Absolute quantitation of brain metabolites with respect to heterogeneous tissue compositions in 1H-MR spectroscopic volumes

  • Alexander GussewEmail author
  • Marko Erdtel
  • Patrick Hiepe
  • Reinhard Rzanny
  • Jürgen R. Reichenbach
Research Article



Referencing metabolite intensities to the tissue water intensity is commonly applied to determine metabolite concentrations from in vivo 1H-MRS brain data. However, since the water concentration and relaxation properties differ between grey matter, white matter and cerebrospinal fluid (CSF), the volume fractions of these compartments have to be considered in MRS voxels.

Materials and methods

The impact of partial volume correction was validated by phantom measurements in voxels containing mixtures of solutions with different NAA and water concentrations as well as by analyzing in vivo 1H-MRS brain data acquired with various voxel compositions.


Phantom measurements indicated substantial underestimation of NAA concentrations when assuming homogeneously composed voxels, especially for voxels containing solution, which simulated CSF (error: ≤92%). This bias was substantially reduced by taking into account voxel composition (error: ≤10%). In the in vivo study, tissue correction reduced the overall variation of quantified metabolites by up to 35% and revealed the expected metabolic differences between various brain tissues.


Tissue composition affects extraction of metabolite concentrations and may cause misinterpretations when comparing measurements performed with different voxel sizes. This variation can be reduced by considering the different tissue types by means of combined analysis of spectroscopic and imaging data.


1H-MRS Absolute quantitation Brain Tissue segmentation Partial volume effect correction 



Proton magnetic resonance spectroscopy



T1 and T2

Longitudinal and transversal relaxation time constants


Absolute concentrations of metabolites and water


Quantitated intensity of metabolite


Quantitated intensity of water


Number of hydrogen nuclei within the metabolite molecule


Brain’s grey and white matter and cerebrospinal fluid

S1, S2, S3

Phantom solutions 1, 2 and 3

fGM, fWM, fCSF

Relative volume fractions of GM, WM and CSF within a voxel

fS1, fS2, fS3

Relative volume fractions of GM, WM and CSF within a voxel


Factor to consider the relaxation related signal attenuation


Free water concentration


Relative water content in tissue

NAA, Cr, tCho

N-acetyl-aspartate, creatine, total choline


Nominal water concentration in a phantom solution


Nominal NAA concentration in a phantom solution


Repetition time, echo time, inversion time


Field of view


Volunteer groups 1 and 2 (each consisting of seven persons)


Number of averaged single acquisitions


Signal to noise ratio


Full width at half maximum


Cramer Rao lower bound


Metabolite concentration calculated by assuming homogeneous tissue composition in MRS voxel


Metabolite concentration calculated by considering the heterogeneous tissue composition in MRS voxel



This study was supported by the Centre for Interdisciplinary Prevention of Diseases related to Professional Activities (KIP) founded by the Friedrich-Schiller-University Jena and the Accident Prevention and Insurance Association for Food and Restaurants (Berufsgenossenschaft Nahrungsmittel und Gaststätten, BGN, Germany). A. G. acknowledges support from a stipend provided by KIP (project 1.1.29). This project was also supported by the Deutsche Forschungsgemeinschaft (DFG 1123/11-1) and by the Bernstein Group for Computational Neuroscience Jena (BMBF 01GQ0703). We acknowledge Mary Atterbury for her support in manuscript preparation and proof reading.


  1. 1.
    Mountford CE, Stanwell P, Lin A, Ramadan S, Ross B (2010) Neurospectroscopy: the past, present and future. Chem Rev 110(5):3060–3086PubMedCrossRefGoogle Scholar
  2. 2.
    Mason GF, Krystal JH (2006) MR spectroscopy: its potential role for drug development for the treatment of psychiatric diseases. NMR Biomed 19(6):690–701PubMedCrossRefGoogle Scholar
  3. 3.
    Gussew A, Rzanny R, Güllmar D, Scholle H-C, 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):1315–1323PubMedCrossRefGoogle Scholar
  4. 4.
    Reinert M, Schneider P, Hofmann E, Semmler W (2010) Quantitative MR-spectroscopy: implementation and quality assurance on a clinical MR-scanner. Z Med Phys 20(3):176–187PubMedGoogle Scholar
  5. 5.
    Jansen JFA, Backes WH, Nicolay K, Kooi ME (2006) 1H-MR spectroscopy of the brain: absolute quantification of metabolites. Radiology 240(2):318–332PubMedCrossRefGoogle Scholar
  6. 6.
    Ernst T, Kreis R, Ross B (1993) Absolute quantitation of water and metabolites in the human brain. I. Compartments and water. J Magn Reson B 102:1–8CrossRefGoogle Scholar
  7. 7.
    Mlynárik V, Gruber S, Moser E (2001) Proton T1 and T2 relaxation times of human brain metabolites at 3 Tesla. NMR Biomed 14(5):325–331PubMedCrossRefGoogle Scholar
  8. 8.
    Stanisz GJ, Odrobina EE, Pun J, Escaravage M, Graham SJ, Bronskill MJ, Henkelman RM (2005) T1, T2 relaxation and magnetization transfer in tissue at 3T. Magn Reson Med 54(3):507–512PubMedCrossRefGoogle Scholar
  9. 9.
    Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG, Posse S, Jung RE, Morrison LA (2006) Use of tissue water as a concentration reference for proton spectroscopic imaging. Magn Reson Med 55(6):1219–1226PubMedCrossRefGoogle Scholar
  10. 10.
    Hetherington HP, Pan JW, Mason GF, Adams D, Vaughn MJ, Twieg DB, Pohost GM (1996) Quantitative 1H spectroscopic imaging of human brain at 4.1 T using image segmentation. Magn Reson Med 36(1):21–29PubMedCrossRefGoogle Scholar
  11. 11.
    Wang Y, Li SJ (1998) Differentiation of metabolic concentrations between gray matter and white matter of human brain by in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 39(1):28–33PubMedCrossRefGoogle Scholar
  12. 12.
    Noworolski SM, Nelson SJ, Henry RG, Day MR, Wald LL, Star-Lack J, Vigneron DB (1999) High spatial resolution 1H-MRSI and segmented MRI of cortical gray matter and subcortical white matter in three regions of the human brain. Magn Reson Med 41(1):21–29PubMedCrossRefGoogle Scholar
  13. 13.
    Brooks JCW, Roberts N, Kemp GJ, Gosney MA, Lye M, Whitehouse GH (2001) A proton magnetic resonance spectroscopy study of age-related changes in frontal lobe metabolite concentrations. Cereb Cortex 11:598–605PubMedCrossRefGoogle Scholar
  14. 14.
    Weber-Fahr W, Ende G, Braus DF, Bachert P, Soher BJ, Henn FA, Büchel C (2002) A fully automated method for tissue segmentation and CSF correction of proton MRSI metabolites corroborates abnormal hippocampal NAA in schizophrenia. Neuroimage 16(1):49–60PubMedCrossRefGoogle Scholar
  15. 15.
    Neuroimaging Informatics Technology Initiative. Accessed April 2009
  16. 16.
    Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9(2):179–194PubMedCrossRefGoogle Scholar
  17. 17.
    Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 9(2):195–207PubMedCrossRefGoogle Scholar
  18. 18.
    Klose U (1990) In vivo proton spectroscopy in presence of eddy currents. Magn Reson Med 14(1):26–30PubMedCrossRefGoogle Scholar
  19. 19.
    Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30(6):672–679PubMedCrossRefGoogle Scholar
  20. 20.
    Seeger U, Klose U, Mader I, Grodd W, Nägele T (2003) Parameterized evaluation of macromolecules and lipids in proton MR spectroscopy of brain diseases. Magn Reson Med 49:19–28PubMedCrossRefGoogle Scholar
  21. 21.
    Lin C, Bernstein M, Huston J, Fain S (2001) Measurements of T1 relaxation times at 3.0: implications for clinical MRA. In: Proceedings of international society for magnetic resonance in medicine. 11, 21–27 Apr 2001, Glasgow, Scotland, p 1391Google Scholar
  22. 22.
    Piechnik SK, Evans J, Bary LH, Wise RG, Jezzard P (2009) Functional changes in CSF volume estimated using measurement of water T2 relaxation. Magn Reson Med 61(3):579–586PubMedCrossRefGoogle Scholar
  23. 23.
    Zaaraoui W, Fleysher L, Fleysher R, Liu S, Soher BJ, Gonen O (2007) Human brain-structure resolved T2 relaxation times of proton metabolites at 3 Tesla. Magn Reson Med 57(6):983–989PubMedCrossRefGoogle Scholar
  24. 24.
    Cavassila S, Deval S, Huegen C, van Ormondt D, Graveron-Demilly D (2001) Cramér-Rao bounds: an evaluation tool for quantitation. NMR Biomed 14(4):278–283PubMedCrossRefGoogle Scholar
  25. 25.
    Pohmann R, von Kienlin M (2001) Accurate phosphorus metabolite images of the human heart by 3D acquisition-weighted CSI. Magn Reson Med 45:817–826PubMedCrossRefGoogle Scholar
  26. 26.
    Malucelli E, Manners DN, Testa C, Tonon C, Lodi R, Barbiroli B, Iotti S (2009) Pitfalls and advantages of different strategies for the absolute quantification of n-acetyl aspartate, creatine and choline in white and grey matter by 1H-MRS. NMR Biomed 22(10):1003–1013PubMedGoogle Scholar
  27. 27.
    Brief EE, Moll R, Li DKB, Mackay AL (2009) Absolute metabolite concentrations calibrated using the total water signal in brain 1H-MRS. NMR Biomed 22(3):349–354PubMedCrossRefGoogle Scholar
  28. 28.
    Natt O, Bezkorovaynyy V, Michaelis T, Frahm J (2005) Use of phased array coils for a determination of absolute metabolite concentrations. Magn Reson Med 53(1):3–8PubMedCrossRefGoogle Scholar
  29. 29.
    Tofts PS, du Boulay EP (1990) Towards quantitative measurements of relaxation times and other parameters in the brain. Neuroradiology 32(5):407–415PubMedCrossRefGoogle Scholar
  30. 30.
    Papanikolaou N, Papadaki E, Karampekios S, Spilioti M, Maris T, Prassopoulos P, Gourtsoyiannis N (2004) T2 relaxation time analysis in patients with multiple sclerosis: correlation with magnetization transfer ratio. Eur Radiol 14:115–122PubMedCrossRefGoogle Scholar
  31. 31.
    Parry A, Clare S, Jenkinson M, Smith S, Palace J, Matthews PM (2002) White matter and lesion T1 relaxation times increase in parallel and correlate with disability in multiple sclerosis. J Neurol 249:1279–1286PubMedCrossRefGoogle Scholar
  32. 32.
    Ashton EA, Takahashi C, Berg MJ, Goodman A, Totterman S, Ekholm S (2003) Accuracy and reproducibility of manual and semiautomated quantification of MS lesions by MRI. J Magn Reson Imaging 17(3):300–308PubMedCrossRefGoogle Scholar
  33. 33.
    Deeley MA, Chen A, Datteri R, Noble JH, Cmelak AJ, Donnelly EFR, Malcolm AW, Moretti L, Jaboin J, Niermann K, Yang ES, Yu DS, Yei F, Koyama T, Ding GX, Dawant BM (2011) Comparison of manual and automatic segmentation methods for brain structures in the presence of space-occupying lesions: a multi-expert study. Phys Med Biol 56:4557–4577PubMedCrossRefGoogle Scholar
  34. 34.
    Martín-Landrove M, Mayobre F, Bautista I, Villalta R (2005) Brain tumor evaluation and segmentation by in vivo proton spectroscopy and relaxometry. Magn Reson Mater Phys Biol Med 18(6):316–331Google Scholar
  35. 35.
    Pollo C, Cuadra MB, Cuisenaire O, Villemure JG, Thiran JP (2005) Segmentation of brain structures in presence of a space-occupying lesion. Neuroimage. 24(4):990–996PubMedCrossRefGoogle Scholar
  36. 36.
    Gasparovic C, Neeb H, Feis DL, Damaraju E, Chen H, Doty MJ, South DM, Mullins PG, Bockholt HJ, Shah NJ (2009) Quantitative spectroscopic imaging with in situ measurements of tissue water T1, T2, and density. Magn Reson Med 62(3):583–590PubMedCrossRefGoogle Scholar
  37. 37.
    Jenkinson M, Smith SM (2001) A global optimisation method for robust affine registration of brain images. Med Image Anal 5(2):143–156PubMedCrossRefGoogle Scholar
  38. 38.
    Woolrich MW, Jbabdi S, Patenaude B, Chappell M, Makni S, Behrens T, Beckmann C, Jenkinson M, Smith SM (2009) Bayesian analysis of neuroimaging data in FSL. NeuroImage 45:S173–S186PubMedCrossRefGoogle Scholar

Copyright information

© ESMRMB 2012

Authors and Affiliations

  • Alexander Gussew
    • 1
    Email author
  • Marko Erdtel
    • 1
    • 2
  • Patrick Hiepe
    • 1
  • Reinhard Rzanny
    • 1
  • Jürgen R. Reichenbach
    • 1
  1. 1.Medical Physics Group, Institute of Diagnostic and Interventional Radiology IJena University Hospital—Friedrich Schiller University JenaJenaGermany
  2. 2.Department of Medical PhysicsNinewells Hospital and Medical School, University of DundeeDundeeUK

Personalised recommendations