The virtual multiple sclerosis patient: on the clinical-radiological paradox

Multiple sclerosis (MS) is typically diagnosed based on the clinical presentation, the presence of structural MRI lesions, and a no better explanation criterion. The structural lesions, disseminated in time and space, are a consequence of autoimmune processes leading to the damage of the myelin sheath in the central nervous system. As such, one would expect that more lesions would relate to higher clinical disability. However, a conflicting scenario is often present, with a high lesion load related to mild clinical impairment, and vice versa, a phenomenon referred to as the clinico-radiological paradox. The myelin damage in MS is widespread, which is likely mirrored in a widespread slowing of conduction velocities. However, conduction velocities are typically measured on selected white-matter tracts (e.g., visual evoked potentials), which do not directly relate to clinical impairment. In this paper, we hypothesize that the overall slowing of conduction velocities (i.e., across all brain tracts) is a better predictor of clinical disability. However, estimating the whole-brain average velocities is challenging. To overcome this obstacle, we estimated patient-specific conduction velocities in MS patients by merging multimodal data (i.e., DTI and source-reconstructed magnetoencephalography) to inform large-scale brain models, fitted on each individual patient. We started from the known reduction of the power of the alpha frequency band, as well as the shift in its peak, observed in MS patients. We then reproduced these individual spectral features in silico using large-scale models based on the individual connectomes. We then used state-of-the-art deep neural networks for Bayesian model inversion to estimate the most likely average conduction velocity in each patient, given the observed spectral features (and the connectomes). Finally, we used the inferred conduction velocities to predict the individual clinical disability. We find that the conduction velocities inferred for patients are significantly lower than those inferred for controls and that they are predictive of individual clinical disability, well above the predictive power of demographic and clinical variables andlesion load. Our results suggest a biologically and physically plausible solution to the clinico-radiological paradox, where the inferred, individual changes in conduction velocities across the whole networks are proposed as causative to the clinical disability. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was supported by the European Union Horizon 2020 research and innovation programme under grant agreement No. 945539 (SGA3); Human Brain Project and Virtual 542 Brain Cloud No. 826421; Ministero Sviluppo Economico; Contratto di sviluppo industriale Farmaceutica e Diagnostica(CDS 000606) and NextGenerationEU (project IR0000011, EBRAINS-Italy). AP & AB were supported by NBRC core funds. AB was supported by Ministry of Youth Affairs and Sports, Government of India, Award ID: F.NO.K-15015/42/2018/SP-V, NBRC Flagship program, Department of Biotechnology, Government of India, Award ID: BT/MED-III/NBRC/Flagship/Flagship2019. ### 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: The study was approved by the Ethics Committee of ASL-NA1 centro (Prot.n.93C.E./Reg. n.14-17OSS) 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data will be available upon request to the corresponding author (Pierpaolo Sorrentino), conditional on appropriate ethics approval at the local site. In case data are requested, the corresponding author will request an amendment to the local ethical committee.