Skip to main content
Top
Published in: Brain Structure and Function 5/2014

01-09-2014 | Original Article

Microstructural organization of axons in the human corpus callosum quantified by diffusion-weighted magnetic resonance spectroscopy of N-acetylaspartate and post-mortem histology

Authors: Itamar Ronen, Matthew Budde, Ece Ercan, Jacopo Annese, Aranee Techawiboonwong, Andrew Webb

Published in: Brain Structure and Function | Issue 5/2014

Login to get access

Abstract

Diffusion-weighted magnetic resonance spectroscopy of brain metabolites offers unique access to compartment-specific microstructural information on neural tissue. Here, we investigated in detail the diffusion characteristics of the neuronal/axonal markers N-acetylaspartate + N-acetyl aspartyl glutamate (tNAA) in a small region of the human corpus callosum at 7 T. The diffusion-weighted spectroscopy data were analyzed by fitting to a model in which information about cross-callosal tract orientation within the spectroscopy volume, obtained from diffusion tensor imaging data, was incorporated. We estimated the microscopic misalignment of axons (σ φ  = 18.6° ± 3.0°) in excellent agreement with independent histological results (σ φ  = 18.1° ± 4.6°) obtained from microscopic analysis of axonal orientations in the body of the corpus callosum from post-mortem human brain slices. We also robustly quantified the diffusion coefficient of tNAA (0.51 ± 0.06 × 10−3 mm2/s) in axonal cytoplasm, unbiased by the tract curvature. This work supports the notion that microscopic axonal misalignment is a dominant microstructural property in white matter tracts and has a strong impact on the evaluation of tissue microstructure using diffusion information, and should therefore be taken into consideration in the evaluation of white matter microstructure. Additionally, this study enabled robust and unbiased assessment of the cytosolic diffusion coefficient of tNAA, a potential biomarker for axonopathy and neuronal degeneration.
Literature
go back to reference Aboitiz F, Scheibel AB, Fisher RS, Zaidel E (1992) Fiber composition of the human corpus callosum. Brain Res 598(1–2):143–153PubMedCrossRef Aboitiz F, Scheibel AB, Fisher RS, Zaidel E (1992) Fiber composition of the human corpus callosum. Brain Res 598(1–2):143–153PubMedCrossRef
go back to reference Annese J (2012) The importance of combining MRI and large-scale digital histology in neuroimaging studies of brain connectivity and disease. Front Neuroinform 6:13PubMedCentralPubMedCrossRef Annese J (2012) The importance of combining MRI and large-scale digital histology in neuroimaging studies of brain connectivity and disease. Front Neuroinform 6:13PubMedCentralPubMedCrossRef
go back to reference Arfanakis K, Haughton VM, Carew JD, Rogers BP, Dempsey RJ, Meyerand ME (2002) Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol 23(5):794–802PubMed Arfanakis K, Haughton VM, Carew JD, Rogers BP, Dempsey RJ, Meyerand ME (2002) Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol 23(5):794–802PubMed
go back to reference Assaf Y, Cohen Y (1998a) In vivo and in vitro bi-exponential diffusion of N-acetyl aspartate (NAA) in rat brain: a potential structural probe? NMR Biomed 11(2):67–74PubMedCrossRef Assaf Y, Cohen Y (1998a) In vivo and in vitro bi-exponential diffusion of N-acetyl aspartate (NAA) in rat brain: a potential structural probe? NMR Biomed 11(2):67–74PubMedCrossRef
go back to reference Assaf Y, Cohen Y (1998b) Non-mono-exponential attenuation of water and N-acetyl aspartate signals due to diffusion in brain tissue. J Magn Reson 131(1):69–85PubMedCrossRef Assaf Y, Cohen Y (1998b) Non-mono-exponential attenuation of water and N-acetyl aspartate signals due to diffusion in brain tissue. J Magn Reson 131(1):69–85PubMedCrossRef
go back to reference Assaf Y, Freidlin RZ, Rohde GK, Basser PJ (2004) New modeling and experimental framework to characterize hindered and restricted water diffusion in brain white matter. Magn Reson Med 52(5):965–978PubMedCrossRef Assaf Y, Freidlin RZ, Rohde GK, Basser PJ (2004) New modeling and experimental framework to characterize hindered and restricted water diffusion in brain white matter. Magn Reson Med 52(5):965–978PubMedCrossRef
go back to reference Assaf Y, Blumenfeld-Katzir T, Yovel Y, Basser PJ (2008) AxCaliber: a method for measuring axon diameter distribution from diffusion MRI. Magn Reson Med 59(6):1347–1354PubMedCrossRef Assaf Y, Blumenfeld-Katzir T, Yovel Y, Basser PJ (2008) AxCaliber: a method for measuring axon diameter distribution from diffusion MRI. Magn Reson Med 59(6):1347–1354PubMedCrossRef
go back to reference Avram L, Ozarslan E, Assaf Y, Bar-Shir A, Cohen Y, Basser PJ (2008) Three-dimensional water diffusion in impermeable cylindrical tubes: theory versus experiments. NMR Biomed 21(8):888–898PubMedCrossRef Avram L, Ozarslan E, Assaf Y, Bar-Shir A, Cohen Y, Basser PJ (2008) Three-dimensional water diffusion in impermeable cylindrical tubes: theory versus experiments. NMR Biomed 21(8):888–898PubMedCrossRef
go back to reference Budde MD, Frank JA (2012) Examining brain microstructure using structure tensor analysis of histological sections. Neuroimage 63(1):1–10PubMedCrossRef Budde MD, Frank JA (2012) Examining brain microstructure using structure tensor analysis of histological sections. Neuroimage 63(1):1–10PubMedCrossRef
go back to reference de Graaf RA, van Kranenburg A, Nicolay K (2000) In vivo (31)P-NMR diffusion spectroscopy of ATP and phosphocreatine in rat skeletal muscle. Biophys J 78(4):1657–1664PubMedCentralPubMedCrossRef de Graaf RA, van Kranenburg A, Nicolay K (2000) In vivo (31)P-NMR diffusion spectroscopy of ATP and phosphocreatine in rat skeletal muscle. Biophys J 78(4):1657–1664PubMedCentralPubMedCrossRef
go back to reference Dreher W, Busch E, Leibfritz D (2001) Changes in apparent diffusion coefficients of metabolites in rat brain after middle cerebral artery occlusion measured by proton magnetic resonance spectroscopy. Magn Reson Med 45(3):383–389PubMedCrossRef Dreher W, Busch E, Leibfritz D (2001) Changes in apparent diffusion coefficients of metabolites in rat brain after middle cerebral artery occlusion measured by proton magnetic resonance spectroscopy. Magn Reson Med 45(3):383–389PubMedCrossRef
go back to reference Ellegood J, Hanstock CC, Beaulieu C (2005) Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy. Magn Reson Med 53(5):1025–1032PubMedCrossRef Ellegood J, Hanstock CC, Beaulieu C (2005) Trace apparent diffusion coefficients of metabolites in human brain using diffusion weighted magnetic resonance spectroscopy. Magn Reson Med 53(5):1025–1032PubMedCrossRef
go back to reference Ellegood J, Hanstock CC, Beaulieu C (2006) Diffusion tensor spectroscopy (DTS) of human brain. Magn Reson Med 55(1):1–8PubMedCrossRef Ellegood J, Hanstock CC, Beaulieu C (2006) Diffusion tensor spectroscopy (DTS) of human brain. Magn Reson Med 55(1):1–8PubMedCrossRef
go back to reference Gallyas F (1979) Silver staining of myelin by means of physical development. Neurol Res 1(2):203–209PubMed Gallyas F (1979) Silver staining of myelin by means of physical development. Neurol Res 1(2):203–209PubMed
go back to reference Jenkinson M, Bannister P, Brady M, Smith S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17(2):825–841PubMedCrossRef Jenkinson M, Bannister P, Brady M, Smith S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17(2):825–841PubMedCrossRef
go back to reference Kan HE, Techawiboonwong A, van Osch MJ, Versluis MJ, Deelchand DK, Henry PG, Marjanska M, van Buchem MA, Webb AG, Ronen I (2012) Differences in apparent diffusion coefficients of brain metabolites between grey and white matter in the human brain measured at 7 T. Magn Reson Med 67(5):1203–1209PubMedCrossRef Kan HE, Techawiboonwong A, van Osch MJ, Versluis MJ, Deelchand DK, Henry PG, Marjanska M, van Buchem MA, Webb AG, Ronen I (2012) Differences in apparent diffusion coefficients of brain metabolites between grey and white matter in the human brain measured at 7 T. Magn Reson Med 67(5):1203–1209PubMedCrossRef
go back to reference Kim JH, Budde MD, Liang HF, Klein RS, Russell JH, Cross AH, Song SK (2006) Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol Dis 21(3):626–632PubMedCrossRef Kim JH, Budde MD, Liang HF, Klein RS, Russell JH, Cross AH, Song SK (2006) Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol Dis 21(3):626–632PubMedCrossRef
go back to reference Kroenke CD, Ackerman JJ, Yablonskiy DA (2004) On the nature of the NAA diffusion attenuated MR signal in the central nervous system. Magn Reson Med 52(5):1052–1059PubMedCrossRef Kroenke CD, Ackerman JJ, Yablonskiy DA (2004) On the nature of the NAA diffusion attenuated MR signal in the central nervous system. Magn Reson Med 52(5):1052–1059PubMedCrossRef
go back to reference Leemans A, Jeurissen B, Sijbers J, Jones DK (2009) ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. 17th Annual Meeting of International Society for Magnetic Resonance in Medicine, Hawaii, USA, p 3537 Leemans A, Jeurissen B, Sijbers J, Jones DK (2009) ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. 17th Annual Meeting of International Society for Magnetic Resonance in Medicine, Hawaii, USA, p 3537
go back to reference Leergaard TB, White NS, de Crespigny A, Bolstad I, D’Arceuil H, Bjaalie JG, Dale AM (2010) Quantitative histological validation of diffusion MRI fiber orientation distributions in the rat brain. PLoS ONE 5(1):e8595PubMedCentralPubMedCrossRef Leergaard TB, White NS, de Crespigny A, Bolstad I, D’Arceuil H, Bjaalie JG, Dale AM (2010) Quantitative histological validation of diffusion MRI fiber orientation distributions in the rat brain. PLoS ONE 5(1):e8595PubMedCentralPubMedCrossRef
go back to reference Marchadour C, Brouillet E, Hantraye P, Lebon V, Valette J (2012) Anomalous diffusion of brain metabolites evidenced by diffusion-weighted magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab 32(12):2153–2160PubMedCentralPubMedCrossRef Marchadour C, Brouillet E, Hantraye P, Lebon V, Valette J (2012) Anomalous diffusion of brain metabolites evidenced by diffusion-weighted magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab 32(12):2153–2160PubMedCentralPubMedCrossRef
go back to reference Merboldt KD, Horstermann D, Hanicke W, Bruhn H, Frahm J (1993) Molecular self-diffusion of intracellular metabolites in rat brain in vivo investigated by localized proton NMR diffusion spectroscopy. Magn Reson Med 29(1):125–129PubMedCrossRef Merboldt KD, Horstermann D, Hanicke W, Bruhn H, Frahm J (1993) Molecular self-diffusion of intracellular metabolites in rat brain in vivo investigated by localized proton NMR diffusion spectroscopy. Magn Reson Med 29(1):125–129PubMedCrossRef
go back to reference Moonen CT, van Zijl PC, Le Bihan D, DesPres D (1990) In vivo NMR diffusion spectroscopy: 31P application to phosphorus metabolites in muscle. Magn Reson Med 13(3):467–477PubMedCrossRef Moonen CT, van Zijl PC, Le Bihan D, DesPres D (1990) In vivo NMR diffusion spectroscopy: 31P application to phosphorus metabolites in muscle. Magn Reson Med 13(3):467–477PubMedCrossRef
go back to reference Neuman CH (1974) Spin-echo of spins diffusing in a bounded medium. J Chem Phys 60(11):4508–4511CrossRef Neuman CH (1974) Spin-echo of spins diffusing in a bounded medium. J Chem Phys 60(11):4508–4511CrossRef
go back to reference Nicolay K, van der Toorn A, Dijkhuizen RM (1995) In vivo diffusion spectroscopy. An overview. NMR Biomed 8(7–8):365–374PubMedCrossRef Nicolay K, van der Toorn A, Dijkhuizen RM (1995) In vivo diffusion spectroscopy. An overview. NMR Biomed 8(7–8):365–374PubMedCrossRef
go back to reference Nicolay K, Braun KP, Graaf RA, Dijkhuizen RM, Kruiskamp MJ (2001) Diffusion NMR spectroscopy. NMR Biomed 14(2):94–111PubMedCrossRef Nicolay K, Braun KP, Graaf RA, Dijkhuizen RM, Kruiskamp MJ (2001) Diffusion NMR spectroscopy. NMR Biomed 14(2):94–111PubMedCrossRef
go back to reference Nilsson M, Latt J, Stahlberg F, van Westen D, Hagslatt H (2012) The importance of axonal undulation in diffusion MR measurements: a Monte Carlo simulation study. NMR Biomed 25(5):795–805PubMedCrossRef Nilsson M, Latt J, Stahlberg F, van Westen D, Hagslatt H (2012) The importance of axonal undulation in diffusion MR measurements: a Monte Carlo simulation study. NMR Biomed 25(5):795–805PubMedCrossRef
go back to reference Pfeuffer J, Tkac I, Gruetter R (2000) Extracellular-intracellular distribution of glucose and lactate in the rat brain assessed noninvasively by diffusion-weighted 1H nuclear magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab 20(4):736–746PubMedCrossRef Pfeuffer J, Tkac I, Gruetter R (2000) Extracellular-intracellular distribution of glucose and lactate in the rat brain assessed noninvasively by diffusion-weighted 1H nuclear magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab 20(4):736–746PubMedCrossRef
go back to reference Posse S, Cuenod CA, Le Bihan D (1993) Human brain: proton diffusion MR spectroscopy. Radiology 188(3):719–725PubMedCrossRef Posse S, Cuenod CA, Le Bihan D (1993) Human brain: proton diffusion MR spectroscopy. Radiology 188(3):719–725PubMedCrossRef
go back to reference Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30(6):672–679PubMedCrossRef Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30(6):672–679PubMedCrossRef
go back to reference Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003) Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20(3):1714–1722PubMedCrossRef Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003) Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20(3):1714–1722PubMedCrossRef
go back to reference Tallantyre EC, Bo L, Al-Rawashdeh O, Owens T, Polman CH, Lowe JS, Evangelou N (2010) Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler 16(4):406–411PubMedCrossRef Tallantyre EC, Bo L, Al-Rawashdeh O, Owens T, Polman CH, Lowe JS, Evangelou N (2010) Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler 16(4):406–411PubMedCrossRef
go back to reference Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269PubMedCrossRef Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269PubMedCrossRef
go back to reference Upadhyay J, Hallock K, Erb K, Kim DS, Ronen I (2007) Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy. Magn Reson Med 58(5):1045–1053PubMedCrossRef Upadhyay J, Hallock K, Erb K, Kim DS, Ronen I (2007) Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy. Magn Reson Med 58(5):1045–1053PubMedCrossRef
go back to reference Valette J, Guillermier M, Besret L, Hantraye P, Bloch G, Lebon V (2007) Isoflurane strongly affects the diffusion of intracellular metabolites, as shown by 1H nuclear magnetic resonance spectroscopy of the monkey brain. J Cereb Blood Flow Metab 27(3):588–596PubMedCrossRef Valette J, Guillermier M, Besret L, Hantraye P, Bloch G, Lebon V (2007) Isoflurane strongly affects the diffusion of intracellular metabolites, as shown by 1H nuclear magnetic resonance spectroscopy of the monkey brain. J Cereb Blood Flow Metab 27(3):588–596PubMedCrossRef
go back to reference van der Toorn A, Dijkhuizen RM, Tulleken CA, Nicolay K (1996) Diffusion of metabolites in normal and ischemic rat brain measured by localized 1H MRS. Magn Reson Med 36(6):914–922PubMedCrossRef van der Toorn A, Dijkhuizen RM, Tulleken CA, Nicolay K (1996) Diffusion of metabolites in normal and ischemic rat brain measured by localized 1H MRS. Magn Reson Med 36(6):914–922PubMedCrossRef
go back to reference van Doorn A, Bovendeerd PH, Nicolay K, Drost MR, Janssen JD (1996) Determination of muscle fibre orientation using diffusion-weighted MRI. Eur J Morphol 34(1):5–10PubMedCrossRef van Doorn A, Bovendeerd PH, Nicolay K, Drost MR, Janssen JD (1996) Determination of muscle fibre orientation using diffusion-weighted MRI. Eur J Morphol 34(1):5–10PubMedCrossRef
go back to reference van Gelderen P, DesPres D, van Zijl PC, Moonen CT (1994) Evaluation of restricted diffusion in cylinders. Phosphocreatine in rabbit leg muscle. J Magn Reson B 103(3):255–260PubMedCrossRef van Gelderen P, DesPres D, van Zijl PC, Moonen CT (1994) Evaluation of restricted diffusion in cylinders. Phosphocreatine in rabbit leg muscle. J Magn Reson B 103(3):255–260PubMedCrossRef
go back to reference Wahl M, Lauterbach-Soon B, Hattingen E, Jung P, Singer O, Volz S, Klein JC, Steinmetz H, Ziemann U (2007) Human motor corpus callosum: topography, somatotopy, and link between microstructure and function. J Neurosci 27(45):12132–12138PubMedCrossRef Wahl M, Lauterbach-Soon B, Hattingen E, Jung P, Singer O, Volz S, Klein JC, Steinmetz H, Ziemann U (2007) Human motor corpus callosum: topography, somatotopy, and link between microstructure and function. J Neurosci 27(45):12132–12138PubMedCrossRef
go back to reference Wood ET, Ronen I, Techawiboonwong A, Jones CK, Barker PB, Calabresi P, Harrison D, Reich DS (2012) Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 32(19):6665–6669PubMedCentralPubMedCrossRef Wood ET, Ronen I, Techawiboonwong A, Jones CK, Barker PB, Calabresi P, Harrison D, Reich DS (2012) Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 32(19):6665–6669PubMedCentralPubMedCrossRef
go back to reference Zhang H, Hubbard PL, Parker GJ, Alexander DC (2011) Axon diameter mapping in the presence of orientation dispersion with diffusion MRI. Neuroimage 56(3):1301–1315PubMedCrossRef Zhang H, Hubbard PL, Parker GJ, Alexander DC (2011) Axon diameter mapping in the presence of orientation dispersion with diffusion MRI. Neuroimage 56(3):1301–1315PubMedCrossRef
Metadata
Title
Microstructural organization of axons in the human corpus callosum quantified by diffusion-weighted magnetic resonance spectroscopy of N-acetylaspartate and post-mortem histology
Authors
Itamar Ronen
Matthew Budde
Ece Ercan
Jacopo Annese
Aranee Techawiboonwong
Andrew Webb
Publication date
01-09-2014
Publisher
Springer Berlin Heidelberg
Published in
Brain Structure and Function / Issue 5/2014
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI
https://doi.org/10.1007/s00429-013-0600-0

Other articles of this Issue 5/2014

Brain Structure and Function 5/2014 Go to the issue