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Cognitive impairment after focal brain lesions is better predicted by damage to structural than functional network hubs

Significance Hubs are highly connected brain regions that are important for coordinating processing in brain networks and supporting cognition. There are several different methods for characterizing network hubs in gray and white matter, yet it is unclear which of these hub measures identify sites that are most critical for supporting cognition. Here, we use data from two large cohorts of patients with focal brain damage to show that lesions of white matter regions with dense structural connections have the strongest association with cognitive impairment, while gray matter functional centrality measures have weaker associations. These findings highlight the critical role of densely connected white matter regions in supporting cognition, which helps to explain interindividual differences in cognitive outcomes following brain damage. Hubs are highly connected brain regions important for coordinating processing in brain networks. It is unclear, however, which measures of network “hubness” are most useful in identifying brain regions critical to human cognition. We tested how closely two measures of hubness—edge density and participation coefficient, derived from white and gray matter, respectively—were associated with general cognitive impairment after brain damage in two large cohorts of patients with focal brain lesions (N = 402 and 102, respectively) using cognitive tests spanning multiple cognitive domains. Lesions disrupting white matter regions with high edge density were associated with cognitive impairment, whereas lesions damaging gray matter regions with high participation coefficient had a weaker, less consistent association with cognitive outcomes. Similar results were observed with six other gray matter hubness measures. This suggests that damage to densely connected white matter regions is more cognitively impairing than similar damage to gray matter hubs, helping to explain interindividual differences in cognitive outcomes after brain damage.