Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, UK; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, UK; NeuroPoly Lab, Polytechnique Montreal, Montreal, Canada; CUBRIC, Cardiff University, Cardiff, UK.
Neuroimage Clin. 2021;30:102587. doi: 10.1016/j.nicl.2021.102587. Epub 2021 Feb 12.
In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.
在多发性硬化症 (MS) 中，单胺能系统会发生改变，这是炎症依赖性合成减少和直接结构损伤的结果。异常的单胺能神经传递越来越被认为是导致疲劳病理生理学的主要因素。在这项研究中，我们旨在比较一组 MS 患者（n=68）和健康对照组（n=34）中源自脑干核的单胺能白质纤维束的完整性，并研究其与疲劳的关系。通过新型的基于固定体的分析来评估纤维束的完整性，该分析同时通过“纤维密度”来估计轴突密度，并通过纤维“横截面积”来估计白质萎缩。我们将腹侧被盖区、蓝斑核和中缝核分别作为脑内多巴胺能、去甲肾上腺素能和 5-羟色胺能纤维的主要来源。使用扩散轨迹重建了源自这些脑干核的 14 个感兴趣的投射纤维束，并通过纤维密度和横截面积的乘积（FDC）进行比较。最后，在 MS 患者中评估了单胺能轴突损伤与改良疲劳影响量表评分的相关性。基于固定体的分析显示，与健康对照组相比，MS 患者源自脑干核的选择性单胺能纤维束中存在明显的轴突损伤，这可通过 FDC 减少来衡量；特别是在多巴胺能中脑边缘通路、去甲肾上腺素能投射到前额叶皮质以及 5-羟色胺能投射到小脑的纤维束中。此外，我们观察到源自腹侧被盖区的中脑边缘投射纤维束以及蓝斑核投射到前额叶皮质的纤维束中轴突损伤与认知疲劳严重程度之间存在显著相关性，提示多巴胺能和去甲肾上腺素能通路可能对 MS 中的中枢疲劳有贡献。我们的发现支持了这样一种假说，即单胺能通路中的轴突损伤导致 MS 中单胺类物质的减少/功能障碍，并提供了有关单胺能系统如何导致 MS 发病机制和疲劳的新信息。这支持了进一步研究单胺类物质作为治疗靶点的必要性，旨在对抗和缓解 MS 中的疲劳。
