Longitudinal Changes of Functional Connectivity Dynamism Are Relevant for Disability Worsening in Multiple Sclerosis: A 2.5-Year Study
Giulia D'Amore1, Paola Valsasina2, Paolo Preziosa3, Monica Margoni2, Massimo Filippi4, Maria Rocca3
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 3Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 4Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University
Objective:
To investigate changes in time-varying functional connectivity (TVFC) over 2.5 years of follow-up in multiple sclerosis (MS) patients and their association with disability progression.
Background:
In MS patients, TVFC analysis showed abnormalities of the main functional networks, correlated with more severe clinical and cognitive disability. Preliminary evidence showed that MS-related cognitive decline was associated with progressive TVFC destabilization. However, the clinical relevance of longitudinal TVFC changes has not been investigated yet.
Design/Methods:
3T-MRI scans and clinical evaluations were obtained at baseline and at median follow-up of 2.5 years from 129 right-handed MS patients (103 relapsing-remitting [RR] and 26 progressive [P]) and 28 matched healthy controls (HC). At 2.5-year follow-up, patients were classified as clinically stable/worsened according to their disability change. TVFC was quantified at voxel-wise level as the coefficient of variation (CoV) across sliding-windows of degree centrality.
Results:
At follow-up, 25/129 (19.3%) MS patients worsened clinically. At baseline, MS patients showed reduced TVFC vs HC in the bilateral orbitofrontal cortex (p<0.05, family-wise error corrected), left cerebellum, right precuneus and left thalamus. At 2.5-year follow-up, a widespread reduction of TVFC over time (p<0.05, family-wise error corrected) was found in MS patients in temporal, parietal, occipital and frontal lobes, as well as in the cerebellum. Such a pattern of TVFC reduction was also found when looking at clinically stable MS patients. Clinically worsened MS presented peculiar TVFC reductions in areas of the default-mode network and basal ganglia. Reduced TVFC in the left putamen in clinically worsened vs stable MS patients was significant at time x group interaction analysis.
Conclusions:
After 2.5 years of follow-up, MS patients showed widespread TVFC reduction in cortical lobes and cerebellum. A peculiar involvement of deep grey matter was found in clinically worsened MS patients. Accrual of TVFC abnormalities in deep grey matter regions may represent a biological substrate of disability worsening.