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  • Review Article
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Mind the gap: from neurons to networks to outcomes in multiple sclerosis

Nature Reviews Neurology volume 17, pages 173–184 (2021)Cite this article

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Abstract

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

Key points

  • Multiple sclerosis (MS) pathology affects neuroaxonal structure (for example, via axonal transection) and function (for example, via demyelination), and does so in both lesions and extra-lesional tissues.

  • Multiple pathological processes can combine to affect neural network function.

  • In individuals with MS, white matter tracts are disrupted by lesions, the cortex is relatively disconnected and the grey matter network topology is more random than in healthy controls.

  • Increases and decreases in connectivity, centred around hubs such as the thalamus and default-mode network, are seen; abnormal connectivity seems to evolve rather than simply progress over time, for example, early increases can be followed by later decreases.

  • Both structural and functional network changes are associated with clinical outcomes, and treatments that modify neural network function — not structure — might still have a beneficial effect.

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Fig. 1: From neurons to clinical outcomes in MS.

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Acknowledgements

This work arose out of a Magnetic Resonance Imaging in MS (MAGNIMS) workshop on brain connectivity and networks in multiple sclerosis. The workshop was supported by the Multiple Sclerosis Society UK and Novartis, but they had no involvement in the workshop programme or in the writing of this manuscript.

Author information

Authors and Affiliations

  1. NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK

    Declan T. Chard, Thalis Charalambous, Carmen Tur, Claudia A. M. Gandini Wheeler-Kingshott, Olga Ciccarelli & O. Ciccarelli

  2. National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, UK

    Declan T. Chard, Olga Ciccarelli, Frederik Barkhof, F. Barkhof & O. Ciccarelli

  3. Department of Diagnostic Radiology, Faculty of Applied Medical Science, King Abdulaziz University (KAU), Jeddah, Saudi Arabia

    Adnan A. S. Alahmadi

  4. Aix-Marseille University, CNRS, CRMBM, Marseille, France

    Bertrand Audoin

  5. AP-HM, University Hospital Timone, Department of Neurology, Marseille, France

    Bertrand Audoin

  6. Department of Neurology, Research Unit for Neuronal Repair and Plasticity, Medical University of Graz, Graz, Austria

    Christian Enzinger & C. Enzinger

  7. Department of Radiology, Division of Neuroradiology, Vascular and Interventional Radiology, Medical University of Graz, Graz, Austria

    Christian Enzinger & C. Enzinger

  8. Department of Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Hanneke E. Hulst & Menno M. Schoonheim

  9. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Maria A. Rocca, M. Filippi & M. A. Rocca

  10. Section of Neuroradiology, Department of Radiology Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Àlex Rovira & A. Rovira

  11. Servei de Neurologia/Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Jaume Sastre-Garriga & J. Sastre-Garriga

  12. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Betty Tijms

  13. Department of Neurology, Luton and Dunstable University Hospital, Luton, UK

    Carmen Tur

  14. Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy

    Claudia A. M. Gandini Wheeler-Kingshott

  15. Brain MRI 3T Research Center, IRCCS Mondino Foundation, Pavia, Italy

    Claudia A. M. Gandini Wheeler-Kingshott

  16. Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Alle Meije Wink, Frederik Barkhof, F. Barkhof & H. Vrenken

  17. Institutes of Neurology and Healthcare Engineering, University College London, London, UK

    Frederik Barkhof & F. Barkhof

  18. Department of Neurological and Behavioural Sciences, University of Siena, Siena, Italy

    N. De Stefano

  19. Department of Neurology, Glostrup University Hospital Copenhagen, Copenhagen, Denmark

    J. L. Frederiksen

  20. Department of Neurosciences, San Camillo Forlanini Hospital, Rome, Italy

    C. Gasperini

  21. Department of Neurology, University Hospital, Kantonsspital, Basel, Switzerland

    L. Kappos

  22. Nuffield Department of Clinical Neurology, University of Oxford, Oxford, UK

    J. Palace

  23. Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK

    T. Yousry

  24. Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK

    T. Yousry

Authors
  1. Declan T. Chard
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  2. Adnan A. S. Alahmadi
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  3. Bertrand Audoin
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  4. Thalis Charalambous
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  5. Christian Enzinger
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  6. Hanneke E. Hulst
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  7. Maria A. Rocca
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  8. Àlex Rovira
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  9. Jaume Sastre-Garriga
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  10. Menno M. Schoonheim
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  11. Betty Tijms
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  12. Carmen Tur
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  13. Claudia A. M. Gandini Wheeler-Kingshott
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  14. Alle Meije Wink
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  15. Olga Ciccarelli
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  16. Frederik Barkhof
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Consortia

the MAGNIMS Study Group

  • F. Barkhof
  • , O. Ciccarelli
  • , N. De Stefano
  • , C. Enzinger
  • , M. Filippi
  • , M. A. Rocca
  • , J. L. Frederiksen
  • , C. Gasperini
  • , L. Kappos
  • , J. Palace
  • , A. Rovira
  • , J. Sastre-Garriga
  • , T. Yousry
  •  & H. Vrenken

Contributions

D. T. C., A. A. S. A., B. A., T. C., C. E., H. E. H., M.A.R., J. S.-G., B. T., C. T. and A. M. W. researched data for the article. All authors made a substantial contribution to discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Declan T. Chard.

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Competing interests

Over the last 3 years, D. C. has received honoraria (paid to his employer) from Excemed for faculty-led education work. He is a consultant for Biogen and Hoffmann-La Roche. He has received research funding from the International Progressive MS Alliance, the MS Society UK, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. A. B. reports travel grants from Biogen France SAS, Genzyme, Novartis Pharma SAS, Teva Santé SAS. C. E. has received funding for travel and speaker honoraria from Biogen, Bayer Schering, Celgene, Genzyme, Merck, Novartis, Roche, and Teva Pharmaceutical Industries Ltd/Sanofi-Aventis, received research support from Biogen, Merck, and Teva Pharmaceutical Industries Ltd/Sanofi-Aventis, and serves on scientific advisory boards for Bayer, Biogen, Genzyme, Merck, Novartis, Roche, and Teva Pharmaceutical Industries Ltd/Sanofi-Aventis. H. E. H. has received compensation for consulting services or speaker honoraria from Biogen Idec, Celgene, Merck Serono, and Sanofi Genzyme and serves on the editorial board of the Multiple Sclerosis Journal. M. A. R. has received speaker’s honoraria from Bayer, Biogen Idec, Calgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. A. R. serves as Editorial Board member of Neuroradiology and American Journal of Neuroradiology, on scientific advisory boards for Bayer, Biogen, Novartis, OLEA Medical, Sanofi Genzyme, SyntheticMR and Roche, and has received speaker honoraria from Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries Ltd. J. S.-G. reports grants and personal fees from Genzyme received over the last 36 months and personal fees from Almirall, Bial, Biogen, Celgene, Merck, Novartis, Roche and Teva; he is Director of Revista de Neurologia, for which he does not receive any compensation, and serves as member of the Editorial Board of Multiple Sclerosis Journal, for which he receives compensation. M. M. S. serves on the Editorial Board of Frontiers in Neurology and has received compensation for consulting services or speaker honoraria from Biogen, ExceMed and Genzyme. B. T. received funding from the ZonMW Memorabel grant programme #73305056. C. T. has received a postdoctoral research ECTRIMS fellowship (2015); she has also received honoraria and support for travelling from Bayer, Biogen, Ismar Healthcare, Merck Serono, Novartis, Roche, Sanofi and Teva Pharmaceuticals and provides consultancy services to Roche. C. G. W.-K. reports receiving research funding from the International Spinal Research Trust, the Craig H. Neilsen Foundation (the INSPIRED study), the MS Society (#77), Wings for Life (the INSPIRED study, #169111) and Horizon 2020 (CDS-QUAMRI, #634541). A. M. W. receives funding from the European Prevention of Alzheimer’s Dementia consortium, the Amyloid Imaging to Prevent Alzheimer’s Disease initiative (Innovative Medicines Initiative grants 115736 and 115962) and the European Progression of Neurological Disease Initiative (Horizon 2020 grant 666992). O. C. serves as a consultant for Merck, Novartis, and Roche; she receives an honorarium from the American Academy of Neurology as Associate Editor of Neurology. F. B. serves as an Editorial Board member of Brain, European Radiology, Neurology, Multiple Sclerosis Journal and Radiology; he has accepted consulting fees from Apitope Ltd, Bayer-Schering Pharma, Biogen-IDEC, GeNeuro, Sanofi Genzyme, IXICO Ltd, Jansen Research, Merck Serono, Novartis, Roche, and TEVA and speaker fees from Biogen-IDEC and IXICO. He has received grants from the Amyloid Imaging to Prevent Alzheimer’s Disease Initiative (Innovative Medicines Initiative), the European Progression of Neurological Disease Initiative (H2020), UK MS Society, Dutch MS Society, NIHR University College London Hospital Biomedical Research Centre, the European Committee for Treatment and Research in Multiple Sclerosis and the Magnetic Resonance Imaging in MS network. The other authors declare no competing interests.

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Glossary

Connectomics

The comprehensive study of neural networks with the ultimate aim of generating maps that represent all connections in the CNS.

Hub

A network node that has a high number of direct connections with other nodes.

Nexopathies

The interactions of pathogenic proteins with neural networks that are vulnerable to their effects, resulting in characteristic patterns and spread of abnormalities across the CNS.

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Chard, D.T., Alahmadi, A.A.S., Audoin, B. et al. Mind the gap: from neurons to networks to outcomes in multiple sclerosis. Nat Rev Neurol 17, 173–184 (2021). https://doi.org/10.1038/s41582-020-00439-8

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