Altered lateralization of the cingulum in deployment-related traumatic brain injury: An ENIGMA military-relevant brain injury study

Abstract

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

Keywords: DTI; military; traumatic brain injury.

FIGURE 1

Group differences in cingulum asymmetry. Violin plots are shown for the nontraumatic brain injury (TBI) group (red), and deployment‐related TBI group (blue) with group t‐test p‐values (corrected). The asymmetry analyses were corrected for multiple comparisons across all regions of interest tested using the Li and Ji adjusted Bonferroni correction. The laterality and cingulum fractional anisotropy (FA) analyses were false discovery rate‐corrected across the three post hoc tests. The values on the y‐axis are the normalized residuals for cingulum asymmetry, laterality index, left FA, and right FA, accounting for age, gender, and the nested random effects of cohort and site. As the cingulum is generally left‐lateralized, actual laterality index values are generally positive, but that is not reflected here due to the adjustments and normalization

FIGURE 2

Group differences in tract asymmetry. Results from group analyses are shown comparing deployment‐related traumatic brain injury (TBI) to no TBI, blast‐related TBI to no TBI, and primary blast TBI to no TBI, along with total sample size for each comparison. Cohen's d, 95% CI, and uncorrected p‐values are shown, bolded statistics are those that survive correction for multiple comparisons, italicized statistics are those that do not survive multiple comparisons correction (.05 > p > .003125). Primary blast TBI is blast overpressure with no concurrent blunt injury. ACR, anterior corona radiata; ALIC, anterior limb of internal capsule; CGC, cingulum; CGH, hippocampal cingulum; CR, corona radiata; CST, corticospinal tract; EC, external/extreme capsule; FX/ST, fornix‐stria terminalis; IC, internal capsule; PCR, posterior corona radiata; PLIC, posterior limb of internal capsule; PTR, posterior thalamic radiation; RLIC, retrolenticular limb of internal capsule; ROI, Region of interest; SCR, superior corona radiata; SFO, superior fronto‐occipital fasciculus; SLF, superior longitudinal fasciculus; SS, sagittal stratum; TAP, tapetum; UNC, uncinate.