Journal of Neurology

, Volume 260, Issue 1, pp 242–252 | Cite as

Diffuse axonal injury in mild traumatic brain injury: a 3D multivoxel proton MR spectroscopy study

  • Ivan I. Kirov
  • Assaf Tal
  • James S. Babb
  • Yvonne W. Lui
  • Robert I. Grossman
  • Oded GonenEmail author
Original Communication


Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging (1H-MRSI). T1- and T2-weighted MRI images and three-dimensional 1H-MRSI (480 voxels over 360 cm3, about 30 % of the brain) were acquired at 3 T from 26 mTBI patients (mean Glasgow Coma Scale score 14.7, 18–56 years old, 3–55 days after injury) and 13 healthy matched contemporaries as controls. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-matter/white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. In patients, mean NAA, Cr, Cho and mI concentrations in GM (8.4 ± 0.7, 6.9 ± 0.6, 1.3 ± 0.2, 5.5 ± 0.6 mM) and Cr, Cho and mI in WM (4.8 ± 0.5, 1.4 ± 0.2, 4.6 ± 0.7 mM) were not different from the values in controls. The NAA concentrations in WM, however, were significantly lower in patients than in controls (7.2 ± 0.8 vs. 7.7 ± 0.6 mM, p = 0.0125). The Cho and Cr levels in WM of patients were positively correlated with time since mTBI. This 1H-MRSI approach allowed us to ascertain that early mTBI sequelae are (1) diffuse (not merely local), (2) neuronal (not glial), and (3) in the global WM (not GM). These findings support the hypothesis that, similar to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction rather than cell death dominates shortly after injury.


Brain injury Diffuse axonal injury Magnetic resonance spectroscopy 



This work was supported by National Institutes of Health grants EB01015, NS39135, NS29029 and NS050520. Assaf Tal is also supported by the Human Frontiers Science Project. We thank Ms. Nissa Perry and Mr. Joseph Reaume for subject recruitment.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard

This work has been approved by the appropriate ethics committee and therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.


  1. 1.
    Faul M, Xu L, Wald M, Coronado V (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths, 2002–2006. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, AtlantaGoogle Scholar
  2. 2.
    Zaloshnja E, Miller T, Langlois JA, Selassie AW (2008) Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J Head Trauma Rehabil 23:394–400PubMedCrossRefGoogle Scholar
  3. 3.
    Snell FI, Halter MJ (2010) A signature wound of war: mild traumatic brain injury. J Psychosoc Nurs Ment Health Serv 48:22–28PubMedCrossRefGoogle Scholar
  4. 4.
    Tanelian T, Jaycox LH (2008) Invisible wounds of war report. RAND Corporation, Santa Monica, p 305Google Scholar
  5. 5.
    Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84PubMedCrossRefGoogle Scholar
  6. 6.
    MacGregor AJ, Shaffer RA, Dougherty AL, Galarneau MR, Raman R, Baker DG, Lindsay SP, Golomb BA, Corson KS (2010) Prevalence and psychological correlates of traumatic brain injury in operation Iraqi freedom. J Head Trauma Rehabil 25:1–8PubMedCrossRefGoogle Scholar
  7. 7.
    Ruff R (2005) Two decades of advances in understanding of mild traumatic brain injury. J Head Trauma Rehabil 20:5–18PubMedCrossRefGoogle Scholar
  8. 8.
    Buki A, Povlishock JT (2006) All roads lead to disconnection? – traumatic axonal injury revisited. Acta Neurochir (Wien) 148:181–193 (discussion 193–184)CrossRefGoogle Scholar
  9. 9.
    Iverson GL (2005) Outcome from mild traumatic brain injury. Curr Opin Psychiatry 18:301–317PubMedCrossRefGoogle Scholar
  10. 10.
    Inglese M, Bomsztyk E, Gonen O, Mannon LJ, Grossman RI, Rusinek H (2005) Dilated perivascular spaces: hallmarks of mild traumatic brain injury. AJNR Am J Neuroradiol 26:719–724PubMedGoogle Scholar
  11. 11.
    Bigler ED (2010) Neuroimaging in mild traumatic brain injury. Psychol Injury Law 3(1):36–49CrossRefGoogle Scholar
  12. 12.
    Wilson JT, Wiedmann KD, Hadley DM, Condon B, Teasdale G, Brooks DN (1988) Early and late magnetic resonance imaging and neuropsychological outcome after head injury. J Neurol Neurosurg Psychiatry 51:391–396PubMedCrossRefGoogle Scholar
  13. 13.
    Niogi SN, Mukherjee P (2010) Diffusion tensor imaging of mild traumatic brain injury. J Head Trauma Rehabil 25:241–255PubMedCrossRefGoogle Scholar
  14. 14.
    Mayer AR, Mannell MV, Ling J, Gasparovic C, Yeo RA (2011) Functional connectivity in mild traumatic brain injury. Hum Brain Mapp 32(11):1825–1835PubMedCrossRefGoogle Scholar
  15. 15.
    Marino S, Ciurleo R, Bramanti P, Federico A, De Stefano N (2010) 1H-MR spectroscopy in traumatic brain injury. Neurocrit Care 14:127–133CrossRefGoogle Scholar
  16. 16.
    Gasparovic C, Yeo R, Mannell M, Ling J, Elgie R, Phillips J, Doezema D, Mayer A (2009) Neurometabolite concentrations in gray and white matter in mild traumatic brain injury: a 1H magnetic resonance spectroscopy study. J Neurotrauma 26(10):1635–1643PubMedCrossRefGoogle Scholar
  17. 17.
    Yeo RA, Gasparovic C, Merideth F, Ruhl D, Doezema D, Mayer AR (2011) A longitudinal proton magnetic resonance spectroscopy study of mild traumatic brain injury. J Neurotrauma 28:1–11PubMedCrossRefGoogle Scholar
  18. 18.
    Kirov II, George IC, Jayawickrama N, Babb JS, Perry NN, Gonen O (2012) Longitudinal inter- and intra-individual human brain metabolic quantification over 3 years with proton MR spectroscopy at 3 T. Magn Reson Med 67:27–33PubMedCrossRefGoogle Scholar
  19. 19.
    Tal A, Kirov II, Grossman RI, Gonen O (2012) The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging. NMR Biomed. doi: 10.1002/nbm.2812
  20. 20.
    Kreis R, Slotboom J, Hofmann L, Boesch C (2005) Integrated data acquisition and processing to determine metabolite contents, relaxation times, and macromolecule baseline in single examinations of individual subjects. Magn Reson Med 54:761–768PubMedCrossRefGoogle Scholar
  21. 21.
    Hu J, Javaid T, Arias-Mendoza F, Liu Z, McNamara R, Brown TR (1995) A fast, reliable, automatic shimming procedure using 1H chemical-shift-imaging spectroscopy. J Magn Reson B 108:213–219PubMedCrossRefGoogle Scholar
  22. 22.
    Goelman G, Liu S, Hess D, Gonen O (2006) Optimizing the efficiency of high-field multivoxel spectroscopic imaging by multiplexing in space and time. Magn Reson Med 56:34–40PubMedCrossRefGoogle Scholar
  23. 23.
    Ashburner J, Friston K (1997) Multimodal image coregistration and partitioning – a unified framework. Neuroimage 6:209–217PubMedCrossRefGoogle Scholar
  24. 24.
    Soher BJ, Young K, Govindaraju V, Maudsley AA (1998) Automated spectral analysis III: application to in vivo proton MR spectroscopy and spectroscopic imaging. Magn Reson Med 40:822–831PubMedCrossRefGoogle Scholar
  25. 25.
    Traber F, Block W, Lamerichs R, Gieseke J, Schild HH (2004) 1H metabolite relaxation times at 3.0 tesla: measurements of T1 and T2 values in normal brain and determination of regional differences in transverse relaxation. J Magn Reson Imaging 19:537–545PubMedCrossRefGoogle Scholar
  26. 26.
    Kirov II, Fleysher L, Fleysher R, Patil V, Liu S, Gonen O (2008) Age dependence of regional proton metabolites T2 relaxation times in the human brain at 3 T. Magn Reson Med 60:790–795PubMedCrossRefGoogle Scholar
  27. 27.
    Posse S, Otazo R, Caprihan A, Bustillo J, Chen H, Henry PG, Marjanska M, Gasparovic C, Zuo C, Magnotta V, Mueller B, Mullins P, Renshaw P, Ugurbil K, Lim KO, Alger JR (2007) Proton echo-planar spectroscopic imaging of J-coupled resonances in human brain at 3 and 4 Tesla. Magn Reson Med 58(2):236–244PubMedCrossRefGoogle Scholar
  28. 28.
    Cecil KM, Hills EC, Sandel ME, Smith DH, McIntosh TK, Mannon LJ, Sinson GP, Bagley LJ, Grossman RI, Lenkinski RE (1998) Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients. J Neurosurg 88:795–801PubMedCrossRefGoogle Scholar
  29. 29.
    Govindaraju V, Gauger GE, Manley GT, Ebel A, Meeker M, Maudsley AA (2004) Volumetric proton spectroscopic imaging of mild traumatic brain injury. AJNR Am J Neuroradiol 25:730–737PubMedGoogle Scholar
  30. 30.
    Govind V, Gold S, Kaliannan K, Saigal G, Falcone S, Arheart KL, Harris L, Jagid J, Maudsley AA (2010) Whole-brain proton MR spectroscopic imaging of mild-to-moderate traumatic brain injury and correlation with neuropsychological deficits. J Neurotrauma 27:483–496PubMedCrossRefGoogle Scholar
  31. 31.
    Garnett MR, Blamire AM, Rajagopalan B, Styles P, Cadoux-Hudson TA (2000) Evidence for cellular damage in normal-appearing white matter correlates with injury severity in patients following traumatic brain injury: a magnetic resonance spectroscopy study. Brain 123:1403–1409PubMedCrossRefGoogle Scholar
  32. 32.
    Vagnozzi R, Signoretti S, Tavazzi B, Floris R, Ludovici A, Marziali S, Tarascio G, Amorini AM, Di Pietro V, Delfini R, Lazzarino G (2008) Temporal window of metabolic brain vulnerability to concussion: a pilot 1H-magnetic resonance spectroscopic study in concussed athletes – part III. Neurosurgery 62:1286–1295 (discussion 1295–1296)PubMedCrossRefGoogle Scholar
  33. 33.
    Vagnozzi R, Signoretti S, Cristofori L, Alessandrini F, Floris R, Isgro E, Ria A, Marziale S, Zoccatelli G, Tavazzi B, Del Bolgia F, Sorge R, Broglio SP, McIntosh TK, Lazzarino G (2010) Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients. Brain 133:3232–3242PubMedCrossRefGoogle Scholar
  34. 34.
    Son BC, Park CK, Choi BG, Kim EN, Choe BY, Lee KS, Kim MC, Kang JK (2000) Metabolic changes in pericontusional oedematous areas in mild head injury evaluated by 1H MRS. Acta Neurochir 76:13–16Google Scholar
  35. 35.
    Nakabayashi M, Suzaki S, Tomita H (2007) Neural injury and recovery near cortical contusions: a clinical magnetic resonance spectroscopy study. J Neurosurg 106:370–377PubMedCrossRefGoogle Scholar
  36. 36.
    Kirov I, Fleysher L, Babb JS, Silver JM, Grossman RI, Gonen O (2007) Characterizing ‘mild’ in traumatic brain injury with proton MR spectroscopy in the thalamus: initial findings. Brain Inj 21:1147–1154PubMedCrossRefGoogle Scholar
  37. 37.
    Farkas O, Povlishock JT (2007) Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. Prog Brain Res 161:43–59PubMedCrossRefGoogle Scholar
  38. 38.
    Graham DI, McIntosh TK, Maxwell WL, Nicoll JA (2000) Recent advances in neurotrauma. J Neuropathol Exp Neurol 59:641–651PubMedGoogle Scholar
  39. 39.
    Biasca N, Maxwell WL (2007) Minor traumatic brain injury in sports: a review in order to prevent neurological sequelae. Prog Brain Res 161:263–291PubMedCrossRefGoogle Scholar
  40. 40.
    Kraus MF, Susmaras T, Caughlin BP, Walker CJ, Sweeney JA, Little DM (2007) White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain 130:2508–2519PubMedCrossRefGoogle Scholar
  41. 41.
    Frahm J, Hanefeld F (1997) Localized proton magnetic spectroscopy of brain disorders in childhood. In: Bachelard HS (ed) Magnetic resonance spectroscopy and imaging in neurochemistry. Plenum Press, New York, pp 329–402CrossRefGoogle Scholar
  42. 42.
    Di Giovanni S, Movsesyan V, Ahmed F, Cernak I, Schinelli S, Stoica B, Faden AI (2005) Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci U S A 102:8333–8338PubMedCrossRefGoogle Scholar
  43. 43.
    Friedman SD, Brooks WM, Jung RE, Chiulli SJ, Sloan JH, Montoya BT, Hart BL, Yeo RA (1999) Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology 52:1384–1391PubMedCrossRefGoogle Scholar
  44. 44.
    Stein SC, Ross SE (1992) Mild head injury: a plea for routine early CT scanning. J Trauma 33:11–13PubMedCrossRefGoogle Scholar
  45. 45.
    Borg J, Holm L, Cassidy JD, Peloso PM, Carroll LJ, von Holst H, Ericson K (2004) Diagnostic procedures in mild traumatic brain injury: results of the WHO collaborating centre task force on mild traumatic brain injury. J Rehabil Med (43 Suppl):61–75Google Scholar
  46. 46.
    Culotta VP, Sementilli ME, Gerold K, Watts CC (1996) Clinicopathological heterogeneity in the classification of mild head injury. Neurosurgery 38:245–250PubMedCrossRefGoogle Scholar
  47. 47.
    Johnson VE, Stewart W, Smith DH (2012) Axonal pathology in traumatic brain injury. Exp Neurol (in press)Google Scholar
  48. 48.
    Baker EH, Basso G, Barker PB, Smith MA, Bonekamp D, Horska A (2008) Regional apparent metabolite concentrations in young adult brain measured by (1)H MR spectroscopy at 3 Tesla. J Magn Reson Imaging 27:489–499PubMedCrossRefGoogle Scholar
  49. 49.
    Ge Y, Grossman RI, Babb JS, Rabin ML, Mannon LJ, Kolson DL (2002) Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis. AJNR Am J Neuroradiol 23:1327–1333PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ivan I. Kirov
    • 1
  • Assaf Tal
    • 1
  • James S. Babb
    • 1
  • Yvonne W. Lui
    • 1
  • Robert I. Grossman
    • 1
  • Oded Gonen
    • 1
    Email author
  1. 1.Department of RadiologyNew York University School of MedicineNew YorkUSA

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