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Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis

Molecular Psychiatry volume 27, pages 1765–1773 (2022)Cite this article

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Abstract

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

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Fig. 1: Time-varying functional connectivity analysis: progressive vs relapsing-remitting multiple sclerosis patients.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

AC is supported by a MAGNIMS/ECTRIMS research fellowship programme.

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Authors and Affiliations

  1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Antonio Carotenuto, Paola Valsasina, Milagros Hidalgo de la Cruz, Laura Cacciaguerra, Paolo Preziosa, Olga Marchesi, Massimo Filippi & Maria A. Rocca

  2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Laura Cacciaguerra, Paolo Preziosa, Massimo Filippi & Maria A. Rocca

  3. Vita-Salute San Raffaele University, Milan, Italy

    Laura Cacciaguerra, Massimo Filippi & Maria A. Rocca

  4. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  5. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

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  1. Antonio Carotenuto
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Contributions

MAR contributed to the conception and design of the study. AC, PV, MHdlC, LC, PP, OM, MF, MAR contributed to the acquisition and analysis of data. AC, PV, MHdlC, LC, PP, OM, MF, MAR contributed to drafting the text and preparing the figures. All the authors gave their approval to the current version of the manuscript.

Corresponding author

Correspondence to Maria A. Rocca.

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Competing interests

AC has received research grants from the ECTRIMS-MAGNIMS and from Almirall, and served on advisory boards for: Merk, Novartis, Roche and Almirall. PV received speaker honoraria from Biogen Idec. MHdlC reports no disclosures. LC received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi. PP received speaker honoraria from Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme. He is supported by a senior research fellowship FISM – Fondazione Italiana Sclerosi Multipla – cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding. OM reports no disclosures. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

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Carotenuto, A., Valsasina, P., Hidalgo de la Cruz, M. et al. Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis. Mol Psychiatry 27, 1765–1773 (2022). https://doi.org/10.1038/s41380-021-01401-w

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