Acute pediatric traumatic brain injury severity predicts long-term verbal memory performance through suppression by white matter integrity on diffusion tensor imaging

Abstract

Mediation analysis was used to investigate the role of white matter integrity in the relationship between injury severity and verbal memory performance in participants with chronic pediatric traumatic brain injury (TBI). DTI tractography was used to measure fractional anisotropy (FA) within the corpus callosum, fornix, cingulum bundles, perforant pathways, and uncinate fasciculi. Injury severity was indexed using Glasgow Coma Scale (GCS) scores obtained at the time of the injury. Verbal memory was measured by performance on the long-delay free recall (LDFR) trial of the California Verbal Learning Test-Children's version. Participants were between the ages of 10-18 and included 21 children with TBI (injured before age 9) and 19 typically-developing children (TDC). Children with TBI showed lower FA across all pathways and poorer LDFR performance relative to TDC. Within the TBI group, mediation analysis revealed neither a significant total effect of GCS on LDFR nor significant direct effects of GCS on LDFR across pathways; however, the indirect effects of GCS on LDFR through FA of the corpus callosum, left perforant pathway, and left uncinate fasciculus were significant and opposite in sign to their respective direct effects. These results suggests that the predictive validity of GCS for LDFR is initially suppressed by the substantial variance accounted for by FA, which is uncorrelated with GCS, and the predictive validity of GCS increases only when FA is considered, and the opposing path is controlled. These findings illustrate the complex associations between acute injury severity, white matter pathways, and verbal memory several years following pediatric TBI.

Keywords: Diffusion tensor imaging tractography; Fractional anisotropy; Injury severity; Pediatric traumatic brain injury; Verbal memory.

Fig. 1

Mediation models demonstrating the total effect (c) of a predictor variable (X) on an outcome variable (Y; top) and the indirect effect (ab) of X on Y through a mediator variable (M; bottom). Path a represents the bivariate relationship between and X and M, where a one-unit change in X is associated with a change of a units in M. Path b represents the bivariate relationship between M and Y, where a one-unit change in M is associated with a change of b units in Y when X is held constant. Path c’ represents the direct effect of X on Y when M is included in the model but held constant. When mediation occurs, the direct effect is smaller than the total effect (c’ < c). When suppression occurs, the direct effect is smaller than the total effect and opposite in sign to the indirect effect

Fig. 2

Mediation models demonstrating the total effect of injury severity (GCS) on verbal memory (LDFR; top) and the indirect effect of GCS on LDFR through fractional anisotropy (FA; lower eight) of the corpus callosum (CC), fornix (FX), right and left cingulum bundle (CB_R, CB_L), right and left perforant pathway (PP_R, PP_L), and right and left uncinate fasciculus (UF_R, UF_L). For each white matter pathway, bivariate and linear regression models were used to assess the bivariate relationship between GCS and FA, the bivariate relationship between FA and LDFR, holding GCS constant, and the direct effect of GCS on LDFR, holding FA constant. Each estimate along the path represents the standardized β coefficient from the regression model. Asterisks reflect statistically significant relationships (p < .05), and dashed arrows are indicative of indirect effects where GCS predicts LDFR through suppression by FA