| Summary: | Summary: Stroke causes focal brain lesions that disrupt functional connectivity (FC), a measure of activity synchronization, throughout distributed brain networks. It is often assumed that FC disruptions reflect damage to specific cortical regions. However, an alternative explanation is that they reflect the structural disconnection (SDC) of white matter pathways. Here, we compare these explanations using data from 114 stroke patients. Across multiple analyses, we find that SDC measures outperform focal damage measures, including damage to putative critical cortical regions, for explaining FC disruptions associated with stroke. We also identify a core mode of structure-function covariation that links the severity of interhemispheric SDCs to widespread FC disruptions across patients and that correlates with deficits in multiple behavioral domains. We conclude that a lesion’s impact on the structural connectome is what determines its impact on FC and that interhemispheric SDCs may play a particularly important role in mediating FC disruptions after stroke. : Disruptions of brain network function in patients with focal brain lesions are often assumed to reflect damage to critical gray matter regions. Griffis et al. challenge this assumption by showing that network dysfunction primarily reflects the disconnection of white matter pathways, rather than the destruction of gray matter regions. Keywords: stroke, functional connectivity, structural connectivity, functional MRI, diffusion MRI, lesion, structural disconnection, brain networks, resting state, structure-function
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