More than the sum of its parts: disrupted core-periphery of multiplex networks in multiple sclerosis

Disruptions to brain networks, measured using either structural (sMRI), diffusion (dMRI), or resting-state functional (rs-fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the importance of damage to regions in the core of the connectome. Here, using a multilayer network approach, we aimed to integrate these three modalities to portray an enriched representation of the brain’s core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, 1048 PwMS (695F, mean±SD age: 43.3±11.4yr), and 436 healthy controls (250F, mean±SD age: 38.3±11.8yr) with complete multimodal brain MRI acquisitions were selected from 13 European centres within the MAGNIMS network. Clinical variables included the Expanded Disability Status Scale (EDSS) and the Symbol Digit Modalities Test (SDMT), measuring physical disability and cognition, respectively. SMRI, dMRI, and rs-fMRI data were parcellated into 100 cortical (Schaefer atlas) and 14 subcortical (FSL-FIRST) regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity, respectively. Following statistical harmonization and preprocessing, connectivity matrices were merged in a multiplex, from which regional coreness, defined as the probability of a node being part of the multiplex core, and coreness disruption index (κ), quantifying the global weakening of the core-periphery structure, were computed. The associations of regional coreness and κ with disease status (PwMS versus healthy controls), clinical phenotype, and physical (EDSS) and cognitive (SDMT z-scores) disability were tested with permutation testing, one-way ANOVA, and Spearman and Pearson correlation, respectively. We used random forest permutation feature importance to assess the relative weights of κ in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), for the prediction of disease status, level of physical disability (EDSS≥4 vs EDSS<4), and cognitive impairment (SDMT z-score<-1.5). PwMS showed widespread deviations in regional coreness compared to healthy controls, with a prominent decrease in the thalami (Hedges’ g>0.90). At the global level, PwMS showed significant disruption of the multiplex core-periphery organization (κ=-0.19, Hedges’ g=0.61, p <0.001), correlating with clinical phenotype (F=5.42, p =0.001), EDSS (rho=-0.08, p =0.01) and SDMT (r=0.19, p <0.0001). Multiplex κ was the only connectomic measure adding to conventional MRI for the prediction of disease status and cognitive impairment, while physical disability depended also on single-layer contributions. We show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential novel biomarker for disease severity and cognitive impairment in multiple sclerosis. ### Competing Interest Statement M.C. received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. Si.Co. serves on scientific advisory board for Amicus Therapeurics, has received speaker honoraria from Sanofi and research grants from Fondazione Italiana Sclerosi Multipla and Telethon. R.S. was awarded a MAGNIMS-ECTRIMS fellowship in 2019. M.F. 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, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (iii) research support from Siemens, GeNeuro, Roche. C.G. is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Forderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E!113682 HORIZON2020. E.A.H. received honoraria for lecturing and advisory board activity from Biogen, Merck and Sanofi-Genzyme and unrestricted research grant from Merck. S.L. received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. S.M. received honoraria for lecturing and advisory board activity from UCB and Biogen, and travel grant from Roche and Merck. M.M. has received research grants from the ECTRIMS-MAGNIMS, the UK MS Society, and Merck, and honoraria from Biogen, BMS Celgene, Ipsen, Merck, Novartis and Roche. J.P. has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, Sanofi. Grants from Alexion, Roche, Medimmune, UCB, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Acknowledges Partial funding by Highly specialised services NHS England. M.P. discloses travel/meeting expenses from Novartis, Janssen, Roche and Merck, speaking honoraria from HEALTH&LIFE S.r.l., honoraria for consulting services from Biogen and research grants from Baroni Foundation. D.P. has received funding for travel from Merck, Genzyme/Sanofi-Aventis and Biogen, as well as speaking honoraria from Biogen, Novartis and Merck. M.A.R. received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. She receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. A.T. has been supported by grants from MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079), has had meeting expenses from Merck, Biomedia and Biogen Idec and was UK PI for two clinical trials sponsored by MEDDAY (MS-ON - [NCT02220244][1] and MS-SPI2 - [NCT02220244][1]). P.V. received speaker honoraria from Biogen Idec. O.C. is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. M.M.S. serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. F.B.: Steering committee and iDMC member for Biogen, Merck, Roche, EISAI. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder and share-holder of Queen Square Analytics LTD. The remaining authors report no competing interests. ### Funding Statement G.P. was supported by the ECTRIMS-MAGNIMS Research Fellowship Programme (2020). F.P. and B.K. are supported by the UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at UCLH and UCL. A.C. is supported by EUROSTAR E!113682 HORIZON2020. Sa.Co. is supported by a Rosetrees Trust Grant (PGL21/10079). M.A.F. is supported by a grant from the MRC (MR/S026088/1). L.D. Is supported by the Dutch Research Council (NWO, Vidi 198.015). The study was supported by grants from The Research Council of Norway (NFR, grant number 240102) and the South-Eastern Health Authorities of Norway (grant number 257955). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of University College London gave approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data from patients are controlled by the respective centers (listed in Supplementary Table 1) and therefore are not publicly available. Request to access raw data should be forwarded to data controllers via the corresponding author. Derived data supporting the findings of this study can be requested by qualified investigators from the corresponding author. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02220244&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F18%2F2022.12.17.22283623.atom