Castellazzi Gloria, Debernard Laetitia, Melzer Tracy R, Dalrymple-Alford John C, D'Angelo Egidio, Miller David H, Gandini Wheeler-Kingshott Claudia A M, Mason Deborah F
NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom.
Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
Front Neurol. 2018 Aug 20;9:690. doi: 10.3389/fneur.2018.00690. eCollection 2018.
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 (MS) and RRMS with similar disability but longer disease duration (MS), we found that MS and MS 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.
静息态功能磁共振成像（rs-fMRI）为研究处于不同疾病阶段的多发性硬化症（MS）患者的功能重组提供了重要见解。在这项横断面研究中，我们首先通过rs-fMRI评估了62例轻度残疾（MSSS < 3）的复发缓解型MS（RRMS）患者的总体T2病变负荷（T2LL）和MS严重程度评分（MSSS）对静息态网络（RSNs）的影响。独立成分分析（ICA）随后进行双回归分析证实，与健康对照相比，RRMS患者中许多RSN的功能连接（FC）发生了改变。前默认模式网络（DMNa）和顶上叶网络（PNsup）显示FC降低的区域最大，而感觉运动网络区域M1（SMNm1）和内侧视觉网络（MVN）显示FC增加的区域最大。为了更好地理解这些改变的本质以及MS中功能改变的机制，我们提出了一种基于线性回归的方法，该方法考虑了FC变化及其与T2LL和MSSS的相关性。根据FC与T2LL之间相关性的符号，以及与MSSS相关性的符号，我们提出了以下可能的潜在机制来解释FC改变：（1）由MS病变驱动的FC降低，（2）“真正的”功能代偿机制，（3a）功能代偿尝试，（3b）“假的”功能代偿，（4a）神经变性，（4b）症状前状态（损伤先于MS临床表现）。我们的数据显示满足这6种情况中的4种（即1、2、3b、4b）的区域，支持了增加的FC具有复杂性质的观点，这可能超出了试图限制MS进展所导致脑损伤的潜在代偿机制的简单假设。探索疾病持续时间短的RRMS患者（MS）与具有相似残疾但疾病持续时间长的RRMS患者（MS）之间的差异，我们发现MS和MS具有明显不同的FC模式，分别主要涉及感觉和认知网络。总体而言，这些结果表明，分析多个大规模网络中与放射学（T2LL）和临床（MSSS、疾病持续时间）状态相关的FC改变，可能为复发型MS演变的病理生理学提供新的见解。
