Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: aquaporin-4 antibodies in neuromyelitis optica

Nature Clinical Practice Neurology volume 4, pages 202–214 (2008)Cite this article

Abstract

Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow–Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology—which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions—and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.

Key Points

  • Neuromyelitis optica (NMO) is an inflammatory disorder of the CNS of putative autoimmune etiology that predominantly affects the spinal cord and optic nerves

  • NMO is histologically characterized by extensive demyelination and substantial axonal damage; the presence of IgG and complement deposits suggests a humoral pathogenesis

  • Recently, a new serum reactivity (called NMO-IgG), characterized by binding of IgG to structures adjacent to the microvasculature and pia mater, has been detected in patients with NMO

  • Aquaporin-4, the most abundant water channel in the CNS, has been identified as the target antigen of NMO-IgG

  • Indirect evidence from immunobiological and histological studies suggests an important role for NMO-IgG/AQP4-Ab in the pathogenesis of NMO

  • These new findings facilitate the diagnosis of NMO and might soon translate into new therapeutic approaches

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diagnosis of neuromyelitis optica and longitudinally extensive transverse myelitis.
Figure 2: The structure and localization of aquaporin-4.
Figure 3: Complement deposits at sites of aquaporin-4 loss in neuromyelitis optica but not in multiple sclerosis.
Figure 4: Aquaporin-4 expression in neuromyelitis optica and multiple sclerosis.
Figure 5: Aquaporin-4 loss seems to be primary rather than secondary to astrocyte loss in neuromyelitis optica.

Similar content being viewed by others

References

  1. Devic E (1894) Subacute myelitis complicated by optic neuritis [French]. Bull Med 8: 1033–1034

    Google Scholar 

  2. Devic E (1895) Acute dorsolumbar myelitis with optic neuritis, autopsy [French]. Congress Francais Medicine 1: 434–439

    Google Scholar 

  3. Allbutt TC (1870) On the ophthalmoscopic signs of spinal disease. Lancet 1: 76–88

    Article  Google Scholar 

  4. Erb W (1879) About the concurrence of optic neuritis and subacute myelitis [German]. Arch Psychiatr Nervenkr 1: 146–157

    Google Scholar 

  5. Lucchinetti CF et al. (2002) A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 125: 1450–1461

    Article  PubMed  Google Scholar 

  6. Lennon VA et al. (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364: 2106–2112

    Article  CAS  PubMed  Google Scholar 

  7. Lennon VA et al. (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202: 473–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Paul F et al. (2007) Antibody to aquaporin-4 in the diagnosis of neuromyelitis optica. PLoS Med 4: e133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jarius S et al. (2007) NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 68: 1076–1077

    Article  CAS  PubMed  Google Scholar 

  10. Wingerchuk DM et al. (2006) Revised diagnostic criteria for neuromyelitis optica. Neurology 66: 1485–1489

    Article  CAS  PubMed  Google Scholar 

  11. Wingerchuk DM et al. (1999) The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 53: 1107–1114

    Article  CAS  PubMed  Google Scholar 

  12. Pittock SJ et al. (2006) Brain abnormalities in neuromyelitis optica. Arch Neurol 63: 390–396

    Article  PubMed  Google Scholar 

  13. de Seze J et al. (2002) Devic's neuromyelitis optica: clinical, laboratory, MRI and outcome profile. J Neurol Sci 197: 57–61

    Article  CAS  PubMed  Google Scholar 

  14. Wingerchuk DM et al. (2007) A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 68: 603–605

    Article  CAS  PubMed  Google Scholar 

  15. Ghezzi A et al. (2004) Clinical characteristics, course and prognosis of relapsing Devic's neuromyelitis optica. J Neurol 251: 47–52

    Article  PubMed  Google Scholar 

  16. O'Riordan JI et al. (1996) Clinical, CSF, and MRI findings in Devic's neuromyelitis optica. J Neurol Neurosurg Psychiatry 60: 382–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nakashima I et al. (2006) Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG. J Neurol Neurosurg Psychiatry 77: 1073–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jeffery AR and Buncic JR (1996) Pediatric Devic's neuromyelitis optica. J Pediatr Ophthalmol Strabismus 33: 223–229

    CAS  PubMed  Google Scholar 

  19. Filley CM et al. (1984) Neuromyelitis optica in the elderly. Arch Neurol 41: 670–672

    Article  CAS  PubMed  Google Scholar 

  20. Filippi M and Rocca MA (2004) MR imaging of Devic's neuromyelitis optica. Neurol Sci 25 (Suppl 4): S371–S373

    Article  PubMed  Google Scholar 

  21. Lycklama G et al. (2000) Spinal-cord MRI in multiple sclerosis. Lancet Neurol 2: 555–562

    Article  Google Scholar 

  22. Tartaglino LM et al. (1995) Multiple sclerosis in the spinal cord: MR appearance and correlation with clinical parameters. Radiology 195: 725–732

    Article  CAS  PubMed  Google Scholar 

  23. Lin F et al. (2006) Discriminative analysis of relapsing neuromyelitis optica and relapsing–remitting multiple sclerosis based on two-dimensional histogram from diffusion tensor imaging. Neuroimage 31: 543–549

    Article  PubMed  Google Scholar 

  24. Benedetti B et al. (2006) Grading cervical cord damage in neuromyelitis optica and MS by diffusion tensor MRI. Neurology 67: 161–163

    Article  CAS  PubMed  Google Scholar 

  25. Green AJ et al. (2007) Funduscopic and optical coherence tomography findings in neuromyelitis optica compared to multiple sclerosis. Neurology 68 (Suppl 1): SA355

    Google Scholar 

  26. Cabrera-Gomez JA et al. (2007) Brain magnetic resonance imaging findings in relapsing neuromyelitis optica. Mult Scler 13: 186–192

    Article  PubMed  Google Scholar 

  27. Pittock SJ et al. (2006) Neuromyelitis optica brain lesions localized at sites of high aquaporin-4 expression. Arch Neurol 63: 964–968

    Article  PubMed  Google Scholar 

  28. Zaffaroni M (2004) Cerebrospinal fluid findings in Devic's neuromyelitis optica. Neurol Sci 25 (Suppl 4): S368–S370

    Article  PubMed  Google Scholar 

  29. Bergamaschi R et al. (2004) Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler 10: 2–4

    Article  CAS  PubMed  Google Scholar 

  30. Melamud L et al. (2006) Cerebrospinal fluid findings in Devic's neuromyelitis optica. Mult Scler 12: P246

    Google Scholar 

  31. Reiber H et al. (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4: 111–117

    Article  CAS  PubMed  Google Scholar 

  32. Meinl E et al. (2006) B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59: 880–892

    Article  CAS  PubMed  Google Scholar 

  33. Jarius S et al. Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry, in press

  34. Satoh J et al. (2003) Detection of the 14-3-3 protein in the cerebrospinal fluid of Japanese multiple sclerosis patients presenting with severe myelitis. J Neurol Sci 212: 11–20

    Article  CAS  PubMed  Google Scholar 

  35. Petzold A (2007) NMO-IgG serology in chronic relapsing inflammatory optic neuropathy. Mult Scler 13 (Suppl 2): SP538

    Google Scholar 

  36. Matiello M (2007) NMO-IgG predicts the outcome of recurrent optic neuritis. Mult Scler 13 (Suppl 2): SP536

    Google Scholar 

  37. Jacobi C et al. (2006) Neuromyelitis optica (Devic's syndrome) as first manifestation of systemic lupus erythematosus. Lupus 15: 107–109

    Article  CAS  PubMed  Google Scholar 

  38. Weinshenker B et al. (2006) The relationship between neuromyelitis optica and systemic auto-immune disease. Mult Scler 12: O79

    Google Scholar 

  39. Scott TF et al. (2006) Neuromyelitis optica IgG status in acute partial transverse myelitis. Arch Neurol 63: 1398–1400

    Article  PubMed  Google Scholar 

  40. Takahashi T et al. (2007) Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130: 1235–1243

    Article  PubMed  Google Scholar 

  41. Yang B et al. (1995) cDNA cloning, gene organization, and chromosomal localization of a human mercurial insensitive water channel: evidence for distinct transcriptional units. J Biol Chem 270: 22907–22913

    Article  CAS  PubMed  Google Scholar 

  42. Lu M et al. (1996) The human AQP4 gene: definition of the locus encoding two water channel polypeptides in brain. Proc Natl Acad Sci USA 93: 10908–10912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jung JS et al. (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 91: 13052–13056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hiroaki Y et al. (2006) Implications of the aquaporin-4 structure on array formation and cell adhesion. J Mol Biol 355: 628–639

    Article  CAS  PubMed  Google Scholar 

  45. Amiry-Moghaddam M and Ottersen OP (2003) The molecular basis of water transport in the brain. Nat Rev Neurosci 4: 991–1001

    Article  CAS  PubMed  Google Scholar 

  46. Nielsen S et al. (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17: 171–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Roemer SF et al. (2007) Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130: 1194–1205

    Article  PubMed  Google Scholar 

  48. Watanabe S et al. (2007) Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler 13: 968–974

    Article  CAS  PubMed  Google Scholar 

  49. Ma T et al. (1997) Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J Clin Invest 100: 957–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Amiry-Moghaddam M et al. (2004) Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 129: 999–1010

    Article  CAS  PubMed  Google Scholar 

  51. Hoch W (1999) Formation of the neuromuscular junction: agrin and its unusual receptors. Eur J Biochem 265: 1–10

    Article  CAS  PubMed  Google Scholar 

  52. Manley GT et al. (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6: 159–163

    Article  CAS  PubMed  Google Scholar 

  53. Amiry-Moghaddam M et al. (2003) Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of α-syntrophin-null mice. Proc Natl Acad Sci USA 100: 13615–13620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vincent A (2002) Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2: 797–804

    Article  CAS  PubMed  Google Scholar 

  55. Compston A (2004) 'The marvellous harmony of the nervous parts': the origins of multiple sclerosis. Clin Med 4: 346–354

    Article  Google Scholar 

  56. Weinshenker BG et al. (2006) OSMS is NMO, but not MS: proven clinically and pathologically. Lancet Neurol 5: 110–111

    Article  PubMed  Google Scholar 

  57. Ito H et al. (1998) HLA-DP-associated susceptibility to the optico-spinal form of multiple sclerosis in the Japanese. Tissue Antigens 52: 179–182

    Article  CAS  PubMed  Google Scholar 

  58. Kira J et al. (1996) Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol 40: 569–574

    Article  CAS  PubMed  Google Scholar 

  59. Fukazawa T et al. (2006) HLA-dPB1*0501 is not uniquely associated with opticospinal multiple sclerosis in Japanese patients: important role of DPB1*0301. Mult Scler 12: 19–23

    Article  CAS  PubMed  Google Scholar 

  60. Jacob A (2007) HLA DPB1*0501 allele is not associated with neuromyelitis optica. Mult Scler 13 (Suppl 2): SP674

    Google Scholar 

  61. Cloys DE and Netsky MG (1970) Neuromyelitis optica. In Handbook of Clinical Neurology, vol 9, 426–436 (Eds Viken PJ and Bruyn GW) Amsterdam: North-Holland

    Google Scholar 

  62. Prineas JW and McDonald WI (1997) Demyelinating diseases. In Greenfield's Neuropathology, edn 6, 813–896 (Eds Graham DI and Lantos PL) London: Edward Arnold

    Google Scholar 

  63. Lucchinetti C et al. (2000) Heterogeneity of multiple sclerosis legions: implications for the pathogenesis of demyelination. Ann Neurol 47: 707–717

    Article  CAS  PubMed  Google Scholar 

  64. Mandler RN et al. (1993) Devic's neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 34: 162–168

    Article  CAS  PubMed  Google Scholar 

  65. Goehler LE et al. (2006) Neural–immune interface in the rat area postrema. Neuroscience 140: 1415–1434

    Article  CAS  PubMed  Google Scholar 

  66. Schulz M and Engelhardt B (2005) The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res 2: 8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Simard M and Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129: 877–896

    Article  CAS  PubMed  Google Scholar 

  68. Correale J and Fiol M (2004) Activation of humoral immunity and eosinophils in neuromyelitis optica. Neurology 63: 2363–2370

    Article  PubMed  Google Scholar 

  69. Ishizu T et al. (2005) Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain 128: 988–1002

    Article  PubMed  Google Scholar 

  70. Takahashi T et al. (2006) Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica. Tohoku J Exp Med 210: 307–313

    Article  CAS  PubMed  Google Scholar 

  71. Hinson SR et al. (2007) Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 69: 2221–2231

    Article  CAS  PubMed  Google Scholar 

  72. Misu T et al. (2006) Loss of aquaporin-4 in active perivascular lesions in neuromyelitis optica: a case report. Tohoku J Exp Med 209: 269–275

    Article  PubMed  Google Scholar 

  73. Aoki-Yoshino K et al. (2005) Enhanced expression of aquaporin-4 in human brain with inflammatory diseases. Acta Neuropathol 110: 281–288

    Article  CAS  PubMed  Google Scholar 

  74. Holley JE et al. (2003) Astrocyte characterization in the multiple sclerosis glial scar. Neuropathol Appl Neurobiol 29: 434–444

    Article  CAS  PubMed  Google Scholar 

  75. Ayers MM et al. (2004) Early glial responses in murine models of multiple sclerosis. Neurochem Int 45: 409–419

    Article  CAS  PubMed  Google Scholar 

  76. Auguste KI et al. (2007) Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. FASEB J 21: 108–116

    Article  CAS  PubMed  Google Scholar 

  77. Bergamaschi R (2007) Immune agents for the treatment of Devic's neuromyelitis optica. Neurol Sci 28: 238–240

    Article  CAS  PubMed  Google Scholar 

  78. Wingerchuk DM (2007) Diagnosis and treatment of neuromyelitis optica. Neurologist 13: 2–11

    Article  PubMed  Google Scholar 

  79. Aguilera AJ et al. (1985) Lymphocytaplasmapheresis in Devic's syndrome. Transfusion 25: 54–56

    Article  CAS  PubMed  Google Scholar 

  80. Mandler RN et al. (1998) Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 51: 1219–1220

    Article  CAS  PubMed  Google Scholar 

  81. Nozaki I et al. (2006) Fulminant Devic disease successfully treated by lymphocytapheresis. J Neurol Neurosurg Psychiatry 77: 1094–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Weinshenker BG et al. (1999) A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 46: 878–886

    Article  CAS  PubMed  Google Scholar 

  83. Keegan M et al. (2002) Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 58: 143–146

    Article  CAS  PubMed  Google Scholar 

  84. Cree BA et al. (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64: 1270–1272

    Article  CAS  PubMed  Google Scholar 

  85. Fidler JM et al. (1986) Selective immunomodulation by the antineoplastic agent mitoxantrone. I: suppression of B lymphocyte function. J Immunol 137: 727–732

    CAS  PubMed  Google Scholar 

  86. Fidler JM et al. (1986) Selective immunomodulation by the antineoplastic agent mitoxantrone. II: nonspecific adherent suppressor cells derived from mitoxantrone-treated mice. J Immunol 136: 2747–2754

    CAS  PubMed  Google Scholar 

  87. Weinstock-Guttman B et al. (2006) Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol 63: 957–963

    Article  PubMed  Google Scholar 

  88. Sinclair C et al. (2007) Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 113: 187–194

    Article  CAS  PubMed  Google Scholar 

  89. Waters P et al. Aquaporin-4 antibodies in neuromyelitis optica and longitudinally-extensive transverse myelitis. Arch Neurol, in press

  90. Lennon VA et al. (1984) Membrane array of acetylcholine receptors determines complement-dependent mononuclear phagocytosis in experimental myasthenia gravis. Fed Proc 43: 1764

    Google Scholar 

  91. Lalive PH et al. (2006) Identification of new serum autoantibodies in neuromyelitis optica using protein microarrays. Neurology 67: 176–177

    Article  CAS  PubMed  Google Scholar 

  92. Lee KH et al. (1991) Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 41: 657–660

    Article  CAS  PubMed  Google Scholar 

  93. Magana SM et al. (2007) NMO-IgG status in fulminant CNS inflammatory demyelinating disorders (IDD). Neurology 68: A18–A19

    Google Scholar 

Download references

Acknowledgements

The work of S Jarius was supported by a fellowship from the European Neurological Society. The authors are very grateful to Professor Margaret Esiri for helpful comments on the manuscript, and to Dr Isabel Leite and Dr Saiju Jacob for allowing us to show unpublished data.

Author information

Authors and Affiliations

  1. S Jarius is a Neurologist and Neuroimmunologist and P Waters is a Postdoctoral Scientist in the Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, UK.,

    Sven Jarius & Patrick Waters

  2. F Paul is a Neurologist and Senior Physician, and F Zipp is Professor of Neurology at the Cecilie Vogt Clinic for Neurology, Charité–Universitaetsmedizin Berlin, Germany.,

    Friedemann Paul & Frauke Zipp

  3. D Franciotta is Head of the Laboratory of Neuroimmunology at the Neurological Institute “C. Mondino”, Pavia, Italy.,

    Diego Franciotta

  4. R Hohlfeld is Professor of Neurology and Clinical Neurosciences at the Ludwig Maximilian University, Munich, Germany.,

    Reinhard Hohlfeld

  5. A Vincent is Professor of Neuroimmunology and Head of the Neurosciences Group, University of Oxford.,

    Angela Vincent

  6. B Wildemann is Professor of Neurology and Head of the Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Germany.,

    Brigitte Wildemann

Authors
  1. Sven Jarius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Friedemann Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego Franciotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick Waters
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frauke Zipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reinhard Hohlfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Angela Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brigitte Wildemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela Vincent.

Ethics declarations

Competing interests

A Vincent is a consultant and patent holder for Athena Diagnostics and RSR Ltd. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jarius, S., Paul, F., Franciotta, D. et al. Mechanisms of Disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Rev Neurol 4, 202–214 (2008). https://doi.org/10.1038/ncpneuro0764

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneuro0764

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing