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

ABSTRACT: 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.

SUBMITTER: Reber J

PROVIDER: S-EPMC8126860 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Reber Justin J Hwang Kai K Bowren Mark M Bruss Joel J Mukherjee Pratik P Tranel Daniel D Boes Aaron D AD

Proceedings of the National Academy of Sciences of the United States of America 20210501 19

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 ...[more]

PMID: 33941692

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Project description:Traumatic brain injury affects brain connectivity by producing traumatic axonal injury. This disrupts the function of large-scale networks that support cognition. The best way to describe this relationship is unclear, but one elegant approach is to view networks as graphs. Brain regions become nodes in the graph, and white matter tracts the connections. The overall effect of an injury can then be estimated by calculating graph metrics of network structure and function. Here we test which graph metrics best predict the presence of traumatic axonal injury, as well as which are most highly associated with cognitive impairment. A comprehensive range of graph metrics was calculated from structural connectivity measures for 52 patients with traumatic brain injury, 21 of whom had microbleed evidence of traumatic axonal injury, and 25 age-matched controls. White matter connections between 165 grey matter brain regions were defined using tractography, and structural connectivity matrices calculated from skeletonized diffusion tensor imaging data. This technique estimates injury at the centre of tract, but is insensitive to damage at tract edges. Graph metrics were calculated from the resulting connectivity matrices and machine-learning techniques used to select the metrics that best predicted the presence of traumatic brain injury. In addition, we used regularization and variable selection via the elastic net to predict patient behaviour on tests of information processing speed, executive function and associative memory. Support vector machines trained with graph metrics of white matter connectivity matrices from the microbleed group were able to identify patients with a history of traumatic brain injury with 93.4% accuracy, a result robust to different ways of sampling the data. Graph metrics were significantly associated with cognitive performance: information processing speed (R(2) = 0.64), executive function (R(2) = 0.56) and associative memory (R(2) = 0.25). These results were then replicated in a separate group of patients without microbleeds. The most influential graph metrics were betweenness centrality and eigenvector centrality, which provide measures of the extent to which a given brain region connects other regions in the network. Reductions in betweenness centrality and eigenvector centrality were particularly evident within hub regions including the cingulate cortex and caudate. Our results demonstrate that betweenness centrality and eigenvector centrality are reduced within network hubs, due to the impact of traumatic axonal injury on network connections. The dominance of betweenness centrality and eigenvector centrality suggests that cognitive impairment after traumatic brain injury results from the disconnection of network hubs by traumatic axonal injury.

Project description:A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.

Dataset Information

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

Publications

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

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