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Original research
Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial
  1. Maria A Rocca1,2,3,
  2. Paola Valsasina1,
  3. Francesco Romanò1,
  4. Nicolò Tedone1,
  5. Maria Pia Amato4,5,
  6. Giampaolo Brichetto6,7,
  7. Vincenzo Daniele Boccia8,
  8. Jeremy Chataway9,10,
  9. Nancy D Chiaravalloti11,12,
  10. Gary Cutter13,
  11. Ulrik Dalgas14,
  12. John DeLuca11,12,
  13. Rachel A Farrell9,
  14. Peter Feys15,16,
  15. Jennifer Freeman17,
  16. Matilde Inglese8,18,
  17. Cecilia Meza19,
  18. Robert W Motl20,
  19. Amber Salter21,
  20. Brian M Sandroff11,12,
  21. Anthony Feinstein19,
  22. Massimo Filippi1,2,3,22,23
  23. The Cogex Research Team
    1. 1Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
    2. 2Neurology Unit, IRCCS Ospedale San Raffaele, Milan, Italy
    3. 3Vita-Salute San Raffaele University, Milan, Italy
    4. 4Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy
    5. 5IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
    6. 6Scientific Research Area, Italian Multiple Sclerosis Foundation (FISM), Genoa, Italy
    7. 7AISM Rehabilitation Service, Italian Multiple Sclerosis Society, Genoa, Italy
    8. 8Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
    9. 9Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
    10. 10National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK
    11. 11Kessler Foundation, West Orange, NJ, USA
    12. 12Department of Physical Medicine & Rehabilitation, Rutgers New Jersey Medical School, Newark, New Jersey, USA
    13. 13Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
    14. 14Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark
    15. 15REVAL, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium
    16. 16University MS Center, Hasselt University, Pelt, Belgium
    17. 17Faculty of Health, School of Health Professions, University of Plymouth, Plymouth, Devon, UK
    18. 18IRCCS Ospedale Policlinico San Martino, Genoa, Italy
    19. 19Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
    20. 20Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, Illinois, USA
    21. 21Department of Neurology, Section on Statistical Planning and Analysis, UT Southwestern Medical Center, Dallas, Texas, USA
    22. 22Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy
    23. 23Neurophysiology Service, IRCCS Ospedale San Raffaele, Milan, Italy
    1. Correspondence to Professor Maria A Rocca, Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milano 20132, Italy; rocca.mara{at}hsr.it

    Abstract

    Background Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings.

    Methods Participants were randomised to: ‘CR plus EX’, ‘CR plus sham EX (EX-S)’, ‘EX plus sham CR (CR-S)’ and ‘CR-S plus EX-S‘ and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task).

    Results 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25–62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in ‘CR plus EX-S’ (p=0.02). Groups performing CR (ie, ‘CR plus EX’ and ‘CR plus EX-S’) exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. ‘CR plus EX-S’ patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula.

    Conclusions In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements.

    Trial registration number NCT03679468.

    • MULTIPLE SCLEROSIS
    • COGNITION
    • REHABILITATION
    • MRI

    Data availability statement

    Data are available upon reasonable request. Anonymised data are available one year after publication, upon reasonable request. Please make the request to the corresponding author, MAR. A CogEx Committee will review the request for approval. A data sharing agreement will be produced before any data are shared. The study protocol and statistical analysis plan were previously published.

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    Data availability statement

    Data are available upon reasonable request. Anonymised data are available one year after publication, upon reasonable request. Please make the request to the corresponding author, MAR. A CogEx Committee will review the request for approval. A data sharing agreement will be produced before any data are shared. The study protocol and statistical analysis plan were previously published.

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    Footnotes

    • X @Nico_Ted1

    • Collaborators The Cogex Research Team Collaborators: Aarhus University, Aarhus, Denmark: Anne Sophie Michelsen, Laurits Emil Taul Madsen, Marie-Louise Kjeldgaard Jørgensen, Mette Dahl Diedmann. Hasselt University, Hasselt, Belgium: Charly Keytsman, Ellen Vanzeir, Joke Lenaerts, Leen Knevels, Mieke D’Hooge, Natasja De Weerdt, Renee Veldkamp, Rudi Donnee, Séline Vandecasteele, Veerle Vandael. IRCCS San Raffaele Scientific Institute, Milano, Italy: Claudio Cordani, Mauro Sibilia, Carmen Vizzino, Gianna Carla Riccitelli, Paolo Preziosa. Italian Multiple Sclerosis Foundation: Jessica Podda, Ludovico Pedullà, Andrea Tacchino. Kessler Foundation, West Orange, New Jersey, USA: Angela Smith, Blake Bichler, Jimmy Morecraft, Michael DiBenedetto, Nancy Moore. Plymouth University, Plymouth, UK: Catherine Holme, Chris Cole, Kimberley Algie, Sara Chatfield. Sunnybrook Hospital, Toronto, Canada: Juliana Puopolo, Laura Kenton, Laura Toll. The University of Alabama at Birmingham: Ashlie Kristin Ithurburn, Brendon Truax, Catherine Danielle Jones, Jessica Baird, Petra Silic. University College London Hospital, London, UK: Michelle Koch, Patrizia Pajak, Alexsandra Pietrusz, Catherine Smith, Holly Wilkinson, James Braisher, Marie Braisher, Rebecca Bex Walters. University of Florence, Florence, Italy: Claudia Niccolai, Guido Pasquini, Irene Mosca, Sara Della Bella, Fedrica Vannetti, Filippo Gerli. University of Genoa: Chiara Pollio, Eleonora Colombo, Elisa Pelosin, Maria Cellerino, Matteo Pardini. UT Southwestern Medical Center, Dallas, Texas, USA: Roberto Hernandez. Washington University School of Medicine in St. Louis, St. Louis, USA: Michele Curran.

    • Contributors MAR contributed to study concept, analysis and interpretation of data, and to drafting/revising the manuscript. PV contributed to analysis and interpretation of data, and to drafting/revising the manuscript. FR contributed to data collection, interpretation of the data and drafting/revising the manuscript. NT contributed to data collection, interpretation of the data and drafting/revising the manuscript. MPA contributed to study concept, data collection and drafting/revising the manuscript. GB contributed to study concept, data collection and drafting/revising the manuscript. VDB contributed to data collection and drafting/revising the manuscript. JC contributed to study concept, data collection and interpretation and drafting/revising the manuscript. NC contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. GC contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. UD contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. JD contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. RAF contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. PF contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. JF contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. MI contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. CM contributed to data collection and drafting/revising the manuscript. RWM contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. AS contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. BMS contributed to study concept, data collection and interpretation, and drafting/revising the manuscript. AF contributed to study concept, data interpretation, and drafting/revising the manuscript. MF contributed to study concept, data interpretation, and drafting/revising the manuscript. Guarantors: MAR and AF.

    • Funding This study was funded by a grant from the Multiple Sclerosis Society of Canada (grant no. #EGID3185). Ancillary funding was provided by the Consortium of Multiple Sclerosis Centres, the Danish Multiple Sclerosis Society and the US National Multiple Sclerosis Society.

    • Competing interests MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research and Fondazione Italiana Sclerosi Multipla, she is Associate Editor for Multiple Sclerosis and Related Disorders. PV received speaker honoraria from Biogen Idec. FR has nothing to disclose. NT has nothing to disclose. MPA received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. GB has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. VDB has nothing to disclose. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust, he is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK, he has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Ionis, Novartis and Roche, and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. NC is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. GC is a member of Data and Safety Monitoring Boards for AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), he is on Consulting or Advisory Boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics, he is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc, a private consulting company located in Birmingham AL. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. JD is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review, received compensation for consulting services and/or speaking activities from Biogen Idec, Celgene, MedRhythms and Novartis, and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers and National Institutes of Health. RAF has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Genzyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen, she is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. PF is editorial board member of NNR, MSJ and Frontiers in Rehabilitation Sciences (section ‘Strengthening Health Systems’), provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. JF has been awarded research grants from the NIHR, UK. MI is Co-Editor for Controversies for Multiple Sclerosis Journal, received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. CM has nothing to disclose. RWM has nothing to disclose. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of editorial board for Neurology. BMS has nothing to disclose. AF is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker’s honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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