To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial). From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed. Compared to controls and non-fatigued MS (n = 86), fatigued MS patients (n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue. Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue.

Background: The features of functional network connectivity reorganization at the earliest stages of MS have not been investigated yet. Objective: To combine static and dynamic analysis of resting state (RS) functional connectivity (FC) to identify mechanisms of clinical dysfunction and recovery occurring in clinically isolated syndrome (CIS) patients. Methods: RS functional magnetic resonance imaging (fMRI) and clinical data were prospectively acquired from 50 CIS patients and 13 healthy controls (HC) at baseline, month 12 and month 24. Between-group differences and longitudinal evolution of network FC were analysed across 41 functionally relevant networks. Results: At follow-up, 47 patients developed MS. Disability remained stable (and relatively low). CIS and HC exhibited two recurring RS FC states (states 1 and 2, showing low and high internetwork connectivity, respectively). At baseline, patients showed reduced state 2 connectivity strength in the default-mode and cerebellar networks, and no differences in global dynamism versus HC. A selective FC reduction in networks affected by the clinical attack was also detected. At follow-up, increased state 2 connectivity strength and global connectivity dynamism was observed in patients versus HC. Conclusion: Longitudinal FC modifications occurring relatively early in the course of multiple sclerosis may represent a protective mechanism contributing to preserve clinical function over time.

Background: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood. Objectives: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes. Methods: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment. Result: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)- R² = 0.19, p-range = <0.001–0.04), z9HPT (right: OOB- R² = 0.14; left: OOB- R² = 0.24, p-range = <0.001–0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB- R² = 0.16, p-range = 0.02–0.04). Conclusion: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.

Introduction. Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. Here, 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 fMRI and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, 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=range 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 vs RRMS patients. In MS, dFC decrease in sensorimotor, default-mode and frontal/attention networks were 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.