev, A., Gritskova, A., Manzhurtsev, A. et al. Dynamics of γ-aminobutyric acid concentration in the human brain in response to short visual stimulation. Magn Reson Mater Phy 37, 39–51 (2024). https://doi.org/10.1007/s10334-023-01118-7

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