Background

More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue is only partly explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain properties.

Objectives

To investigate the relationship of dynamic functional connectivity (dFC) with fatigue in MS patients and to compare dFC with commonly used clinical and MRI parameters.

Methods

In 35 relapsing-remitting MS patients (age: 42.83 years, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HCs) (age: 41.38 years, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at 6-month follow-up. All subjects underwent structural and resting-state functional MRI at baseline. Global static functional connectivity (sFC) and dynamic functional connectivity (dFC) were calculated. dFC was assessed using a sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cv) across windows. Moreover, regional connectivity between regions previously associated with fatigue in MS was estimated (i.e. basal ganglia and regions of the Default Mode Network (DMN): medial prefrontal, posterior cingulate and precuneal cortices). Hierarchical regression analyses were performed with forward selection to identify the most important correlates of fatigue at baseline. Results were not corrected for multiple testing due to the exploratory nature of the study.

Results

Patients were more fatigued than HCs at baseline (p = 0.001) and follow-up (p = 0.002) and fatigue in patients was stable over time (p = 0.213). Patients had significantly higher baseline global dFC than HCs, but no difference in basal ganglia-DMN dFC. In the regression model for baseline fatigue in patients, basal ganglia-DMN dFC-cv (standardized β = -0.353) explained 12.5% additional variance on top of EDSS (p = 0.032). Post-hoc analysis revealed higher basal ganglia-DMN dFC-cv in non-fatigued patients compared to healthy controls (p = 0.013), whereas fatigued patients and healthy controls showed similar basal ganglia-DMN dFC.

Conclusions

Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. Within patients, lower dynamics of these connections could relate to lower efficiency and increased fatigue. Increased dynamics in non-fatigued patients compared to healthy controls might represent a network organization that protects against fatigue or signal early network dysfunction.

中文翻译：

---

动态功能连接作为多发性硬化症疲劳的神经关联

背景

超过80％的多发性硬化症（MS）患者经历疲劳症状。与MS相关的疲劳仅部分由大脑的结构（病变和萎缩）和功能（大脑激活以及传统的静态功能连接）来解释。

目标

调查动态功能连接（dFC）与MS患者疲劳的关系，并将dFC与常用的临床和MRI参数进行比较。

方法

在35名复发缓解型MS患者中（年龄：42.83岁，女性/男性：20/15，病程：11岁）和19位健康对照（HCs）（年龄：41.38岁，女性/男性：11/8），疲劳在基线和6个月的随访中使用CIS-20r问卷进行测量。所有受试者在基线时均接受结构性和静息态功能性MRI检查。计算了全局静态功能连接（sFC）和动态功能连接（dFC）。dFC使用滑动窗口方法通过计算各窗口的总差（diff）和变异系数（cv）进行评估。此外，估计了先前与MS疲劳相关的区域之间的区域连通性（即基底神经节和默认模式网络（DMN）的区域：内侧前额叶，后扣带和前皮质）。进行层次回归分析并进行正向选择，以识别基线时疲劳的最重要关联。由于研究的探索性，未对多项测试的结果进行校正。

结果

在基线 和随访期间，患者比HCs更加疲劳（p = 0.001）（p  = 0.002），并且患者的疲劳随着时间的推移稳定（p  = 0.213）。患者的基线总体dFC明显高于HC，但基底神经节-DMN dFC无差异。在患者基线疲劳的回归模型中，基底神经节-DMN dFC-cv（标准β= -0.353）解释了EDSS之上12.5％的额外方差（p  = 0.032）。事后分析显示，与健康对照组相比，无疲劳患者的基底神经节-DMN dFC-cv较高（p  = 0.013），而疲劳患者和健康对照组的基底神经节-DMN dFC相似。

结论

与残疾状态无关，基底神经节与皮质之间的动态连接性降低与MS患者的疲劳程度更高有关。在患者内部，这些连接的动态降低可能与效率降低和疲劳增加有关。与健康对照组相比，未疲劳患者的动态增加可能代表了一个网络组织，可以防止疲劳或发出早期网络功能障碍的信号。