A comparison of sLASER and MEGA-sLASER using simultaneous interleaved acquisition for measuring GABA in the human brain at 7T


Autoři: Donghyun Hong aff001;  Seyedmorteza Rohani Rankouhi aff001;  Jan-Willem Thielen aff001;  Jack J. A. van Asten aff003;  David G. Norris aff001
Působiště autorů: Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen, Germany aff001;  Department for Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany aff002;  Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands aff003;  Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223702

Souhrn

γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter, is challenging to measure using proton spectroscopy due to its relatively low concentration, J-coupling and overlapping signals from other metabolites. Currently, the prevalent methods for detecting GABA at ultrahigh field strengths (≥ 7 T) are GABA-editing and model fitting of non-editing single voxel spectra. These two acquisition approaches have their own advantages: the GABA editing approach directly measures the GABA resonance at 3 ppm, whereas the fitting approach on the non-editing spectrum allows the detection of multiple metabolites, and has an SNR advantage over longer echo time (TE) acquisitions. This study aims to compare these approaches for estimating GABA at 7 T. We use an interleaved sequence of semi-LASER (sLASER: TE = 38 ms) and MEGA-sLASER (TE = 80 ms). This simultaneous interleaved acquisition minimizes the differential effect of extraneous factors, and enables an accurate comparison of the two acquisition methods. Spectra were acquired with an 8 ml isotropic voxel at six different brain regions: anterior-cingulate cortex, dorsolateral-prefrontal cortex, motor cortex, occipital cortex, posterior cingulate cortex, and precuneus. Spectral fitting with LCModel quantified the GABA to total Cr (tCr: Creatine + Phosphocreatine) concentration ratio. After correcting the T2 relaxation time variation, GABA/tCr ratios were similar between the two acquisition approaches. GABA editing showed smaller spectral fitting error according to Cramér–Rao lower bound than the sLASER approach for all regions examined. We conclude that both acquisition methods show similar accuracy but the precision of the MEGA-editing approach is higher for GABA measurement. In addition, the 2.28 ppm GABA resonance was found to be important for estimating GABA concentration without macromolecule contamination in the GABA-edited acquisition, when utilizing spectral fitting with LCModel.

Klíčová slova:

Cingulate cortex – Gamma-aminobutyric acid – Linear regression analysis – Metabolites – Positron emission tomography – Prefrontal cortex – Lipid signaling – Magnetic resonance spectroscopy


Zdroje

1. McCormick DA. GABA as an inhibitory neurotransmitter in human cerebral cortex. J Neurophysiol. 1989;62(5):1018–27. doi: 10.1152/jn.1989.62.5.1018 2573696

2. Bellance N, Pabst L, Allen G, Rossignol R, Nagrath D. Oncosecretomics coupled to bioenergetics identifies α-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes. Biochimica Et Biophysica Acta (BBA)-Bioenergetics. 2012;1817(11):2060–71.

3. Cawley N, Solanky BS, Muhlert N, Tur C, Edden RA, Wheeler-Kingshott CA, et al. Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis. Brain. 2015;138(9):2584–95.

4. Bai X, Edden RA, Gao F, Wang G, Wu L, Zhao B, et al. Decreased γ‐aminobutyric acid levels in the parietal region of patients with Alzheimer's disease. J Magn Reson Imaging. 2015;41(5):1326–31. doi: 10.1002/jmri.24665 24863149

5. Petroff OA, Rothman DL, Behar KL, Mattson RH. Initial Observations on Effect of Vigabatrin on In Vivo 1H Spectroscopic Measurements of γ‐Aminobutyric Acid, Glutamate, and Glutamine in Human Brain. Epilepsia. 1995;36(5):457–64. doi: 10.1111/j.1528-1157.1995.tb00486.x 7614922

6. Marsman A, Mandl RC, Klomp DW, Bohlken MM, Boer VO, Andreychenko A, et al. GABA and glutamate in schizophrenia: A 7 T 1H-MRS study. NeuroImage: Clinical. 2014;6:398–407.

7. Oblak AL, Gibbs TT, Blatt GJ. Reduced GABA A receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 2011;1380:218–28. doi: 10.1016/j.brainres.2010.09.021 20858465

8. Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S, Cunningham VJ, et al. Imaging the GABA-benzodiazepine receptor subtype containing the α5-subunit in vivo with [11C] Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22(7):878–89. doi: 10.1097/00004647-200207000-00013 12142573

9. Verhoeff NPL, Petroff OA, Hyder F, Zoghbi SS, Fujita M, Rajeevan N, et al. Effects of vigabatrin on the GABAergic system as determined by [123I] iomazenil SPECT and GABA MRS. Epilepsia. 1999;40(10):1433–8. doi: 10.1111/j.1528-1157.1999.tb02016.x 10528940

10. Keltner JR, Wald LL, Christensen JD, Maas LC, Moore CM, Cohen BM, et al. A technique for detecting GABA in the human brain with PRESS localization and optimized refocusing spectral editing radiofrequency pulses. Magn Reson Med. 1996;36(3):458–61. doi: 10.1002/mrm.1910360319 8875418

11. Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H, et al. Magnetic resonance imaging of glutamate. Nat Med. 2012;18(2):302. doi: 10.1038/nm.2615 22270722

12. Yan G, Zhang T, Dai Z, Yi M, Jia Y, Nie T, et al. A Potential Magnetic Resonance Imaging Technique Based on Chemical Exchange Saturation Transfer for In Vivo γ-Aminobutyric Acid Imaging. PLoS One. 2016;11(10):e0163765. doi: 10.1371/journal.pone.0163765 27711138

13. Godlewska BR, Clare S, Cowen PJ, Emir UE. Ultra-high-field magnetic resonance spectroscopy in psychiatry. Frontiers in psychiatry. 2017;8:123. doi: 10.3389/fpsyt.2017.00123 28744229

14. Puts NA, Edden RA. In vivo magnetic resonance spectroscopy of GABA: a methodological review. Progress in nuclear magnetic resonance spectroscopy. 2012;60:29–41. doi: 10.1016/j.pnmrs.2011.06.001 22293397

15. Rothman DL, Petroff O, Behar KL, Mattson RH. Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proceedings of the national academy of sciences. 1993;90(12):5662–6.

16. Mescher M, Tannus A, Johnson MN, Garwood M. Solvent suppression using selective echo dephasing. Journal of Magnetic Resonance, Series A. 1996;123(2):226–9.

17. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R. Simultaneous in vivo spectral editing and water suppression. NMR Biomed. 1998;11(EPFL-ARTICLE-177509):266–72.

18. Shen J, Rothman DL, Brown P. In vivo GABA editing using a novel doubly selective multiple quantum filter. Magn Reson Med. 2002;47(3):447–54. doi: 10.1002/mrm.10104 11870830

19. Chen C, Sigurdsson HP, Pépés SE, Auer DP, Morris PG, Morgan PS, et al. Activation induced changes in GABA: functional MRS at 7 T with MEGA-sLASER. Neuroimage. 2017;156:207–13. doi: 10.1016/j.neuroimage.2017.05.044 28533117

20. Andreychenko A, Boer VO, Arteaga de Castro CS, Luijten PR, Klomp DW. Efficient spectral editing at 7 T: GABA detection with MEGA‐sLASER. Magn Reson Med. 2012;68(4):1018–25. doi: 10.1002/mrm.24131 22213204

21. Houtepen LC, Schür RR, Wijnen JP, Boer VO, Boks M, Kahn RS, et al. Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study. NeuroImage: Clinical. 2017;14:195–200.

22. Edden RA, Puts NA, Barker PB. Macromolecule‐suppressed GABA‐edited magnetic resonance spectroscopy at 3T. Magn Reson Med. 2012;68(3):657–61. doi: 10.1002/mrm.24391 22777748

23. Harris AD, Glaubitz B, Near J, John Evans C, Puts NA, Schmidt‐Wilcke T, et al. Impact of frequency drift on gamma‐aminobutyric acid‐edited MR spectroscopy. Magn Reson Med. 2014;72(4):941–8. doi: 10.1002/mrm.25009 24407931

24. Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672–9. doi: 10.1002/mrm.1910300604 8139448

25. Provencher SW. Automatic quantitation of localized in vivo1H spectra with LCModel. NMR Biomed. 2001;14(4):260–4. 11410943

26. Napolitano A, Kockenberger W, Auer DP. Reliable gamma aminobutyric acid measurement using optimized PRESS at 3 T. Magn Reson Med. 2013;69(6):1528–33. doi: 10.1002/mrm.24397 22807127

27. Near J, Andersson J, Maron E, Mekle R, Gruetter R, Cowen P, et al. Unedited in vivo detection and quantification of γ‐aminobutyric acid in the occipital cortex using short‐TE MRS at 3 T. NMR Biomed. 2013;26(11):1353–62. doi: 10.1002/nbm.2960 23696182

28. Öz G, Terpstra M, Tkáč I, Aia P, Lowary J, Tuite PJ, et al. Proton MRS of the unilateral substantia nigra in the human brain at 4 tesla: detection of high GABA concentrations. Magnetic Resonance in Medicine: An Official Journal of the International Society for Magnetic Resonance in Medicine. 2006;55(2):296–301.

29. Wijtenburg SA, Rowland LM, Edden RA, Barker PB. Reproducibility of brain spectroscopy at 7T using conventional localization and spectral editing techniques. J Magn Reson Imaging. 2013;38(2):460–7. doi: 10.1002/jmri.23997 23292856

30. Ganji SK, An Z, Banerjee A, Madan A, Hulsey KM, Choi C. Measurement of regional variation of GABA in the human brain by optimized point‐resolved spectroscopy at 7 T in vivo. NMR Biomed. 2014;27(10):1167–75. doi: 10.1002/nbm.3170 25088346

31. Pradhan S, Bonekamp S, Gillen JS, Rowland LM, Wijtenburg SA, Edden RA, et al. Comparison of single voxel brain MRS AT 3 T and 7 T using 32-channel head coils. Magn Reson Imaging. 2015;33(8):1013–8. doi: 10.1016/j.mri.2015.06.003 26117693

32. Terpstra M, Vaughan T, Ugurbil K, Lim KO, Schulz SC, Gruetter R. Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia. Magnetic Resonance Materials in Physics, Biology and Medicine. 2005;18(5):276.

33. Frahm J, Merboldt K-D, Hänicke W. Localized proton spectroscopy using stimulated echoes. Journal of Magnetic Resonance (1969). 1987;72(3):502–8.

34. Granot J. Selected volume excitation using stimulated echoes (VEST). Applications to spatially localized spectroscopy and imaging. Journal of Magnetic Resonance (1969). 1986;70(3):488–92.

35. Kimmich R, Hoepfel D. Volume-selective multipulse spin-echo spectroscopy. Journal of Magnetic Resonance (1969). 1987;72(2):379–84.

36. Sanaei Nezhad F, Anton A, Parkes LM, Deakin B, Williams SR. Quantification of glutathione in the human brain by MR spectroscopy at 3 Tesla: Comparison of PRESS and MEGA‐PRESS. Magn Reson Med. 2017;78(4):1257–66. doi: 10.1002/mrm.26532 27797108

37. Ordidge RJ, Connelly A, Lohman JA. Image-selected in vivo spectroscopy (ISIS). A new technique for spatially selective NMR spectroscopy. Journal of Magnetic Resonance (1969). 1986;66(2):283–94.

38. Bottomley P, Charles H, Roemer P, Flamig D, Engeseth H, Edelstein W, et al. Human in vivo phosphate metabolite imaging with 31P NMR. Magn Reson Med. 1988;7(3):319–36. doi: 10.1002/mrm.1910070309 3205148

39. Chen C, Morris P, Francis S, Gowland P, editors. A comparison of MEGA-sLASER and STEAM for in vivo quantification of GABA at 7T. Proc Int Soc Magn Reson Med; 2015.

40. Behar KL, Rothman DL, Spencer DD, Petroff OA. Analysis of macromolecule resonances in 1H NMR spectra of human brain. Magn Reson Med. 1994;32(3):294–302. doi: 10.1002/mrm.1910320304 7984061

41. Behar KL, Ogino T. Characterization of macromolecule resonances in the 1H NMR spectrum of rat brain. Magn Reson Med. 1993;30(1):38–44. doi: 10.1002/mrm.1910300107 8371672

42. Mullins PG, McGonigle DJ, O'gorman RL, Puts NA, Vidyasagar R, Evans CJ, et al. Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage. 2014;86:43–52. doi: 10.1016/j.neuroimage.2012.12.004 23246994

43. Scheenen TW, Heerschap A, Klomp DW. Towards 1H-MRSI of the human brain at 7T with slice-selective adiabatic refocusing pulses. Magnetic Resonance Materials in Physics, Biology and Medicine. 2008;21(1–2):95.

44. Scheenen TW, Klomp DW, Wijnen JP, Heerschap A. Short echo time 1H‐MRSI of the human brain at 3T with minimal chemical shift displacement errors using adiabatic refocusing pulses. Magn Reson Med. 2008;59(1):1–6. doi: 10.1002/mrm.21302 17969076

45. Ogg RJ, Kingsley R, Taylor JS. WET, a T1-and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy. Journal of Magnetic Resonance, Series B. 1994;104(1):1–10.

46. Terpstra M, Cheong I, Lyu T, Deelchand DK, Emir UE, Bednařík P, et al. Test‐retest reproducibility of neurochemical profiles with short‐echo, single‐voxel MR spectroscopy at 3T and 7T. Magn Reson Med. 2016;76(4):1083–91. doi: 10.1002/mrm.26022 26502373

47. Boer V, van Lier A, Hoogduin J, Wijnen J, Luijten P, Klomp D. 7‐T 1H MRS with adiabatic refocusing at short TE using radiofrequency focusing with a dual‐channel volume transmit coil. NMR Biomed. 2011;24(9):1038–46. doi: 10.1002/nbm.1641 21294206

48. Ip IB, Berrington A, Hess AT, Parker AJ, Emir UE, Bridge H. Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. Neuroimage. 2017;155:113–9. doi: 10.1016/j.neuroimage.2017.04.030 28433623

49. Mugler JP, Brookeman JR. Three‐dimensional magnetization‐prepared rapid gradient‐echo imaging (3D MP RAGE). Magn Reson Med. 1990;15(1):152–7. doi: 10.1002/mrm.1910150117 2374495

50. Gruetter R, Tkáč I. Field mapping without reference scan using asymmetric echo‐planar techniques. Magn Reson Med. 2000;43(2):319–23. doi: 10.1002/(sici)1522-2594(200002)43:2<319::aid-mrm22>3.0.co;2-1 10680699

51. Roemer PB, Edelstein WA, Hayes CE, Souza SP, Mueller O. The NMR phased array. Magn Reson Med. 1990;16(2):192–225. doi: 10.1002/mrm.1910160203 2266841

52. Naressi A, Couturier C, Devos J, Janssen M, Mangeat C, De Beer R, et al. Java-based graphical user interface for the MRUI quantitation package. Magnetic resonance materials in physics, biology and medicine. 2001;12(2–3):141.

53. Naressi A, Couturier C, Castang I, De Beer R, Graveron-Demilly D. Java-based graphical user interface for MRUI, a software package for quantitation of in vivo/medical magnetic resonance spectroscopy signals. Comput Biol Med. 2001;31(4):269–86. doi: 10.1016/s0010-4825(01)00006-3 11334636

54. Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13(3):129–53. 10861994

55. Govind V, Young K, Maudsley AA. Corrigendum: Proton NMR chemical shifts and coupling constants for brain metabolites. Govindaraju V Young K, Maudsley AA, NMR Biomed. 2000; 13: 129–153. NMR Biomed. 2015;28(7):923–4. 10861994

56. Provencher SW. LCModel & LCMgui user’s manual. LCModel Version. 2016:6.3-1L.

57. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A, et al. Reduction in occipital cortex γ-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry. 2007;61(6):806–12. doi: 10.1016/j.biopsych.2006.08.048 17210135

58. Raschke F, Fuster‐Garcia E, Opstad K, Howe F. Classification of single‐voxel 1H spectra of brain tumours using LCModel. NMR Biomed. 2012;25(2):322–31. doi: 10.1002/nbm.1753 21796709

59. Chowdhury FA, O'Gorman RL, Nashef L, Elwes RD, RA Edden, JB Murdoch, et al. Investigation of glutamine and GABA levels in patients with idiopathic generalized epilepsy using MEGAPRESS. J Magn Reson Imaging. 2015;41(3):694–9. doi: 10.1002/jmri.24611 24585443

60. Kreis R. The trouble with quality filtering based on relative Cramér‐Rao lower bounds. Magn Reson Med. 2016;75(1):15–8. doi: 10.1002/mrm.25568 25753153

61. Edden RA, Intrapiromkul J, Zhu H, Cheng Y, Barker PB. Measuring T2 in vivo with J‐difference editing: Application to GABA at 3 tesla. J Magn Reson Imaging. 2012;35(1):229–34. doi: 10.1002/jmri.22865 22045601

62. Intrapiromkul J, Zhu H, Cheng Y, Barker PB, Edden RA. Determining the in vivo transverse relaxation time of GABA in the human brain at 7T. J Magn Reson Imaging. 2013;38(5):1224–9. doi: 10.1002/jmri.23979 23239232

63. Bland JM, Altman D. Statistical methods for assessing agreement between two methods of clinical measurement. The lancet. 1986;327(8476):307–10.

64. Joanna L, James P, Anthony A, Garnette RS. Nuclear magnetic resonance study of cerebrospinal fluid from patients with multiple sclerosis. Can J Neurol Sci. 1993;20(3):194–8. 8221382

65. Bhattacharyya P, Phillips M, Stone L, Lowe M. In-vivo MRS measurement of gray-matter and white-matter GABA concentration in sensorimotor cortex using a motion-controlled MEGA-PRESS Sequence. Magn Reson Imaging. 2011;29(3):374. doi: 10.1016/j.mri.2010.10.009 21232891

66. Rohani Rankouhi S, Hong D, Dyvorne H, Balchandani P, Norris DG. MASE‐sLASER, a short‐TE, matched chemical shift displacement error sequence for single‐voxel spectroscopy at ultrahigh field. NMR Biomed. 2018;31(7):e3940. doi: 10.1002/nbm.3940 29856517

67. Choi I-Y, Lee S-P, Merkle H, Shen J. In vivo detection of gray and white matter differences in GABA concentration in the human brain. Neuroimage. 2006;33(1):85–93. doi: 10.1016/j.neuroimage.2006.06.016 16884929

68. Perry T, Berry K, Hansen S, Diamond S, Mok C. Regional distribution of amino acids in human brain obtained at autopsy. J Neurochem. 1971;18(3):513–9. doi: 10.1111/j.1471-4159.1971.tb11979.x 5559257

69. Chen M, Li G, Zhang Z, Chen L, Pei M, Yan X, et al. The anterior cingulate cortex GABA levels with varied tissue composition measured by in vivo single voxel MRS. Proc Int Soc Magn Reson Med. 2016.

70. Mikkelsen M, Singh KD, Brealy JA, Linden DE, Evans CJ. Quantification of γ‐aminobutyric acid (GABA) in 1H MRS volumes composed heterogeneously of grey and white matter. NMR Biomed. 2016;29(11):1644–55. doi: 10.1002/nbm.3622 27687518

71. Öngür D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF. Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry. 2010;68(7):667–70. doi: 10.1016/j.biopsych.2010.05.016 20598290

72. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews PM, et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol. 2008;11(2):255–60. doi: 10.1017/S1461145707007924 17625025

73. Durst CR, Michael N, Tustison NJ, Patrie JT, Raghavan P, Wintermark M, et al. Noninvasive evaluation of the regional variations of GABA using magnetic resonance spectroscopy at 3 Tesla. Magn Reson Imaging. 2015;33(5):611–7. doi: 10.1016/j.mri.2015.02.015 25708260

74. Veen JWvd, Shen J. Regional difference in GABA levels between medial prefrontal and occipital cortices. J Magn Reson Imaging. 2013;38(3):745–50. doi: 10.1002/jmri.24009 23349060

75. Richardson M, Koepp M, Duncan J, Brooks D, Fish D. Benzodiazepine receptors in focal epilepsy with cortical dysgenesis: An 11C‐flumazenil PET study. Ann Neurol. 1996;40(2):188–98. doi: 10.1002/ana.410400210 8773600

76. D’Hulst C, Heulens I, Van der Aa N, Goffin K, Koole M, Porke K, et al. Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients. PLoS One. 2015;10(7):e0131486. doi: 10.1371/journal.pone.0131486 26222316

77. Nagamitsu S, Sakurai R, Matsuoka M, Chiba H, Ozono S, Tanigawa H, et al. Altered SPECT 123I-iomazenil Binding in the Cingulate Cortex of Children with Anorexia Nervosa. Frontiers in psychiatry. 2016;7. doi: 10.3389/fpsyt.2016.00007

78. Choi C, Banerjee A, Ganji S, Dimitrov I, Ghose S, Tamminga C. Contamination-free measurement of GABA in the human brain by optimized PRESS at 7.0 T in vivo Proc Intl Soc Mag Reson Med. 2012.

79. Shungu DC, Mao X, Gonzales R, Soones TN, Dyke JP, Veen JW, et al. Brain γ‐aminobutyric acid (GABA) detection in vivo with the J‐editing 1H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test–retest reliability. NMR Biomed. 2016;29(7):932–42. doi: 10.1002/nbm.3539 27173449

80. Mikkelsen M, Singh KD, Sumner P, Evans CJ. Comparison of the repeatability of GABA‐edited magnetic resonance spectroscopy with and without macromolecule suppression. Magn Reson Med. 2016;75(3):946–53. doi: 10.1002/mrm.25699 25920455


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