White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, affect a wide range of cognitive dysfunctions, including spatial neglect. The latter is a disorder of spatial attention and exploration typically after right hemisphere brain damage. To explore the impact of WMH on neglect‐related structural disconnections, the present study investigated the indirectly quantified structural disconnectome induced by either stroke lesion alone, WMH alone, or their combination. Furthermore, we compared different measures of structural disconnection—voxel‐wise, pairwise, tract‐wise, and parcel‐wise—to identify neural correlates and predict acute neglect severity. We observed that WMH‐derived disconnections alone were not associated with neglect behavior. However, when combined with disconnections derived from individual stroke lesions, pre‐stroke WMH contributed to post‐stroke neglect severity by affecting right frontal and subcortical substrates, like the middle frontal gyrus, basal ganglia, thalamus, and the fronto‐pontine tract. Predictive modeling demonstrated that voxel‐wise disconnection data outperformed other measures of structural disconnection, explaining 42% of the total variance; interestingly, the best model used predictors of stroke‐based disconnections only. We conclude that prestroke alterations in the white matter microstructure due to WMH contribute to poststroke deficits in spatial attention, likely by impairing the integrity of human attention networks.
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