Increased functional network connectivity following cognitive rehabilitation in progressive multiple sclerosis with moderate to severe disabilty: findings from the CogEx study.

Francesco Romanò, Paola Valsasina, Matteo Albergoni, Maria Pia Amato, Giampaolo Brichetto, Jeremy Chataway, Nancy D Chiaravalloti, Gary Cutter, Ulrik Dalgas, John DeLuca, Rachel Farrell, Peter Feys, Jennifer Freeman, Matilde Inglese, Emilio Cipriano, Cecilia Meza, Robert W Motl, Amber Salter, Brian M Sandroff, Anthony Feinstein, Maria A Rocca, Massimo Filippi

Journal: Journal of neurology 2026;273(6):

PMID: 42165958

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Abstract

BACKGROUND

Functional neuroplasticity likely occurs following cognitive rehabilitation (CR) and aerobic exercise (EX) in progressive multiple sclerosis (PMS). We explored network resting state (RS) functional connectivity (FC) changes and associations with cognitive measure modifications in CogEx study participants.

METHODS

Patients with PMS were randomly assigned to four groups and underwent 12 weeks of treatment with a combination of CR and EX or sham therapies. Cognitive and fMRI assessments were performed at baseline, immediately post-intervention (week-12) and 6 months post-intervention (month-9). RS FC within the main cognitive brain networks was extracted and compared between groups at whole-network and voxel-wise levels and correlated with cognitive changes.

RESULTS

We included 87 PMS patients with moderate-to-severe disability (Expanded Disability Status Scale score 4.0-6.5). There were no differences in whole-network RS FC between the four groups. When comparing patients performing CR vs CR-S, we found increased salience (p = 0.01) and default-mode network (p = 0.02) RS FC at week-12, and increased left (p = 0.05) and right frontoparietal network (p = 0.04) RS FC at month-9 in CR compared with CR-S groups. Increased default-mode network RS FC correlated weakly with increased verbal memory in CR (rho = 0.27, p = 0.06). At voxel-wise level, we found increased RS FC in most analyzed networks in CR groups (p < 0.001, uncorrected) and decreased RS FC in CR-S groups at week-12 (p < 0.05, family-wise error corrected).

CONCLUSIONS

CR modulated RS FC in cognitive networks of patients with PMS, suggesting treatment-related functional plasticity of large-scale networks even in late, disabling MS phases. These network-level changes may reflect neural processes that support cognitive improvement following CR.

Address: Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.; Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.; NeuroBRITE Research Center, Italian Multiple Sclerosis Foundation (FISM), Genoa, Italy.; AISM Rehabilitation Service, Italian Multiple Sclerosis Society, Genoa, Italy.; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, WC1B 5EH, UK.; National Institute for Health Research, Biomedical Research Centre, University College London Hospitals, London, W1T 7DN, UK.; Kessler Foundation, West Orange, NJ, USA.; Department of Physical Medicine & Rehabilitation, Rutgers NJ Medical School, Rutgers University Newark, Newark, NJ, USA.; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.; Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark.; Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, WC1B 5EH, UK.; REVAL, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium.; UMSC Hasselt, Pelt, Belgium.; Faculty of Health, School of Health Professions, University of Plymouth, Plymouth, UK.; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.; IRCCS Azienda Ospedaliera Metropolitana, Genoa, Italy.; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.; Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, Canada.; Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA.; Department of Neurology, Section On Statistical Planning and Analysis, UT Southwestern Medical Center, Dallas, TX, USA.; Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.; Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.; Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy.; Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy. [email protected].; Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy. [email protected].; Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy. [email protected].; Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy. [email protected].; Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy. [email protected].

DOI: 10.1007/s00415-026-13869-z

MeSH Terms: Humans, Male, Female, Middle Aged, Magnetic Resonance Imaging, Multiple Sclerosis, Chronic Progressive, Adult, Nerve Net, Connectome, Brain, Neuronal Plasticity, Exercise Therapy, Cognitive Training