Functional Connectivity Modifications in Monoaminergic Circuits Underpin Fatigue Development in MS Patients
Maria Rocca1, Monica Margoni3, Paola Valsasina4, Anna Bacchetti4, Damiano Mistri4, Nicolò Tedone4, 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; and Vita-Salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience; Neurology Unit; and Neurorehabilitation Unit, 4Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Objective:
To investigate changes over time of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with fatigue development in multiple sclerosis (MS).
Background:
Fatigue affects a large proportion of MS patients. Dysregulation of monoaminergic networks might have a role in fatigue pathogenesis.
Design/Methods:
Eighty-nine right-handed MS patients and 49 matched healthy controls (HC) underwent neurological, fatigue and 3.0T RS functional MRI assessment at baseline and after 1.3 year median follow-up (interquartile range=1.01-2.01 years). Fatigue was evaluated at baseline and follow-up using the modified fatigue impact scale (MFIS) score. Patients were considered as fatigued if MFIS was >38. Monoaminergic-related RS FC was estimated using an independent component analysis constrained to PET atlases for dopamine, noradrenaline and serotonin transporters.
Results:
At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (devFAT) at follow-up and 43 remained NF (noFAT). At baseline, F-MS patients were characterized by increased monoaminergic-related RS FC in hippocampal, postcentral, temporal and occipital cortices, as well as by decreased RS FC in the insular cortex. During the follow-up, noFAT MS patients showed limited dopamine-related RS FC changes over time. Conversely, devFAT MS patients showed increased dopamine-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the noradrenaline-related network, noFAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both devFAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, devFAT MS patients presented increased serotonin-related RS FC over time in the angular and middle occipital gyri, while this latter region showed decreased serotonin-related RS FC at follow-up vs baseline in F-MS.
Conclusions:
Specific patterns of monoaminergic networks changes over time characterized MS patients according to fatigue status.