Differences in Brain Volume in Military Service Members and Veterans after Blast-Related Mild TBI: A LIMBIC-CENC Study

Importance: Blast-related mild traumatic brain injuries (TBIs), the "signature injury"of post-9/11 conflicts, are associated with clinically relevant, long-term cognitive, psychological, and behavioral dysfunction and disability; however, the underlying neural mechanisms remain unclear. Objective: To investigate associations between a history of remote blast-related mild TBI and regional brain volume in a sample of US veterans and active duty service members. Design, Setting, and Participants: Prospective cohort study of US veterans and active duty service members from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), which enrolled more than 1500 participants at 5 sites used in this analysis between 2014 and 2023. Participants were recruited from Veterans Affairs medical centers across the US; 774 veterans and active duty service members of the US military met eligibility criteria for this secondary analysis. Assessment dates were from January 6, 2015, to March 31, 2023; processing and analysis dates were from August 1, 2023, to January 15, 2024. Exposure: All participants had combat exposure, and 82% had 1 or more lifetime mild TBIs with variable injury mechanisms. Main Outcomes and Measures: Regional brain volume was calculated using tensor-based morphometry on 3-dimensional, T1-weighted magnetic resonance imaging scans; history of TBI, including history of blast-related mild TBI, was assessed by structured clinical interview. Cognitive performance and psychiatric symptoms were assessed with a battery of validated instruments. We hypothesized that regional volume would be smaller in the blast-related mild TBI group and that this would be associated with cognitive performance. Results: A total of 774 veterans (670 [87%] male; mean [SD] age, 40.1 [9.8] years; 260 [34%] with blast-related TBI) were included in the sample. Individuals with a history of blast-related mild TBI had smaller brain volumes than individuals without a history of blast-related mild TBI (which includes uninjured individuals and those with non-blast-related mild TBI) in several clusters, with the largest centered bilaterally in the superior corona radiata and subcortical gray and white matter (cluster peak Cohen d range, -0.23 to -0.38; mean [SD] Cohen d, 0.28 [0.03]). Additionally, causal mediation analysis revealed that these volume differences significantly mediated the association between blast-related mild TBI and performance on measures of working memory and processing speed. Conclusions and Relevance: In this cohort study of 774 veterans and active duty service members, robust volume differences associated with blast-related TBI were identified. Furthermore, these volume differences significantly mediated the association between blast-related mild TBI and cognitive function, indicating that this pattern of brain differences may have implications for daily functioning.