Altered Lateralization of the Cingulum in Deployment-Related Traumatic Brain Injury: An ENIGMA Military-Relevant Brain Injury Study
Authors: Dennis Emily L , Newsome Mary R , Lindsey Hannah M , Adams Maheen M , Austin Tara A , Disner Seth G , Eapen Blessen C , Esopenko Carrie , Franz Carol E , Geuze Elbert , Haswell Courtney , Hinds Sidney R , Hodges Cooper B , Irimia Andrei , Kenney Kimbra , Koerte Inga K , Kremen William S , Levin Harvey S , Morey Rajendra A , Ollinger John , Rowland Jared A , Scheibel Randall S , Shenton Martha E , Sullivan Danielle R , Talbert Leah D , Thomopoulos Sophia I , Troyanskaya Maya , Walker William C , Wang Xin , Ware Ashley L , Werner J Kent , Williams Wright , Thompson Paul M , Tate David F , Wilde Elisabeth A 
Published: May 2022

Traumatic brain injury (TBI), a significant concern in military populations, is associated with alterations in brain structure and function, cognition, as well as physical and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) is particularly sensitive to changes in brain structure following TBI, as alterations in white matter (WM) microstructure are common. However, dMRI studies in mild TBI (mTBI) are conflicting, likely due to relatively small samples, sample heterogeneity (demographics, pre- and comorbidities) and injury characteristics (mechanism; chronicity). Furthermore, few studies account for brain asymmetry, which may impact cognitive functions subserved by WM tracts. Examining brain asymmetry in large samples may increase sensitivity to detect heterogeneous areas of subtle WM alteration in mTBI.

Through the Enhancing Neuroimaging and Genetics through Meta-analysis (ENIGMA) 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=2,598; 2,321 males/277 females; age 19-85 years). 1,080 reported a deployment-related TBI, 480 had a history of only non-military-related TBI, 823 reported no history of TBI, and 215 did not differentiate between military and non-military TBI. dMRI data were processed in a harmonized manner along with harmonized demographic, injury, psychiatric, and cognitive measures. Hemispheric asymmetry of fractional anisotropy (FA, a common proxy for myelin organization) was calculated for 19 WM tracts and compared between those with and without TBI history.

FA in the cingulum showed greater asymmetry in individuals with a history of deployment-related TBI; this effect was driven by greater left lateralization in the group with TBI. There was a trend towards lower FA of the right cingulum in the TBI group. These results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness and were driven primarily by individuals who had sustained their worst TBI before age 40. We further found that alterations in the cingulum were associated with slower processing speed and poorer set shifting.

The results indicate an enhancement of the previously reported natural left laterality, possibly due to vulnerability of the non-dominant 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.