Cercignani Mara, Dipasquale Ottavia, Bogdan Iulia, Carandini Tiziana, Scott James, Rashid Waqar, Sabri Osama, Hesse Swen, Rullmann Michael, Lopiano Leonardo, Veronese Mattia, Martins Daniel, Bozzali Marco
Department of Neuroscience, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9RR, UK.
Neuroimaging Laboratory, Santa Lucia Foundation, 00179 Rome, Italy.
Brain Commun. 2021 Mar 5;3(2):fcab023. doi: 10.1093/braincomms/fcab023. eCollection 2021.
Fatigue is a highly prevalent and debilitating symptom in multiple sclerosis, but currently the available treatment options have limited efficacy. The development of innovative and efficacious targeted treatments for fatigue in multiple sclerosis has been marred by the limited knowledge of the underlying mechanisms. One of the hypotheses postulates that multiple sclerosis pathology might cause reduced monoaminergic release in the central nervous system with consequences on motivation, mood and attention. Here, we applied the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets method to investigate whether patients with high and low fatigue differ in the functional connectivity (FC) of the monoamine circuits in the brain. We recruited 55 patients with multiple sclerosis, which were then classified as highly fatigued or mildly fatigued based on their scores on the cognitive sub-scale of the Modified Fatigue Impact scale. We acquired resting-state functional MRI scans and derived individual maps of connectivity associated with the distribution of the dopamine, noradrenaline and serotonin transporters as measured by positron emission tomography. We found that patients with high fatigue present decreased noradrenaline transporter (NAT)-enriched connectivity in several frontal and prefrontal areas when compared to those with lower fatigue. The NAT-enriched FC predicted negatively individual cognitive fatigue scores. Our findings support the idea that alterations in the catecholaminergic functional circuits underlie fatigue in multiple sclerosis and identify the NAT as a putative therapeutic target directed to pathophysiology.
疲劳是多发性硬化症中一种非常普遍且使人衰弱的症状，但目前可用的治疗方案疗效有限。由于对潜在机制的了解有限，针对多发性硬化症疲劳的创新且有效的靶向治疗的开发受到了阻碍。其中一种假说是，多发性硬化症病理可能导致中枢神经系统中单胺能释放减少，从而对动机、情绪和注意力产生影响。在此，我们应用最近开发的基于靶点的功能连接富集分析方法，来研究高疲劳和低疲劳的患者在大脑单胺能回路的功能连接（FC）方面是否存在差异。我们招募了55名多发性硬化症患者，然后根据他们在改良疲劳影响量表认知子量表上的得分，将其分为高度疲劳或轻度疲劳组。我们获取了静息态功能磁共振成像扫描，并得出了与正电子发射断层扫描测量的多巴胺、去甲肾上腺素和血清素转运体分布相关的个体连接图谱。我们发现，与低疲劳患者相比，高疲劳患者在几个额叶和前额叶区域的去甲肾上腺素转运体（NAT）富集连接减少。NAT富集的FC与个体认知疲劳得分呈负相关。我们的研究结果支持这样一种观点，即儿茶酚胺能功能回路的改变是多发性硬化症疲劳的基础，并确定NAT为针对病理生理学的一个假定治疗靶点。
