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Pathophysiological and diagnostic implications of cortical dysfunction in ALS

Nature Reviews Neurology volume 12, pages 651–661 (2016)Cite this article

Subjects

Key Points

  • Cortical hyperexcitability is an early pathophysiological feature of amyotrophic lateral sclerosis (ALS)

  • Cortical hyperexcitability potentially mediates motor neuron degeneration in ALS via a dying-forward, trans-synaptic, glutaminergic mechanism

  • The identification of the C9orf72 hexanucleotide repeat expansion as a major cause of familial and apparently sporadic ALS, as well as frontotemporal dementia, underscored the importance of cortical dysfunction

  • Cortical hyperexcitability is an important diagnostic biomarker of ALS, and could enable more-definitive diagnosis at an earlier stage of the disease process

Abstract

Cortical dysfunction — specifically, the development of hyperexcitability — seems to be an early and intrinsic feature of sporadic and familial amyotrophic lateral sclerosis (ALS) phenotypes, preceding the onset of lower motor neuron dysfunction and correlating with ensuing lower motor neuron dysfunction and degeneration. In fact, cortical dysfunction could provide a pathogenic basis for ALS, with corticomotor neuronal hyperexcitability mediating motor neuron degeneration via a trans-synaptic, glutamate-mediated, excitotoxic mechanism. The recent identification of C9orf72 repeat expansion as an important genetic risk factor for both ALS and frontotemporal dementia has underscored the importance of cortical function in ALS pathogenesis, and has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. Changes in cortical function that develop in ALS could prove useful as diagnostic biomarkers, potentially enhancing the diagnosis of ALS at an early stage of the disease process. Pathophysiological and diagnostic biomarkers of cortical function might also provide insights to guide the development of future therapeutic approaches, including stem cell and genetic interventions, thereby providing potential for more-effective management of patients with ALS.

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Figure 1: Disease onset and progression in amyotrophic lateral sclerosis.
Figure 2: GABAergic inhibitory circuits in the motor cortex.
Figure 3: Pathophysiological mechanisms in amyotrophic lateral sclerosis.
Figure 4: Apical dendrite defects and spine loss in mouse models of motor neuron disease.
Figure 5: Threshold tracking transcranial magnetic stimulation.
Figure 6: Loss of cortical inhibition in amyotrophic lateral sclerosis.

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References

  1. Kiernan, M. C. et al. Amyotrophic lateral sclerosis. Lancet 377, 942–955 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Vucic, S., Rothstein, J. D. & Kiernan, M. C. Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies. Trends Neurosci. 37, 433–442 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Eisen, A., Kim, S. & Pant, B. Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron? Muscle Nerve 15, 219–224 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Geevasinga, N. et al. Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia. Eur. J. Neurol. 22, 826–831, e57–e58 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Vucic, S. & Kiernan, M. C. Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 78, 849–852 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Williamson, T. L. & Cleveland, D. W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci. 2, 50–56 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).

    Article  PubMed  Google Scholar 

  8. Ravits, J., Paul, P. & Jorg, C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 68, 1571–1575 (2007).

    Article  PubMed  Google Scholar 

  9. Charcot, J. & Joffroy, A. Deux cas d'atrophie musculaire progressive avec lesion de la substance grise et des faisceaux antero-lateraux de la moelle epiniere. Arch. Physiol. Neurol. Pathol. 2, 744–754 (in French) (1869).

    Google Scholar 

  10. Nihei, K., McKee, A. C. & Kowall, N. W. Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol. 86, 55–64 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, W. et al. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat. Neurosci. 19, 557–559 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eisen, A. & Weber, M. The motor cortex and amyotrophic lateral sclerosis. Muscle Nerve 24, 564–573 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Hirota, N., Eisen, A. & Weber, M. Complex fasciculations and their origin in amyotrophic lateral sclerosis and Kennedy's disease. Muscle Nerve 23, 1872–1875 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Devine, M. S., Kiernan, M. C., Heggie, S., McCombe, P. A. & Henderson, R. D. 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, 481–487 (2014).

    Article  PubMed  Google Scholar 

  15. Al-Chalabi, A. et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol. 13, 1108–1113 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Eisen, A., Kiernan, M., Mitsumoto, H. & Swash, M. Amyotrophic lateral sclerosis: a long preclinical period? J. Neurol. Neurosurg. Psychiatry 85, 1232–1238 (2014).

    Article  PubMed  Google Scholar 

  17. Heath, P. R. & Shaw, P. J. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve 26, 438–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Dong, H. et al. Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J. Neurosci. 19, 6930–6941 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Vandenberg, R. J. Molecular pharmacology and physiology of glutamate transporters in the central nervous system. Clin. Exp. Pharmacol. Physiol. 25, 393–400 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Simeone, T. A., Sanchez, R. M. & Rho, J. M. Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J. Child Neurol. 19, 343–360 (2004).

    Article  PubMed  Google Scholar 

  21. Spalloni, A., Nutini, M. & Longone, P. Role of the N-methyl-d-aspartate receptors complex in amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1832, 312–322 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Jaiswal, M. K. Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation. Mol. Cell. Ther. 2, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jiang, M., Schuster, J. E., Fu, R., Siddique, T. & Heckman, C. J. Progressive changes in synaptic inputs to motoneurons in adult sacral spinal cord of a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 29, 15031–15038 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Urushitani, M. et al. N-methyl-d-aspartate receptor-mediated mitochondrial Ca2+ overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca2+ influx. J. Neurosci. Res. 63, 377–387 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Sanelli, T., Ge, W., Leystra-Lantz, C. & Strong, M. J. Calcium mediated excitotoxicity in neurofilament aggregate-bearing neurons in vitro is NMDA receptor dependant. J. Neurol. Sci. 256, 39–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Van Damme, P., Braeken, D., Callewaert, G., Robberecht, W. & Van Den Bosch, L. GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 64, 605–612 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Kwak, S. & Kawahara, Y. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J. Mol. Med. 83, 110–120 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Takuma, H., Kwak, S., Yoshizawa, T. & Kanazawa, I. Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann. Neurol. 46, 806–815 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Boillee, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Trotti, D., Rolfs, A., Danbolt, N. C., Brown, R. H. Jr & Hediger, M. A. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat. Neurosci. 2, 427–433 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Boston-Howes, W. et al. Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J. Biol. Chem. 281, 14076–14084 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Gibb, S. L. et al. A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis. J. Biol. Chem. 282, 32480–32490 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Rothstein, J. D. et al. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Pieri, M., Carunchio, I., Curcio, L., Mercuri, N. B. & Zona, C. Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. Exp. Neurol. 215, 368–379 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Saba, L. et al. Altered functionality, morphology, and vesicular glutamate transporter expression of cortical motor neurons from a presymptomatic mouse model of amyotrophic lateral sclerosis. Cereb. Cortex 26, 1512–1528 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Fogarty, M. J., Noakes, P. G. & Bellingham, M. C. Motor cortex layer V pyramidal neurons exhibit dendritic regression, spine loss, and increased synaptic excitation in the presymptomatic hSOD1G93A mouse model of amyotrophic lateral sclerosis. J. Neurosci. 35, 643–647 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jara, J. H., Villa, S. R., Khan, N. A., Bohn, M. C. & Özdinler, P. H. AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS. Neurobiol. Dis. 47, 174–183 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Özdinler, P. H. et al. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G93A transgenic ALS mice. J. Neurosci. 31, 4166–4177 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kuo, J. J. et al. Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. J. Neurophysiol. 91, 571–575 (2004).

    Article  PubMed  Google Scholar 

  41. Lemon, R. N. & Griffiths, J. Comparing the function of the corticospinal system in different species: organizational differences for motor specialization? Muscle Nerve 32, 261–279 (2005).

    Article  PubMed  Google Scholar 

  42. Imbrici, P., D'Adamo, M. C., Kullmann, D. M. & Pessia, M. Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvβ1.1 and Kv1.4-1.1/Kvβ1.2. Eur. J. Neurosci. 24, 3073–3083 (2006).

    Article  PubMed  Google Scholar 

  43. Jara, J. H., Genc, B., Klessner, J. L. & Ozdinler, P. H. Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Front. Neuroanat. 8, 16 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jara, J. H. et al. Corticospinal motor neurons are susceptible to increased ER stress and display profound degeneration in the absence of UCHL1 function. Cereb. Cortex 25, 4259–4272 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1–11 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Devlin, A. C. et al. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat. Commun. 6, 5999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Naujock, M. et al. 4-Aminopyridine induced activity rescues hypoexcitable motor neurons from amyotrophic lateral sclerosis patient-derived induced pluripotent stem cells. Stem Cells 34, 1563–1575 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Kuo, J. J., Siddique, T., Fu, R. & Heckman, C. J. Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice. J. Physiol. 563, 843–854 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kanai, K. et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 129, 953–962 (2006).

    Article  PubMed  Google Scholar 

  50. Vucic, S. & Kiernan, M. C. Upregulation of persistent sodium conductances in familial ALS. J. Neurol. Neurosurg. Psychiatry 81, 222–227 (2010).

    Article  PubMed  Google Scholar 

  51. Menon, P., Kiernan, M. C. & Vucic, S. ALS pathophysiology: insights form the split-hand phenomenon. Clin. Neurophysiol. 125, 186–193 (2014).

    Article  PubMed  Google Scholar 

  52. Geevasinga, N. et al. Axonal ion channel dysfunction in C9orf72 familial amyotrophic lateral sclerosis. JAMA Neurol. 72, 49–57 (2015).

    Article  PubMed  Google Scholar 

  53. van Es, M. A. et al. ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol. 6, 869–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Ince, P. et al. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease. Neuropathol. Appl. Neurobiol. 19, 291–299 (1993).

    Article  CAS  PubMed  Google Scholar 

  55. Amendola, J. & Durand, J. Morphological differences between wild-type and transgenic superoxide dismutase 1 lumbar motoneurons in postnatal mice. J. Comp. Neurol. 511, 329–341 (2008).

    Article  PubMed  Google Scholar 

  56. Quinlan, K. A. Links between electrophysiological and molecular pathology of amyotrophic lateral sclerosis. Integr. Comp. Biol. 51, 913–925 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Shaw, P. & Kuncl, R. W. in Motor Neuron Disease (ed. Kuncl, R. W. ) 37–73 (W. B. Saunders, 2002).

    Google Scholar 

  58. Saxena, S. et al. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron 80, 80–96 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Leroy, F., Lamotte d'Incamps, B., Imhoff-Manuel, R. D. & Zytnicki, D. Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. eLife 3, e04046 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat. Biotechnol. 29, 824–828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl Med. 7, 307ra153 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347, 1425–1431 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Bensimon, G., Lacomblez, L. & Meininger, V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 330, 585–591 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Vucic, S. et al. Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain 136, 1361–1370 (2013).

    Article  PubMed  Google Scholar 

  65. Higgins, C. M., Jung, C. & Xu, Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 4, 16 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Kirkinezos, I. G. et al. Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. J. Neurosci. 25, 164–172 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lederer, C. W., Torrisi, A., Pantelidou, M., Santama, N. & Cavallaro, S. Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis. BMC Genomics 8, 26 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xu, Z., Jung, C., Higgins, C., Levine, J. & Kong, J. Mitochondrial degeneration in amyotrophic lateral sclerosis. J. Bioenerg. Biomembr. 36, 395–399 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Dugan, L. L. & Choi, D. W. Excitotoxicity, free radicals, and cell membrane changes. Ann. Neurol. 35, S17–S21 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Bowling, A. C. & Beal, M. F. Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci. 56, 1151–1171 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Comi, G. P. et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann. Neurol. 43, 110–116 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Li, Q. et al. ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import. Proc. Natl Acad. Sci. USA 107, 21146–21151 (2010).

    Article  PubMed  Google Scholar 

  73. Bilsland, L. G. et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc. Natl Acad. Sci. USA 107, 20523–20528 (2010).

    Article  PubMed  Google Scholar 

  74. MacAskill, A. F. et al. Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61, 541–555 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Menon, P., Kiernan, M. & Vucic, S. Biomarkers and future targets for development in amyotrophic lateral sclerosis. Curr. Med. Chem. 21, 3535–3550 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Bogdanov, M. B., Ramos, L. E., Xu, Z. & Beal, M. F. Elevated “hydroxyl radical” generation in vivo in an animal model of amyotrophic lateral sclerosis. J. Neurochem. 71, 1321–1324 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Abe, K. et al. Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. Neurol. Res. 19, 124–128 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Beal, M. F. et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644–654 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Hensley, K. et al. On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. Antioxid. Redox Signal. 8, 2075–2087 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron 72, 257–268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Turner, M. R. et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12, 310–322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Al-Sarraj, S. et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 122, 691–702 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Burrell, J. R., Kiernan, M. C., Vucic, S. & Hodges, J. R. Motor neuron dysfunction in frontotemporal dementia. Brain 134, 2582–2594 (2011).

    Article  PubMed  Google Scholar 

  86. Burrell, J. R. et al. The frontotemporal dementia–motor neuron disease continuum. Lancet http://dx.doi.org/10.1016/S0140-6736(16)00737-6 (2016).

  87. Di Lazzaro, V. et al. Transcranial direct current stimulation effects on the excitability of corticospinal axons of the human cerebral cortex. Brain Stimul. 6, 641–643 (2013).

    Article  PubMed  Google Scholar 

  88. Vucic, S., Ziemann, U., Eisen, A., Hallett, M. & Kiernan, M. C. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J. Neurol. Neurosurg. Psychiatry 84, 1161–1170 (2013).

    Article  PubMed  Google Scholar 

  89. Chen, R. et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin. Neurophysiol. 119, 504–532 (2008).

    Article  PubMed  Google Scholar 

  90. Kiers, L., Cros, D., Chiappa, K. H. & Fang, J. Variability of motor potentials evoked by transcranial magnetic stimulation. Electroencephalogr. Clin. Neurophysiol. 89, 415–423 (1993).

    Article  CAS  PubMed  Google Scholar 

  91. Fisher, R. J., Nakamura, Y., Bestmann, S., Rothwell, J. C. & Bostock, H. Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking. Exp. Brain Res. 143, 240–248 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Vucic, S., Howells, J., Trevillion, L. & Kiernan, M. C. Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 33, 477–486 (2006).

    Article  PubMed  Google Scholar 

  93. Stefan, K., Kunesch, E., Benecke, R. & Classen, J. Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann. Neurol. 49, 536–539 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Zanette, G. et al. Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis. Clin. Neurophysiol. 113, 1688–1697 (2002).

    Article  PubMed  Google Scholar 

  95. Vucic, S. & Kiernan, M. C. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129, 2436–2446 (2006).

    Article  PubMed  Google Scholar 

  96. Vucic, S. & Kiernan, M. C. Cortical excitability testing distinguishes Kennedy's disease from amyotrophic lateral sclerosis. Clin. Neurophysiol. 119, 1088–1096 (2008).

    Article  PubMed  Google Scholar 

  97. Vucic, S., Nicholson, G. A. & Kiernan, M. C. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540–1550 (2008).

    Article  PubMed  Google Scholar 

  98. Menon, P. et al. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 14, 478–484 (2015).

    Article  PubMed  Google Scholar 

  99. Menon, P., Kiernan, M. C. & Vucic, S. Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS. Clin. Neurophysiol. 126, 803–809 (2015).

    Article  PubMed  Google Scholar 

  100. Menon, P., Geevasinga, N., Yiannikas, C., Kiernan, M. C. & Vucic, S. Cortical contributions to the flail leg syndrome: pathophysiological insights. Amyotroph. Lateral Scler. Frontotemporal Degener. 17, 389–396 (2016).

    Article  PubMed  Google Scholar 

  101. Williams, K. L. et al. Pathophysiological insights into ALS with C9ORF72 expansions. J. Neurol. Neurosurg. Psychiatry 84, 931–935 (2013).

    Article  PubMed  Google Scholar 

  102. Geevasinga, N. et al. Cortical function in asymptomatic carriers and patients with C9orf72 amyotrophic lateral sclerosis. JAMA Neurol. 72, 1268–1274 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Blair, I. P. et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J. Neurol. Neurosurg. Psychiatry 81, 1286–1288 (2010).

    Article  Google Scholar 

  104. Vucic, S., Cheah, B. C., Yiannikas, C. & Kiernan, M. C. Cortical excitability distinguishes ALS from mimic disorders. Clin. Neurophysiol. 122, 1860–1866 (2011).

    Article  PubMed  Google Scholar 

  105. Vucic, S., Nicholson, G. A. & Kiernan, M. C. Cortical excitability in hereditary motor neuronopathy with pyramidal signs: comparison with ALS. J. Neurol. Neurosurg. Psychiatry 81, 97–100 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Turner, M. R. et al. Neuroimaging in amyotrophic lateral sclerosis. Biomark. Med. 6, 319–337 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Verstraete, E. et al. Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 83, 383–388 (2012).

    Article  PubMed  Google Scholar 

  108. Walhout, R. et al. Cortical thickness in ALS: towards a marker for upper motor neuron involvement. J. Neurol. Neurosurg. Psychiatry 86, 288–294 (2015).

    Article  PubMed  Google Scholar 

  109. van der Graaff, M. M. et al. Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study. Brain 134, 1211–1228 (2011).

    Article  PubMed  Google Scholar 

  110. Zarei, M. et al. Two-dimensional population map of cortical connections in the human internal capsule. J. Magn. Reson. Imaging 25, 48–54 (2007).

    Article  PubMed  Google Scholar 

  111. Menke, R. L. et al. Fractional anisotropy in the posterior limb of the internal capsule and prognosis in amyotrophic lateral sclerosis. Arch. Neurol. 69, 1493–1498 (2012).

    Article  PubMed  Google Scholar 

  112. Sarro, L. et al. Cognitive functions and white matter tract damage in amyotrophic lateral sclerosis: a diffusion tensor tractography study. AJNR Am. J. Neuroradiol. 32, 1866–1872 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Walhout, R. et al. Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers. Neurology 85, 1780–1788 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Verstraete, E., Veldink, J. H., Mandl, R. C., van den Berg, L. H. & van den Heuvel, M. P. Impaired structural motor connectome in amyotrophic lateral sclerosis. PLoS ONE 6, e24239 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Verstraete, E., Veldink, J. H., van den Berg, L. H. & van den Heuvel, M. P. Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis. Hum. Brain Mapp. 35, 1351–1361 (2014).

    Article  PubMed  Google Scholar 

  116. Schmidt, R., de Reus, M. A., Scholtens, L. H., van den Berg, L. H. & van den Heuvel, M. P. Simulating disease propagation across white matter connectome reveals anatomical substrate for neuropathology staging in amyotrophic lateral sclerosis. Neuroimage 124, 762–769 (2016).

    Article  PubMed  Google Scholar 

  117. Eisen, A. A. & Shtybel, W. AAEM minimonograph #35: clinical experience with transcranial magnetic stimulation. Muscle Nerve 13, 995–1011 (1990).

    Article  CAS  PubMed  Google Scholar 

  118. Wilbourn, A. J. The “split hand syndrome”. Muscle Nerve 23, 138 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Kuwabara, S. et al. Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis: frequency, extent, and specificity. Muscle Nerve 37, 426–430 (2008).

    Article  PubMed  Google Scholar 

  120. Menon, P., Kiernan, M. C. & Vucic, S. Cortical dysfunction underlies the development of the split-hand in amyotrophic lateral sclerosis. PLoS ONE 9, e87124 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Menon, P., Kiernan, M. C. & Vucic, S. Cortical excitability differences in hand muscles follow a split-hand pattern in healthy controls. Muscle Nerve 49, 836–844 (2014).

    Article  PubMed  Google Scholar 

  122. Menon, P., Bae, J. S., Mioshi, E., Kiernan, M. C. & Vucic, S. Split-hand plus sign in ALS: differential involvement of the flexor pollicis longus and intrinsic hand muscles. Amyotroph. Lateral Scler. Frontotemporal Degener. 14, 315–318 (2013).

    Article  PubMed  Google Scholar 

  123. Bae, J. S., Menon, P., Mioshi, E., Kiernan, M. C. & Vucic, S. Cortical hyperexcitability and the split-hand plus phenomenon: pathophysiological insights in ALS. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 250–256 (2014).

    Article  PubMed  Google Scholar 

  124. Turner, M. R. et al. Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 82, 853–854 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Reid, C. S. & Serrien, D. J. Handedness and the excitability of cortical inhibitory circuits. Behav. Brain Res. 230, 144–148 (2012).

    Article  PubMed  Google Scholar 

  126. Brooks, B. R., Miller, R. G., Swash, M. & Munsat, T. L. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 293–299 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. de Carvalho, M. et al. Electrodiagnostic criteria for diagnosis of ALS. Clin. Neurophysiol. 119, 497–503 (2008).

    Article  PubMed  Google Scholar 

  128. Brooks, B. R. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J. Neurol. Sci. 124, 96–107 (1994).

    Article  PubMed  Google Scholar 

  129. Turner, M. R., Kiernan, M. C., Leigh, P. N. & Talbot, K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 8, 94–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Traynor, B. et al. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch. Neurol. 57, 1171–1176 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Paganoni, S. et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 453–456 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Costa, J., Swash, M. & de Carvalho, M. Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review. Arch. Neurol. 69, 1410–1416 (2012).

    Article  PubMed  Google Scholar 

  133. Swash, M. Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis? J. Neurol. Neurosurg. Psychiatry 83, 659–662 (2012).

    Article  PubMed  Google Scholar 

  134. Higashihara, M. et al. Fasciculation potentials in amyotrophic lateral sclerosis and the diagnostic yield of the Awaji algorithm. Muscle Nerve 45, 175–182 (2012).

    Article  PubMed  Google Scholar 

  135. Geevasinga, N., Menon, P., Yiannikas, C., Kiernan, M. C. & Vucic, S. Diagnostic utility of cortical excitability studies in amyotrophic lateral sclerosis. Eur. J. Neurol. 21, 1451–1457 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Komissarow, L. et al. Triple stimulation technique (TST) in amyotrophic lateral sclerosis. Clin. Neurophysiol. 115, 356–360 (2004).

    Article  PubMed  Google Scholar 

  137. Turner, M. R. & Verstraete, E. What does imaging reveal about the pathology of amyotrophic lateral sclerosis? Curr. Neurol. Neurosci. Rep. 15, 45 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Filippi, M. et al. Progress towards a neuroimaging biomarker for amyotrophic lateral sclerosis. Lancet Neurol. 14, 786–788 (2015).

    Article  PubMed  Google Scholar 

  139. Grieve, S. M. et al. Potential structural and functional biomarkers of upper motor neuron dysfunction in ALS. Amyotroph. Lateral Scler. Frontotemporal Degener. 17, 85–92 (2015).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge research support from the Motor Neuron Disease Research Institute of Australia (awarded to N.G.), and the National Health and Medical Research Council of Australia (project grants 510233, 1024915 and 1055778 awarded to M.C.K. and S.V, and Program Grant #1037746 awarded to M.C.K.). S.V. had full access to all the data reviewed in the article, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Western Clinical School, University of Sydney, Westmead Hospital, Cnr Hawkesbury and Darcy Road, Wentworthville, 2045, New South Wales, Australia

    Nimeshan Geevasinga, Parvathi Menon & Steve Vucic

  2. Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, 675 North St Clair Street, Suite 20–100, Chicago, 60611, Illinois, USA

    P. Hande Özdinler

  3. Brain and Mind Research Institute, University of Sydney, 94 Mallett Street, Camperdown, 2050, New South Wales, Australia

    Matthew C. Kiernan

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  1. Nimeshan Geevasinga
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Contributions

N.G, P.M., P.H.Ö. and S.V. researched data for the article. All authors made substantial contributions to discussions of the content. N.G, P.M. and S.V. wrote the article, and P.H.Ö. and M.C.K. reviewed and edited the manuscript before submission.

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Correspondence to Steve Vucic.

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Geevasinga, N., Menon, P., Özdinler, P. et al. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol 12, 651–661 (2016). https://doi.org/10.1038/nrneurol.2016.140

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