Functional connectivity alterations reveal complex mechanisms based on clinical and radiological status in mild relapsing remitting multiple sclerosis (2018)
Type of ContentJournal Article
PublisherFrontiers Media SA
- Science: Journal Articles 
© 2018 Castellazzi, Debernard, Melzer, Dalrymple-Alford, D'Angelo, Miller, Gandini Wheeler-Kingshott and Mason. Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) "true" functional compensatory mechanism, (3a) functional compensation attempt, (3b) "false" functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution.
CitationCastellazzi G, Debernard L, Melzer TR, Dalrymple-Alford JC, D'Angelo E, Miller DH, Wheeler-Kingshott CAMG, Mason DF (2018). Functional connectivity alterations reveal complex mechanisms based on clinical and radiological status in mild relapsing remitting multiple sclerosis. Frontiers in Neurology. 9(AUG).
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Keywordsrelapsing remitting multiple sclerosis; esting state fMRI; functional connectivity; functional impairment; resting state networks
ANZSRC Fields of Research32 - Biomedical and clinical sciences::3202 - Clinical sciences::320222 - Radiology and organ imaging
32 - Biomedical and clinical sciences::3209 - Neurosciences::320905 - Neurology and neuromuscular diseases
52 - Psychology::5203 - Clinical and health psychology::520301 - Clinical neuropsychology
RightsCopyright © 2018 Castellazzi, Debernard, Melzer, Dalrymple-Alford, D’Angelo, Miller, Gandini Wheeler-Kingshott and Mason. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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