Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (­22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (­18.81 ml; 95% CI: ­29.60 to ­8.03 ml; p < 0.001), putamen (­0.40 ml; 95% CI: ­0.69 to ­0.10 ml; p = 0.008) and acumbens (­0.09 ml; 95% CI: ­0.15 to ­0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (­19.23 N; 95% CI: ­35.93 to ­2.53 N; p = 0.02) and an attenuation of upper-limb (­5.77%; 95% CI:­8.61 to ­2.93%; p < 0.0001) and lower-limb (­2.16%; 95% CI:­4.24 to ­0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (­5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation.

Prospero registration Prospero registration number: CRD42016017934

疲劳是多发性硬化症 (PwMS) 患者最令人衰弱的症状之一。通过巩固多样化和相互矛盾的证据基础，这项系统评价和荟萃分析旨在获得对 MS 疲劳神经生物学的新见解。使用医学主题词搜索 MEDLINE、ProQuest、CINAHL、Web of Science 数据库和灰色文献。符合条件的研究比较了经历高（MS-HF）与低（MS-LF）感知 MS 疲劳的人之间的神经影像学和神经生理学数据，如经验证的疲劳问卷切点所定义。数据来自 66 项研究，其中 46 项用于荟萃分析。神经影像学研究显示，MS-HF 与 MS-LF 相比，整个大脑的体积测量值较低（22.74 ml；95% CI：-37.72 至 -7.76 ml；p = 0.003）、灰质（18.81 ml；95% CI：29.60 至 8.03 ml；p  < 0.001）、壳核（0.40 ml；95% CI：0.69 至 0.10 ml；p  = 0.008）和伏隔核（0.09 ml；95% CI：0.15 至 0.03 ml；p  = 0.003）和更高体积的 T1 加权低信号病变（1.10 ml；95% CI：0.47 至 1.73 ml；p  < 0.001）。神经生理学数据显示下肢最大自主力产生减少（19.23 N；95% CI：35.93 至 2.53 N；p  = 0.02）和上肢衰减（5.77%；95% CI：8.61 至 2.93%；p  < 0.0001）和下肢（2.16%；95% CI：4.24 至 0.07%；p = 0.04) 骨骼肌自主激活，伴随着更明显的上肢易疲劳性（5.61%；95% CI：-9.57 至 -1.65%；p  = 0.006）在 MS-HF 与 MS-LF 中。结果表明，MS 疲劳的特征是更大的皮质-皮质下灰质萎缩和神经损伤，并伴有神经生理学减退，包括强度降低和自主激活。

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