Beyond focal lesions

White matter (WM) tracts shape the brain's dynamical activity and their damage (e.g., white matter hyperintensities, WMH) yields relevant functional alterations, ultimately leading to cognitive symptoms. The mechanisms linking the structural damage caused by WMH to the arising alterations of brain dynamics is currently unknown. To estimate the impact of WMH on brain dynamics, we combine neural-mass whole-brain modeling with a virtual-lesioning (disconnectome) approach informed by empirical data. We account for the heterogeneous effects of WMH either on inter-regional communication (i.e., edges) or on dynamics (i.e., nodes) and create models of their local versus global, and edge versus nodal effects using a large fMRI dataset comprising 188 non-demented individuals (120 cognitively normal, 68 with mild cognitive impairment) with varying degrees of WMH. We show that, although WMH mainly determine local damage to specific WM tracts, these lesions yield relevant global dynamical effects by reducing the overall synchronization of the brain through a reduction of global coupling. Alterations of local nodal dynamics through disconnections are less relevant and present only at later stages of WMH damage. Exploratory analyses suggest that education might play a beneficial role in counteracting the reduction in global coupling associated with WMH. This study provides generative models linking the structural damage caused by WMH to alterations in brain dynamics. These models might be used to evaluate the detrimental effects of WMH on brain dynamics in a subject-specific manner. Furthermore, it validates the use of whole-brain modeling for hypothesis-testing of structure–function relationships in diseased states characterized by empirical disconnections.