LAUSR

Abstract Connectomics of brain disorders seeks to reveal how altered brain function emerges from the architecture of cerebral networks; however the causal impact of targeted cellular damage on the whole brain functional and structural connectivity remains unknown. In the central nervous system, demyelination is typically the consequence of an insult targeted at the oligodendrocytes, the cells forming and maintaining the myelin. This triggered perturbation generates cascades of pathological events that most likely alter the brain connectome. Here we induced oligodendrocyte death and subsequent demyelinating pathology via cuprizone treatment in mice and combining mouse brain resting state functional Magnetic Resonance Imaging and diffusion tractography we established functional and structural pathology‐to‐network signatures. We demonstrated that demyelinated brain fundamentally reorganizes its intrinsic functional connectivity paralleled by widespread damage of the structural scaffolding. We evidenced default mode‐like network as core target of demyelination‐induced connectivity modulations and hippocampus as the area with strongest connectional perturbations. Graphical abstract The authors demonstrate via non‐invasive resting state fMRI that intrinsic functional connectivity is fundamentally reorganized in demyelinated mouse brain, paralleled by widespread damage of structural scaffolding and strong modulations of default mode and hippocampal networks. Figure. No Caption available. HighlightsCuprizone pathology disrupts the antagonistic relationship between DMN and TPN.The DMN is the core target of demyelination‐induced connectivity modulations.HPF emerged as area with strong functional and structural connectivity perturbations.Small‐worldness hallmarks imply preserved functional network efficiency.