Reduced Dynamism of Functional Connectivity Is Associated with Cognitive Impairment in Multiple Sclerosis Patients: A Dynamic Functional Connectivity Study in a Multi-Center Setting (P3.379)

Objective: To investigate the relationship between multiple sclerosis (MS)-related cognitive impairment (CI) and time-varying functional connectivity (FC) using a dynamic resting state (RS) FC approach. Background: A large proportion of MS patients has cognitive deficits. One of the core features of cognitive impairment in MS is decreased information processing speed. Design/Methods: RS fMRI scans from 62 MS patients and 65 healthy controls (HC) were obtained at seven European sites of the MAGNIMS network. MS patients underwent clinical/cognitive evaluation. Independent component analysis was used to identify 43 relevant intrinsic FC components. Between-group differences of network FC were evaluated using a dynamic approach (i.e., by assessing RS FC on small temporal segments using sliding windows), and then grouping FC correlation matrices into recurrent states of transient FC. Summary dynamism measures were computed for each study group. Results: Twenty-three MS patients (37%) were cognitively impaired (CI) (≥ two abnormal neuropsychological tests). Dynamic FC analysis revealed, in HC and MS, 3 recurrent FC states: two states characterized by strong internetwork connectivity and one characterized by weak inter-network connectivity. CI-MS patients had a significantly lower dwell time in the high-connectivity State 2 compared to cognitively preserved (CP)-MS (p=0.05). Compared to CP-MS, CI-MS patients exhibited significantly lower dynamic fluidity (defined as less switches between states) (p=0.01) and operated over a restricted dynamic range (p=0.01). Between-group comparison of connectivity strengths revealed lower FC in MS vs HC between cortical-subcortical networks. In connectivity State 3, CI vs CP-MS patients showed reduced FC between cortical-subcortical networks. Conclusions: In both HC and MS patients, dynamic RS FC analysis was able to detect recurrent patterns of strong and weak inter-network RS FC. Time-varying RS FC patterns were markedly less dynamic in CI than in CP-MS patients and HC, suggesting that slow inter-network connectivity is strongly associated with a worse cognitive profile in MS. Disclosure: Dr. D9Ambrosio has nothing to disclose. Dr. Rocca has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Novartis, Teva Neurosciences and Genzyme. Dr. Valsasina has nothing to disclose. Dr. Gallo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Genzyme, Merck, Novartis, Teva, Mylan. Dr. De Stefano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck Serono S.A., Teva Pharmaceutical Industries, Novartis Pharma AG, BayerSchering AG, SanofiAventis and Serono Symposia International Foundation. Dr. Pareto has nothing to disclose. Dr. Barkhof has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Has received personal compensation for activities with Apitope Ltd., GeNeuro, Biogen Idec, Sanofi-Genzyme, Janssen Research, Merck-Serono, Novartis, IXICO Ltd, Roche and TEVA as a consultant. He also received compensation from IXICO Ltd. for development o. Dr. Barkhof has received research support from Grants from AMYPAD (IMI), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI-NWO), NIHR UCLH Biomedical Research Centre (BRC) and ECTRIMS-MAGNIMS. Dr. Ciccarelli has nothing to disclose. Dr. Enzinger has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Bayer Schering Pharma, Merck Serono, Novartis, Shire, Genzyme, and Teva Pharmaceutical Industries Ltd/Sanofi-Aventis. Dr. Enzinger has received research support from Merck Serono, Biogen, and Teva Pharmaceutical Industries Ltd/ Sanofi-Aventis;. Dr. Tedeschi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck Serono, Novartis, Biogen, Genzyme, Teva, Almirall, Roche. Dr. Stromillo has nothing to disclose. Dr. Arevalo has nothing to disclose. Dr. Hulst has nothing to disclose. Dr. Muhlert has nothing to disclose. Dr. Koini has nothing to disclose. Dr. Filippi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Merk-Serono, Novartis, Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in an editorial capacity for Journal of Neurology. Dr. Filippi has received research support from Biogen Idec, Novartis, Teva Pharmaceutical Industries.