Cortical lesions and focal white matter injury are associated with attentional performance in chronic traumatic brain injury

Cognitive impairment, often due to attentional deficits, is a primary driver of disability after traumatic brain injury. It remains unclear whether attentional deficits are caused by injury to specific brain structures or the total burden of injury. In this cross-sectional, multicentre cohort study, we tested whether the association between brain injury and attentional performance varies by neuroanatomic location. Participants in the late effects of traumatic brain injury study were at least 18 years old and at least 1 year after a mild, moderate or severe traumatic brain injury. They underwent MRI and neuropsychological assessment at one of two sites. The primary and secondary outcomes, each measuring aspects of attentional performance, were the Trails A <i>t</i>-score and the standardized score on California Verbal Learning Test 2 Immediate Recall Trial 1. Imaging variables included the size and location (seven regions and seven networks) of encephalomalacic brain lesions and regional white matter fractional anisotropy measured with diffusion MRI (14 regions). We used ANOVA to test whether attentional performance differed by lesion location and linear mixed models to test whether attentional performance differed based on regional fractional anisotropy. One hundred eighty-eight participants met inclusion criteria (mean age 57, 69% male, 88% White). Participants with encephalomalacic brain lesions [<i>N</i> = 73 (39%)] had worse Trails A [mean (95% confidence interval) difference: 4.7 (0.3, 9.1); <i>P</i> = 0.036] but not secondary outcome performance [-0.3 (-0.1, 0.7); <i>P</i> = 0.17]. Among participants with lesions, Trails A performance did not differ by lesion size (<i>P</i> = 0.07) or location (<i>P</i> = 0.41 by region; <i>P</i> = 0.78 by network). We identified a significant interaction between regional fractional anisotropy and attentional performance on both primary (<i>P</i> = 0.001) and secondary (<i>P</i> = 0.001) outcome measures. <i>Post hoc</i> testing identified the strongest associations with Trails A performance in the sagittal stratum [1 SD decrement in Trails A: -0.2 (-0.3, -0.1) SD change in fractional anisotropy; <i>P</i> _Bonferroni = 0.0057] and external capsule [-0.1 (-0.2, -0.1); <i>P</i> _Bonferroni = 0.042] and the strongest association with secondary attentional scores in the corpus callosum [0.2 (0.1, 0.3); <i>P</i> _Bonferroni = 0.014]. In a multivariate model, white matter integrity in the sagittal stratum (<i>P</i> = 0.008), but not encephalomalacic lesions (<i>P</i> = 0.3), was independently associated with Trails A performance. Diminished white matter integrity and cortical injury were each associated with attentional test performance, but only white matter injury demonstrated independent and region-specific effects. The peak statistical association with attentional test performance was in the sagittal stratum, a widely connected white matter region. Further investigation into the connections spanning this and nearby regions may reveal therapeutic targets for neuromodulation.