Monoaminergic Network Dysfunction and Development of Depression in Multiple Sclerosis: A Longitudinal Investigation
Damiano Mistri1, Paola Valsasina1, Loredana Storelli1, Monica Margoni2, Massimo Filippi3, Maria Rocca4
1Neuroimaging Research Unit, Division of Neuroscience, 2Neuroimaging Research Unit, Division of Neuroscience; Neurology Unit; and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 3Neuroimaging Research Unit, Division of Neuroscience; Neurology Unit; Neurorehabilitation Unit; and Neurophysiology Service, 4Neuroimaging Research Unit, Division of Neuroscience; and Neurology Unit, IRCCS San Raffaele Scientific Institute; and Vita-Salute San Raffaele University
Objective:
To investigate the association between development of depressive symptoms in multiple sclerosis (MS) and changes of resting state functional connectivity (RS FC) within monoaminergic networks.
Background:
Monoaminergic network dysfunction is thought to underpin depression in MS patients. However, longitudinal studies are lacking.
Design/Methods:
Forty-nine MS patients without depression (Montgomery-Asberg Depression Scale - MADRS - ≤9) and 27 healthy controls underwent clinical and 3.0T RS FC assessment at baseline and after a median follow-up of 1.6 years (interquartile range=1.0-2.1 years). Monoamine-related RS FC was derived by independent component analysis, constrained to PET atlases for dopamine, noradrenaline and serotonin transporters. Longitudinal changes of RS FC within monoaminergic networks and their correlations with MADRS scores were assessed.
Results:
At baseline, MS patients showed decreased RS FC vs healthy controls in all PET-guided monoaminergic networks in frontal, cingulate and cerebellar cortices, and increased RS FC in parieto-occipital regions. Fourteen (29%) MS patients developed depressive (D) symptoms at follow-up (MADRS >9). Compared to not depressed MS patients, D-MS patients exhibited widespread RS FC decrease over time in the PET-guided dopamine network, mainly in orbitofrontal, occipital, anterior cingulate and precuneal cortices. In D-MS patients, decreased RS FC over time was also observed in parahippocampal and occipital regions of the PET-guided noradrenaline network. Decreased RS FC over time in dopamine and noradrenaline PET-guided networks correlated with concomitant increased MADRS scores (r=range -0.65/-0.61, p<0.001).
Conclusions:
The development of depressive symptoms in MS patients was associated with specific RS FC changes within the dopamine and noradrenaline networks.