Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue.
BACKGROUND
Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis, but its pathophysiological mechanisms are poorly understood. It is in particular unclear whether and how fatigue relates to structural and functional brain changes.


OBJECTIVE
We aimed to analyse the association of fatigue severity with basal ganglia functional connectivity, basal ganglia volumes, white matter integrity and grey matter density.


METHODS
In 44 patients with relapsing-remitting multiple sclerosis and 20 age- and gender-matched healthy controls, resting-state fMRI, diffusion tensor imaging and voxel-based morphometry was performed.


RESULTS
In comparison with healthy controls, patients showed alteration of grey matter density, white matter integrity, basal ganglia volumes and basal ganglia functional connectivity. No association of fatigue severity with grey matter density, white matter integrity and basal ganglia volumes was observed within patients. In contrast, fatigue severity was negatively correlated with functional connectivity of basal ganglia nuclei with medial prefrontal cortex, precuneus and posterior cingulate cortex in patients. Furthermore, fatigue severity was positively correlated with functional connectivity between caudate nucleus and motor cortex.


CONCLUSIONS
Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.
Department of Neurology, Charité - Universitätsmedizin Berlin, Germany/Equal contribution carsten.finke@charite.de.
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Finke
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany/Equal contribution.
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Schlichting
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Papazoglou
Department of Radiology, Charité - Universitätsmedizin Berlin, Germany.
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Scheel
Department of Neuroradiology, Universitätsmedizin Göttingen, Germany.
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Freing
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Soemmer
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Pech
Department of Neurology, Charité - Universitätsmedizin Berlin, Germany.
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Pajkert
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Pfüller
Department of Neuroradiology, Universitätsmedizin Göttingen, Germany.
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Wuerfel
Department of Neurology, Charité - Universitätsmedizin Berlin, Germany.
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Ploner
Department of Neurology, Charité - Universitätsmedizin Berlin, Germany/NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Paul
NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Germany.
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Brandt
D000328:Adult; D000368:Aged; D001479:Basal Ganglia / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging; D005221:Fatigue / Q000209:etiology*; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications* / Q000473:pathology*; D009434:Neural Pathways / Q000473:pathology*
Multiple sclerosis; basal ganglia; diffusion tensor imaging; fatigue; functional neuroimaging; reward system; voxel-based morphometry