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. 2025 Nov 27;272(12):787.
doi: 10.1007/s00415-025-13515-0.

Functional connectivity changes are associated with disability progression in multiple sclerosis: a longitudinal fMRI study

Claudia Piervincenzi  1 , Abhineet Ojha  2 , Silvia Tommasin  2   3 , Federica Satriano  2 , Nikolaos Petsas  4 , Antonio Gallo  5   6 , Alessandro d'Ambrosio  5   6 , Nicola De Stefano  7 , Rosa Cortese  7 , Paola Valsasina  8 , Nicolò Tedone  8   9 , Carlo Pozzilli  2 , Maria A Rocca  8   9   10 , Massimo Filippi  8   9   10   11   12 , Patrizia Pantano  2   13 ; INNI Network
Collaborators, Affiliations

Functional connectivity changes are associated with disability progression in multiple sclerosis: a longitudinal fMRI study

Claudia Piervincenzi et al. J Neurol. .

Abstract

Background: Resting-state functional connectivity (FC) alterations in people with multiple sclerosis (PwMS) have been hypothesized to reflect either adaptive or maladaptive plasticity. Investigating FC longitudinal evolution and its relationship with disability progression can help clarify this issue. This study examined 5-year FC changes in pwMS and their clinical relevance.

Methods: From the Italian Neuroimaging Network Initiative database, we included 156 pwMS with two clinical visits and 3T-MRI scans acquired on the same scanner 4-6 years apart. Clinical/neuropsychological visits included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk Test (T25FWT), Paced Auditory Serial Addition Test (PASAT3), and Symbol Digit Modalities Test (SDMT). One hundred fifty-six age- and sex-matched healthy subjects (HS) with baseline MRI and the same tests were also included. Based on the EDSS, pwMS were divided into three groups: low disability (0-1.5; N = 78), mild disability (2-3.5; N = 50), and high disability (≥ 4; N = 28). Resting-state networks (RSNs) were identified using independent component analysis. Baseline and longitudinal FC changes were correlated with baseline and follow-up clinical/neuropsychological measures.

Results: At baseline, the low-disability group showed significantly higher FC in all RSNs (FDR-corrected p < 0.05) compared to HS, which correlated with better baseline scores (SDMT, T25FWT) and less worsening at follow-up (PASAT3, 9HPT). The mild- and high-disability groups exhibited mixed FC abnormalities, with both higher and lower FC than HS in several RSNs. In the mild-disability group, higher FC was associated with worse baseline scores (SDMT, T25FWT) and greater clinical worsening (PASAT3, 9HPT, T25FWT). In the high-disability group, higher sensorimotor baseline FC correlated only with worse baseline 9HPT. Longitudinally, all RSNs showed FC increase in the low-disability group, but a FC decrease in the other groups. FC increases in the low-disability group generally correlated with better clinical outcome (T25FWT), while FC decreases in the mild-disability group correlated with clinical worsening (9HPT, T25FWT).

Conclusions: FC increases appear to reflect compensatory mechanisms in low-disability pwMS, while in more disabled patients, FC alterations likely represent maladaptive responses. These findings support resting-state FC as a biomarker for monitoring disease progression and treatment response in MS.

Keywords: Magnetic resonance imaging (MRI); Multiple sclerosis (MS); Resting-state functional MRI (fMRI).

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Conflict of interest statement

Declarations. Conflicts of interest: AO, ST, FS, NP, ADA: nothing to disclose. CP: receives research support from Fondazione Italiana Sclerosi Multipla. AG: has received speaker and consulting fees from Biogen, Genzyme, Merck Serono, Mylan, Novartis, Roche, and Teva, and receives research support from Fondazione Italiana Sclerosi Multipla. NDS: has received honoraria from Biogen-Idec, Bristol Myers Squibb, Celgene, Genzyme, Immunic, Merck Serono, Novartis, Roche and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Roche, and Genzyme, Immunic and he has received research grant support from the Italian MS Society. RC: was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria from Roche, Merck Serono and Sanofi and travel support for conferences by Novartis. PV: has received speaker honoraria from Biogen Idec. CP: has served on scientific advisory boards for Novartis, Merck, Biogen, Sanofi, Genzyme, Teva, and Actelion; received funding for travel and speaker honoraria from Biogen, Teva, Sanofi Genzyme, Actelion, and Novartis; received research support from Biogen, Teva, Novartis, and Genzyme. MAR: has received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, 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.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. PP: has received funding for travel from Novartis, Genzyme and Bracco and speaker honoraria from Biogen.

Figures

Fig. 1
Fig. 1
Resting-state networks (RSNs) showing significant within-network functional connectivity differences between people with Multiple Sclerosis (pwMS) groups and corresponding healthy subjects (HS) (p < 0.05, FDR corrected). Results for each RSN are overlaid onto the corresponding network (green) in the MNI152 standard brain. Red–yellow and blue–light-blue colors indicate areas of higher and lower FC in pwMS compared with HS, respectively. Color bars represent t values
Fig. 2
Fig. 2
Resting-state networks (RSNs) showing significant group differences in longitudinal changes of functional connectivity (ΔFC = follow-up—baseline) among people with Multiple Sclerosis (pwMS) with low, mild, and high disability. Results for each RSN (p < 0.05, FDR-corrected) are overlaid onto the corresponding F-map (shown in green) in the MNI152 standard brain. Red–yellow color indicates areas where ΔFC was higher in one group relative to another, respectively. Color bars represent t values
Fig. 3
Fig. 3
Voxel-wise main effects (ME) from the ANCOVA model showing significant longitudinal FC changes within resting-state networks (RSNs) for each disability group (p < 0.05, FDR corrected). Results for each RSN are overlaid onto the corresponding network (green) in the MNI152 standard brain. Red–yellow and blue–light-blue color bars indicate areas of FC increases and decreases, respectively. Color bars represent t values
See this image and copyright information in PMC

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