2023 American Academy of Neurology Abstract Website

Maria Rocca¹, Paola Valsasina³, Maria Teresa Lamanna⁴, Bruno Colombo⁵, Paolo Preziosa¹, Vittorio Martinelli⁵, Massimo Filippi²
¹Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, ²Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele Unviersity, ³Neuroimaging Research Unit, Division of Neuroscience, ⁴Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, ⁵Neurology Unit, IRCCS San Raffaele Scientific Institute

Objective:

To investigate changes over time of fatigue severity and concomitant modifications of resting state (RS) functional connectivity (FC) in monoaminergic networks in 45 fatigued multiple sclerosis (MS) patients after different symptomatic treatments.

Background:

Fatigue is common and disabling in MS. Symptomatic treatments for fatigue rely on drugs reinforcing monoaminergic synaptic transmission, suggesting a role of monoaminergic network abnormalities in fatigue pathogenesis.

Design/Methods:

MS patients were randomly, blindly assigned to treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological and 3T RS fMRI at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls (HC) were acquired twice. Dopamine-, noradrenaline- and serotonin-related RS FC was derived by independent component analysis (ICA), constrained to PET atlases for dopamine, noradrenaline and serotonin transporters, obtained in HCs’ brain. Changes in modified fatigue impact scale (MFIS) score and monoaminergic-related RS FC were assessed.

Results:

MS patients showed baseline abnormalities vs HC in all three networks, with decreased monoamine-related RS FC in temporal, occipital, insular and cerebellar regions, and increased RS FC in frontal, parietal and subcortical areas. At W4, MFIS scores decreased in all patients’ groups, with no time-by-treatment interaction. At W4, fampridine and amantadine patients showed increased dopamine- and noradrenaline-related RS FC in the insular cortex, as well as increased serotonin-related RS FC in the precuneus/posterior cingulate cortex. Amantadine patients also showed increased dopamine- and noradrenaline-related RS FC in the anterior cingulate cortex (ACC). Conversely, placebo patients mostly showed increased noradrenaline-related RS FC in the precuneus and middle cingulate cortex. Fampridine and placebo groups showed trends towards significant correlations between RS FC modifications and MFIS improvements (r=-0.49:-0.52, p=0.07-0.08).

Conclusions:

Fatigue improved in all groups. Concomitant monoaminergic-related RS FC modifications were found in insular, ACC and parietal regions for fampridine and amantadine MS patients, and in medial parietal regions for placebo patients.