<h3>Objective:</h3> To explore hippocampal static (sFC) and time-varying functional connectivity (TVFC) and assess their association with cognition in multiple sclerosis (MS). <h3>Background:</h3> The hippocampus has a key role in cognition. Hippocampal TVFC in MS needs to be further explored. <h3>Design/Methods:</h3> 3T structural and resting-state (RS) functional MRI scans were acquired from 108 MS patients and 63 healthy controls (HC). Subjects underwent neuropsychological evaluation. Sliding-window correlation analysis using the left (L) and right (R) hippocampus as seed regions assessed TVFC, quantified by the standard deviation of connectivity across windows. Mean connectivity indicated sFC. <h3>Results:</h3> MS patients had decreased sFC <i>vs</i> HC between L hippocampus and temporo-parietal regions, and increased sFC between L and R hippocampus and thalamus, precuneus and superior frontal regions. TVFC was decreased in MS patients between L hippocampus and temporo-parietal regions. Conversely, TVFC was increased in MS patients between L and R hippocampus and L pre- and postcentral gyri, cuneus, orbitofrontal cortex and inferior temporal gyrus (ITG). In MS patients, better global cognition correlated with higher TVFC between L hippocampus and L pre- and postcentral gyri (r=0.21–0.28; p=0.04–0.006). Better verbal memory correlated with higher TVFC between L hippocampus and L precentral gyrus (r=0.21, p=0.03), and better visuospatial memory correlated with higher TVFC between L and R hippocampus and L cuneus, pre- and postcentral gyri and ITG (r=0.19–0.23, p=0.02–0.04). Better information processing speed correlated with higher TVFC between L hippocampus and L postcentral gyrus (r=0.21, p=0.03) and with higher sFC between R hippocampus and L superior frontal cortex (SFC) (r=0.21, p=0.03). Finally, better attention scores correlated with higher TVFC between L hippocampus and L temporal cortex (r=0.24, p=0.01) and with higher sFC between R hippocampus and L SFC (r=0.20, p=0.05). <h3>Conclusions:</h3> Increased hippocampal connectivity contributed to explain better cognitive performances in MS, with a peculiar association between higher hippocampal TVFC and better memory scores. <b>Disclosure:</b> Monica Margoni has received research support from MAGNIMS. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Olga Marchesi has nothing to disclose. Carmen Vizzino has nothing to disclose. Damiano Mistri has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received 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). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.
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