Resting State fMRI (RS-fMRI) represents an emerging and powerful tool to explore brain functional connectivity (FC) changes associated with neurologic disorders. Compared to activation/task-related fMRI, RS-fMRI has the advantages that (i) BOLD fMRI signals are self-generated and independent of subject’s performance during the task and (ii) a single dataset is sufficient to extract a set of RS networks (RSNs) that allows to explore whole brain FC. According to these features RS-fMRI appears particularly suitable for the study of FC changes related to multiple sclerosis (MS). In the present review we will first give a brief description of RS-fMRI methodology and then an overview of most relevant studies conducted so far in MS by using this approach. The most interesting results, in particular, regard the default-mode network (DMN), whose FC changes have been correlated with cognitive status of MS patients, and the visual RSN (V-RSN) whose FC changes have been correlated with visual recovery after optic neuritis. The executive control network (ECN), the lateralized frontoparietal network (FPN), and the sensory motor network (SMN) have also been investigated in MS, showing significant FC rearrangements. All together, RS-fMRI studies conducted so far in MS suggest that prominent RS-FC changes can be detected in many RSNs and correlate with clinical and/or structural MRI measures. Future RS-fMRI studies will further clarify the dynamics and clinical impact of RSNs changes in MS. 1. Introduction In the last decade magnetic resonance imaging (MRI) has acquired a central role in the clinical [1] and research setting in multiple sclerosis (MS) [2]. The MRI approach to MS includes traditional MRI techniques, that allow to identify focal white matter (WM) lesions and advanced MRI techniques (A-MRI), which allow to further characterize structural and functional changes related to MS. Among different A-MRI techniques, functional MRI (fMRI) allows to explore the dynamics of cortical functional reorganization associated with MS and its impact on disease evolution [2, 3]. Most of the fMRI studies conducted so far in MS have had an activation paradigm evoked by simple motor tasks, sensory stimulation, cognitive tasks, and so forth. These activation/task-related studies have shown significant and consistent functional changes at the level of relevant cortical networks in MS patients when compared to healthy controls (HCs). Such findings have been further supported by correlations with behavioral measures as well as markers of brain tissue injury, such as T2 lesion load
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