PURPOSE

In multiple sclerosis (MS), how brain functional changes relate to clinical conditions is still a matter of debate. The aim of this study was to investigate how functional connectivity (FC) reorganization at three different scales, ranging from local to whole brain, is related to tissue damage and disability.

METHODS

One-hundred-nineteen patients with MS were clinically evaluated with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite. Patients and 42 healthy controls underwent a multimodal 3 T MRI, including resting-state functional MRI.

RESULTS

We identified 16 resting-state networks via independent component analysis and measured within-network, between-network, and whole-brain (global efficiency and degree centrality) FC. Within-network FC was higher in patients than in controls in default mode, frontoparietal, and executive-control networks, and corresponded to low clinical impairment (default mode network versus Expanded Disability Status Scale r = - 0.31, p < 0.01; right frontoparietal network versus Paced Auditory Serial Addition Test r = 0.33, p < 0.01). All measures of between-network and whole-brain FC, except default mode network global efficiency, were lower in patients than in controls, and corresponded to high disability (i.e., basal ganglia global efficiency versus Timed 25-Foot Walk r = - 0.25, p < 0.03; default mode global efficiency versus Expanded Disability Status Scale r = - 0.44, p < 0.001). Altered measures of within-network, between-network, and whole-brain FC were combined in functional indices that were linearly related to disease duration, Paced Auditory Serial Addition Test and lesion load and non-linearly related to Expanded Disability Status Scale.

CONCLUSION

We suggest that the combined evaluation of functional alterations occurring at different levels, from local to whole brain, could exhaustively describe neuroplastic changes in MS, while increased within-network FC likely represents adaptive compensatory processes, decreased between-network and whole-brain FC likely represent loss of functional network integration consequent to structural disruption.