, Volume 60, Issue 5, pp 505–515 | Cite as

Beyond fractional anisotropy in amyotrophic lateral sclerosis: the value of mean, axial, and radial diffusivity and its correlation with electrophysiological conductivity changes

  • Ana Filipa Geraldo
  • João Pereira
  • Pedro Nunes
  • Sofia Reimão
  • Rita Sousa
  • Miguel Castelo-Branco
  • Susana Pinto
  • Jorge Guedes Campos
  • Mamede de Carvalho
Functional Neuroradiology



This paper aims to analyze the contribution of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in the detection of microstructural abnormalities in amyotrophic lateral sclerosis (ALS) and to evaluate the degree of agreement between structural and functional changes through concomitant diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), and clinical assessment.


Fourteen patients with ALS and 11 healthy, age- and gender-matched controls were included. All participants underwent magnetic resonance imaging including DTI. TMS was additionally performed in ALS patients. Differences in the distribution of DTI-derived measures were assessed using tract-based spatial statistical (TBSS) and volume of interest (VOI) analyses. Correlations between clinical, imaging, and neurophysiological findings were also assessed through TBSS.


ALS patients showed a significant increase in AD and MD involving the corticospinal tract (CST) and the pre-frontal white matter in the right posterior limb of the internal capsule (p < 0.05) when compared to the control group using TBSS, confirmed by VOI analyses. VOI analyses also showed increased AD in the corpus callosum (p < 0.05) in ALS patients. Fractional anisotropy (FA) in the right CST correlated significantly with upper motor neuron (UMN) score (r = − 0.79, p < 0.05), and right abductor digiti minimi central motor conduction time was highly correlated with RD in the left posterior internal capsule (r = − 0.81, p < 0.05). No other significant correlation was found.


MD, AD, and RD, besides FA, are able to further detect and characterize neurodegeneration in ALS. Furthermore, TMS and DTI appear to have a role as complementary diagnostic biomarkers of UMN dysfunction.


Amyotrophic lateral sclerosis Diffusion tensor imaging Magnetic resonance imaging Motor neuron disease Transcranial magnetic stimulation 



Axial diffusivity


Abductor digiti minimi


Abductor hallucis


Amyotrophic lateral sclerosis


Amyotrophic lateral sclerosis functional rate scale revisited


Compound motor action potentials


Central motor conduction time


Cortical silent period


Corticospinal tract


Diffusion tensor imaging


Fractional anisotropy


Lower motor neuron


Mean diffusivity


Motor evoked potential


Magnetic resonance imaging


Motor threshold


Radial diffusivity


Tract-based spatial statistical


Transcranial magnetic stimulation


Upper motor neuron


Volume of interest


Compliance with ethical standards


No funding was received for this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–312. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119:497–403. CrossRefPubMedGoogle Scholar
  3. 3.
    Chiò A, Pagani M, Agosta F, Calvo A, Cistaro A, Filippi M (2014) Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. Lancet Neurol 13:1228–1240. CrossRefPubMedGoogle Scholar
  4. 4.
    Foerster BR, Welsh RC, Feldman EL (2013) 25 years of neuroimaging in amyotrophic lateral sclerosis. Nat Rev Neurol 9:513–524. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chenevert TL, Brunberg JA, Pipe JG (1990) Anisotropic diffusion in human white matter: demonstration with MR techniques in vivo. Radiology 177:401–405CrossRefPubMedGoogle Scholar
  6. 6.
    Agosta F, Pagani E, Petrolini M, Caputo D, Perini M, Prelle A, Salvi F, Filippi M (2010) Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. AJNR Am J Neuroradiol 31:1457–1461. CrossRefPubMedGoogle Scholar
  7. 7.
    Metwalli NS, Benatar M, Nair G, Usher S, Hu X, Carew JD (2010) Utility of axial and radial diffusivity from diffusion tensor MRI as markers of neurodegeneration in amyotrophic lateral sclerosis. Brain Res 1348:156–164. CrossRefPubMedGoogle Scholar
  8. 8.
    Canu E, Agosta F, Riva N, Sala S, Prelle A, Caputo D, Perini M, Comi G, Filippi M (2011) The topography of brain microstructural damage in amyotrophic lateral sclerosis assessed using diffusion tensor MR imaging. AJNR Am J Neuroradiol 32(7):1307–1314. CrossRefPubMedGoogle Scholar
  9. 9.
    Cirillo M, Esposito F, Tedeschi G, Caiazzo G, Sagnelli A, Piccirillo G, Conforti R, Tortora F, Monsurrò MR, Cirillo S, Trojsi F (2012) Widespread microstructural white matter involvement in amyotrophic lateral sclerosis: a whole-brain DTI study. Am J Neuroradiol 33:1102–8.18. CrossRefPubMedGoogle Scholar
  10. 10.
    Rajagopalan V, Yue GH, Pioro EP (2013) Brain white matter diffusion tensor metrics from clinical 1.5 T MRI distinguish between ALS phenotypes. J Neurol 260(10):2532–2540. CrossRefPubMedGoogle Scholar
  11. 11.
    Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. NeuroImage 17(3):1429–1436CrossRefPubMedGoogle Scholar
  12. 12.
    Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, Armstrong RC (2005) Demyelination increases radial diffusivity in corpus callosum of mouse brain. NeuroImage 26(1):132–140CrossRefPubMedGoogle Scholar
  13. 13.
    Janve VA, Zu Z, Yao SY, Li K, Zhang FL, Wilson KJ, Ou X, Does MD, Subramaniam S, Gochberg DF (2013) The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions. NeuroImage 74:298–305. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Klistorner A, Wang C, Fofanova V, Barnett MH, Yiannikas C, Parratt J, You Y, Graham SL (2016) Diffusivity in multiple sclerosis lesions: at the cutting edge? Neuroimage Clin 12:219–226. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Claus D, Brunholzl C, Kerling FP, Henschel S (1995) Transcranial magnetic stimulation as a diagnostic and prognostic test in amyotrophic lateral sclerosis. J Neurol Sci 129:30–34CrossRefPubMedGoogle Scholar
  16. 16.
    Miscio G, Pisano F, Mora G, Mazzini L (1999) Motor neuron disease: usefulness of transcranial magnetic stimulation in improving diagnosis. Clin Neurophysiol 110:975–981CrossRefPubMedGoogle Scholar
  17. 17.
    Triggs WJ, Menkes D, Onorato J, Yan RS, Young MS, Newell K, Sander HW, Soto O, Chiappa KH, Cros D (1999) Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology 53:605–611CrossRefPubMedGoogle Scholar
  18. 18.
    Rosler KM, Truffert A, Hess CW, Magistris MR (2000) Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Clin Neurophysiol 111:2208–2218CrossRefPubMedGoogle Scholar
  19. 19.
    Ellis CM, Simmons A, Jones DK, Bland J, Dawson JM, Horsfield MA, Williams SC, Leigh PN (1999) Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology 53:1051–1058CrossRefPubMedGoogle Scholar
  20. 20.
    Sach M, Winkler G, Glauche V, Liepert J, Heimbach B, Koch MA, Buchel C, Weiller C (2004) Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis. Brain 127:340–350CrossRefPubMedGoogle Scholar
  21. 21.
    Iwata NK, Aoki S, Okabe S, Arai N, Terao Y, Kwak S, Abe O, Kanazawa I, Tsuji S, Ugawa Y (2008) Evaluation of corticospinal tracts in ALS with diffusion tensor MRI and brainstem stimulation. Neurology 70:528–532. CrossRefPubMedGoogle Scholar
  22. 22.
    Furtula J, Johnsen B, Frandsen J, Rodell A, Christensen PB, Pugdahl K, Fuglsang-Frederiksen A (2013) Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI. J Neurol 260:1535–1544. CrossRefPubMedGoogle Scholar
  23. 23.
    Grapperon AM, Verschueren A, Duclos Y, Confort-Gouny S, Soulier E, Loundou AD, Guye M, Cozzone PJ, Pouget J, Ranjeva JP, Attarian S (2014) Association between structural and functional corticospinal involvement in amyotrophic lateral sclerosis assessed by diffusion tensor MRI and triple stimulation technique. Muscle Nerve 49(4):551–557. CrossRefPubMedGoogle Scholar
  24. 24.
    Bae JS, Ferguson M, Tan R, Mioshi E, Simon N, Burrell J, Vucic S, Hodges JR, Kiernan MC, Hornberger M (2000) Dissociation of structural and functional integrities of the motor system in amyotrophic lateral sclerosis and behavioral variant of frontotemporal dementia. J Clin Neurol 12(2):209–217. CrossRefGoogle Scholar
  25. 25.
    Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299CrossRefPubMedGoogle Scholar
  26. 26.
    Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (phase III). J Neurol Sci 169:13–21CrossRefPubMedGoogle Scholar
  27. 27.
    Bohannon RW, Smith MB (1987) Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 67:206–207CrossRefPubMedGoogle Scholar
  28. 28.
    Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multissubject diffusion data. NeuroImage 31:1487–1505CrossRefPubMedGoogle Scholar
  29. 29.
    de Carvalho M, Swash M (2000) Nerve conduction studies in ALS. Muscle Nerve 23:344–352CrossRefPubMedGoogle Scholar
  30. 30.
    Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijević MR, Hallett M, Katayama Y, Lücking CH, Maertens de Noordhout AL, Marsden CD, Murray NMF, Rothwell JC, Swash M, Tomberg C (1994) Noninvasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 91:79–92CrossRefPubMedGoogle Scholar
  31. 31.
    de Carvalho M, Turkman A, Swash M (2003) Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci 210:83–90CrossRefPubMedGoogle Scholar
  32. 32.
    de Carvalho M, Swash M (2010) Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: a six-month longitudinal study. Muscle Nerve 41:208–211. PubMedGoogle Scholar
  33. 33.
    Cerqueira V, de Mendonca A, Minez A, Dias AR, de Carvalho M (2006) Does caffeine modify cortical motor excitability? Neurophysiol Clin 36:219–226CrossRefPubMedGoogle Scholar
  34. 34.
    Sage CA, Peeters RR, Görner A, Robberecht W, Sunaert S (2007) Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis. NeuroImage 34(2):486–499CrossRefPubMedGoogle Scholar
  35. 35.
    Swash M, Scholtz CL, Vowles G, Ingram DA (1988) Selective and asymmetric vulnerability of corticospinal and spinocerebellar tracts in motor neuron disease. J Neurol Neurosurg Psychiatry 51(6):785–789CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Turner MR, Wicks P, Brownstein CA, Massagli MP, Toronjo M, Talbot K, Al-Chalabi A (2011) Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82(8):853–854. CrossRefPubMedGoogle Scholar
  37. 37.
    Devine MS, Kiernan MC, Heggie S, McCombe PA, Henderson RD (2014) Study of motor asymmetry in ALS indicates an effect of limb dominance on onset and spread of weakness, and an important role for upper motor neurons. Amyotroph Lateral Scler Frontotemporal Degener 15(7–8):481–487. CrossRefPubMedGoogle Scholar
  38. 38.
    de Carvalho M, Lopes A, Scotto M, Swash M (2001) Reproducibility of neurophysiological and myometric measurement in the ulnar nerve—abductor digiti minimi system. Muscle Nerve 24(10):1391–1395CrossRefPubMedGoogle Scholar
  39. 39.
    Filippini N, Douaud G, Mackay CE, Knight S, Talbot K, Turner MR (2010) Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology 75(18):1645–1652. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hughes JT (1982) Pathology of amyotrophic lateral sclerosis. Adv Neurol 36:61–74PubMedGoogle Scholar
  41. 41.
    Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J, Chiappelli F, van Kooten C, Vinters HV (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5(4):213–219CrossRefPubMedGoogle Scholar
  42. 42.
    Menke RA, Agosta F, Grosskreutz J, Filippi M, Turner MR (2017) Neuroimaging endpoints in amyotrophic lateral sclerosis. Neurotherapeutics 14:11–23. CrossRefPubMedGoogle Scholar
  43. 43.
    Foerster BR, Dwamena BA, Petrou M, Carlos RC, Callaghan BC, Pomper MG (2012) Diagnostic accuracy using diffusion tensor imaging in the diagnosis of ALS: a meta-analysis. Acad Radiol 19:1075–1086. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bede P, Hardiman O (2014) Lessons of ALS imaging: pitfalls and future directions a critical review. Neuroimage Clin 4:436–443. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ana Filipa Geraldo
    • 1
    • 2
  • João Pereira
    • 3
  • Pedro Nunes
    • 1
  • Sofia Reimão
    • 1
    • 4
  • Rita Sousa
    • 1
    • 4
  • Miguel Castelo-Branco
    • 3
  • Susana Pinto
    • 5
  • Jorge Guedes Campos
    • 1
    • 4
  • Mamede de Carvalho
    • 5
    • 6
  1. 1.Department of NeuroradiologyCHLN-Hospital de Santa MariaLisbonPortugal
  2. 2.Department of Radiology, Neuroradiology UnitCHVNG/E-Centro Hospitalar Vila Nova de GaiaEspinhoPortugal
  3. 3.Institute for Nuclear Sciences Applied to Health (ICNAS), and Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  4. 4.Faculty of MedicineUniversity of LisbonLisbonPortugal
  5. 5.Institute of Physiology, Institute of Molecular Medicine (IMM), Faculty of MedicineUniversity of LisbonLisbonPortugal
  6. 6.Department of Neurosciences and Mental HealthCHLN-Hospital de Santa MariaLisbonPortugal

Personalised recommendations