Abstract
Only a few studies have evaluated the brain functional changes associated with disease-modifying therapies (DMTs) in multiple sclerosis (MS), though none used a composite measure of clinical and MRI outcomes to evaluate DMT-related brain functional connectivity (FC) measures predictive of short-term outcome. Therefore, we investigated the following: (1) baseline FC differences between patients who showed evidence of disease activity after a specific DMT and those who did not; (2) DMT-related effects on FC, and; (3) possible relationships between DMT-related FC changes and changes in performance. We used a previously analyzed dataset of 30 relapsing MS patients who underwent fingolimod treatment for 6 months and applied the “no evidence of disease activity” (NEDA-3) status as a clinical response indicator of treatment efficacy. Resting-state fMRI data were analyzed to obtain within- and between-network FC measures. After therapy, 14 patients achieved NEDA-3 status (hereinafter NEDA), while 16 did not (EDA). The two groups significantly differed at baseline, with the NEDA group having higher within-network FC in the anterior and posterior default mode, auditory, orbitofrontal, and right frontoparietal networks than the EDA. After therapy, NEDA showed significantly reduced within-network FC in the posterior default mode and left frontoparietal networks and increased between-network FC in the posterior default mode/orbitofrontal networks; they also showed PASAT improvement, which was correlated with greater within-network FC decrease in the posterior default mode network and with greater between-network FC increase. No significant longitudinal FC changes were found in the EDA. Taken together, these findings suggest that NEDA status after fingolimod is related to higher within-network FC at baseline and to a consistent functional reorganization after therapy.
Highlights
Multiple sclerosis (MS) is an immune-system-mediated disease characterized by inflammation, demyelination, and degeneration of the central nervous system (CNS), leading to a deterioration in life quality and expectancy [1]
We found a significant decrease in functional connectivity (FC) between this region and posterior cortical areas, which correlated with a significant cognitive improvement as measured by the Paced Auditory Serial Addition Task (PASAT)
There were no significant differences at therapy start (Tst) (Table 1) between NEDA and EDA in terms of age, disease duration, Expanded Disability Status Scale (EDSS) score, number of relapses in the previous year, number of treatmentnaïve patients, and number of patients switching from firstor second-line disease-modifying therapies (DMTs)
Summary
Multiple sclerosis (MS) is an immune-system-mediated disease characterized by inflammation, demyelination, and degeneration of the central nervous system (CNS), leading to a deterioration in life quality and expectancy [1]. Progress has been made in the investigation of DMT effects on the brain in terms of tissue loss, microstructural abnormalities, metabolic changes, and functional plasticity [for a review, see [4]]. Functional MRI (fMRI) has provided important insights into MS-damage-related plasticity and functional reorganization, only a few studies have evaluated brain functional changes associated with DMTs in MS. 2 studies used motor-task-evoked fMRI to investigate therapy-related (IFN-β 1a) functional activity changes in the sensorimotor network [5, 6]. With respect to task-based fMRI, resting-state fMRI is more advantageous in clinical studies because it is applicable, allows the simultaneous investigation of different brain networks, and avoids the confounding effects of disability in performing a given behavioral task [7, 8]
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