Functional connectivity dynamics of monoaminergic circuits related to fatigue in multiple sclerosis

Introduction: Monoaminergic neurotransmitters help regulate the interplay between the central nervous system and the immune system. Aberrant monoaminergic functional connectivity is presumably involved in MS-related fatigue, but mechanisms remain unclear. Aim: To investigate how static and dynamic functional connectivity of monoaminergic circuits relate to fatigue in MS. Methods: 60 healthy controls (HC) and 217 people with MS (pwMS) completed the Fatigue Scale for Motor and Cognitive Functions (FSMC) and underwent functional brain MRI. Brain regions were assigned to resting-state networks. Additionally, PET-derived receptor/transporter density atlases determined assignment to monoaminergic circuits (5-HT_1a/5-HT_2a/5-HTT/ D₁/D₂/DAT/NAT). Per monoaminergic circuit, we compared the frequency of switching between networks (flexibility) and the total number of networks switched to (promiscuity), between HC and pwMS with no fatigue (FSMC < 43), mild/moderate fatigue (43 ≤ FSMC < 63), or severe fatigue (FSMC ≥ 63). For circuits showing flexibility differences, we also compared rates of synchronous (cohesion) and independent switches (disjointedness). Results: Global flexibility was higher in severely fatigued pwMS compared to non-fatigued pwMS (p = 0.025) and HC (p = 0.016). In line, global cohesion was higher in severely fatigued pwMS compared to non-fatigued pwMS (p = 0.022) and HC (p = 0.017). Compared to HC, 5-HT_1a circuit flexibility (p = 0.048) and cohesion (p = 0.031) were higher in severely fatigued pwMS. Static FC showed significant group differences for the 5-HTT, D₁, and D_2/DAT circuits, but no significant pairwise contrasts. Conclusion: Fatigued pwMS show more dynamic functional connectivity, both globally and in the inhibitory serotonergic receptor circuit. Unstable global and serotonergic dynamics likely raise energy expenditure in pwMS and therefore may underlie MS-related fatigue.