Dynamic Functional Connectivity in the Main Clinical Phenotypes of Multiple Sclerosis

Introduction: Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances.

Methods: RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks.

Results: dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC (p = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments (p = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances.

Conclusions: MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage.

Impact statement This is the first study exploring reorganization of dynamic functional connectivity in patients with multiple sclerosis (MS) across the main clinical phenotypes of the disease. Here, we demonstrated abnormalities of connectivity dynamism, which were present at all disease stages, but became more severe in progressive MS and correlated with worse motor and cognitive performances. These findings suggested that progressive MS patients might experience a maladaptive neuronal response to transient loss of dynamic coordination and flexibility among sensory and cognitive brain regions, leading to the progression of clinical impairment.