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Introduction <p>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.</p> Aim <p>To investigate how static and dynamic functional connectivity of monoaminergic circuits relate to fatigue in MS.</p> Methods <p>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<sub>1a</sub>/5-HT<sub>2a</sub>/5-HTT/ D<sub>1</sub>/D<sub>2</sub>/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 &lt; 43), mild/moderate fatigue (43 ≤ FSMC &lt; 63), or severe fatigue (FSMC ≥ 63). For circuits showing flexibility differences, we also compared rates of synchronous (cohesion) and independent switches (disjointedness).</p> Results <p>Global flexibility was higher in severely fatigued pwMS compared to non-fatigued pwMS (<i>p</i> = 0.025) and HC (<i>p</i> = 0.016). In line, global cohesion was higher in severely fatigued pwMS compared to non-fatigued pwMS (<i>p</i> = 0.022) and HC (<i>p</i> = 0.017). Compared to HC, 5-HT<sub>1a</sub> circuit flexibility (<i>p</i> = 0.048) and cohesion (<i>p</i> = 0.031) were higher in severely fatigued pwMS. Static FC showed significant group differences for the 5-HTT, D<sub>1</sub>, and D<sub>2/</sub>DAT circuits, but no significant pairwise contrasts.</p> Conclusion <p>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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年6月2日

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  • Marloes D. A. Bet,
  • Birgit Helmlinger,
  • Tommy A. A. Broeders,
  • Stefanie M. C. Hechenberger,
  • Christian G. Tinauer,
  • Stefan Ropele,
  • Frederik Barkhof,
  • Michael Khalil,
  • Christian Enzinger,
  • Linda Douw,
  • Menno M. Schoonheim,
  • Daniela T. Pinter

摘要

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-HT1a/5-HT2a/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-HT1a 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 D2/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.