Dynamic Triangulation of Resting-State Networks and CSF Metabolites Reveals Bidirectional Causal Pathways in Multiple...

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Emotional disorders significantly drive multiple sclerosis (MS) progression.
• Resting-state functional magnetic resonance imaging (rs-fMRI) and cerebrospinal fluid (CSF) metabolites are implicated in MS, but their causal links are unclear.
• Understanding these mechanisms is vital for developing targeted therapies, including neuromodulation.

Purpose of the Study:

• To investigate the causal relationships between 191 rs-fMRI phenotypes and MS using bidirectional Mendelian randomization (MR).
• To explore the mediating role of 338 CSF metabolites in the relationship between rs-fMRI and MS.
• To identify potential therapeutic targets for MS and associated emotional disorders.

Main Methods:

• Bidirectional two-sample Mendelian randomization (MR) analysis was employed.
• Investigated causal links between 191 rs-fMRI phenotypes and MS.
• Examined the mediating effects of 338 CSF metabolites on rs-fMRI-MS associations.

Main Results:

• Enhanced functional connectivity in saliency and visual networks correlated with increased MS risk.
• Enhanced functional connectivity in motor and attention networks correlated with decreased MS risk.
• Five CSF metabolites (N-formylanthranilic acid, N6-methyllysine, succinimide, methyl glucopyranoside(alpha+beta), hypoxanthine) were identified as key mediators.

Conclusions:

• Established causal rs-fMRI signatures influencing MS susceptibility and progression.
• Identified critical CSF metabolites mediating MS effects through functional brain networks.
• Findings support novel intervention targets for MS and emotional disorders, informing multidimensional neuromodulation strategies.