Brain volume changes following blast-related mild TBI in service members and veterans: a LIMBIC-CENC study

Importance: Blast-related mild traumatic brain injuries (bTBI), 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 bTBI and regional brain volume in a sample of United States (U.S.) Veterans and Active Duty Service Members (VADSM). Design: Prospective case-control study of U.S. VADSM of participants from the Long-term Impact of Military-relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), which enrolled over 1,500 participants at five sites used in this analysis between 2014-2023. Setting: Participants were recruited from Veterans Affairs medical centers across the U.S. Participants: Seven hundred and seventy-four VADSM of the U.S. military met eligibility criteria for this analysis. Exposure: All participants had combat exposure, and 82% had one or more lifetime mild TBIs with variable injury mechanisms. Main Outcomes and Measures: Regional brain volume was calculated using tensor-based morphometry on 3D T1-weighted magnetic resonance imaging scans. TBI history, including history of blast-related injury (bTBI), 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 bTBI group, and that this would be associated with cognitive performance. Results: Individuals with a history of bTBI had smaller brain volumes in several clusters, with the largest centered bilaterally in the superior corona radiata and globus pallidus. Greater volume deficits were associated with a larger number of lifetime bTBIs. Additionally, causal mediation analysis revealed that these volume differences significantly mediated the association between bTBI and performance on measures of working memory and processing speed. Conclusions and Relevance: Our results reveal robust volume differences associated with bTBI. Magnetic resonance elastography atlases reveal that the specific regions affected include the stiffest tissues in the brain, which may underlie their vulnerability to pressure waves from blast exposures. Furthermore, these volume differences significantly mediated the association between bTBI and cognitive function, indicating that this may be a helpful biomarker in tracking outcome after bTBI and suggesting potential treatment targets to prevent or limit chronic dysfunction. ### Competing Interest Statement Dr. Hinds is an employee of SCS Consulting LLC, which has financial affiliations with Major League Soccer Players Association, Nano DX, Owl Therapeutics, Prevent Biometrics, Collaborative Neuropathology Network Characterizing Outcomes of TBI (CONNECT-TBI), United States Army Medical Research and Development Command's Congressionally Directed Medical Research Programs and the National Football League Players Association. Dr. Hinds has not received financial compensation for his work with LIMBIC-CENC. Dr. Hinds is a member of Concussion Legacy Foundation's Veterans Advisory Board; advisory Board member to the University of Michigan Concussion Center; advisor to Gryphon Bio; ad hoc reviewer for VA Brain Health Research; invited reviewer to Congressionally Directed Medical Research Programs; contributor to the National Academy of Science, Engineering, and Medicine 'Accelerating Progress in TBI Research and Care'; NASEM TBI Forum committee member (currently inactive); and former contributor to Post-traumatic Epilepsy Research Program. His former Department of Defense work includes: NFL Scientific Advisory Board member; NCAA-DoD CARE Medical Advisory Board Member; DoD Brain Health Research Coordinating Officer and Medical Advisor to the Principal Assistant for Research and Technology (PAR&T), United States Army Medical Research and; Development Command (USAMRDC); Ex Officio National Advisory Neurological. All other authors report no relevant disclosures. ### Funding Statement This work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Psychological Health/Traumatic Brain Injury Research Program LongTerm Impact of Military Relevant Brain Injury Consortium (LIMBIC) Award W81XWH18PH/TBIRPLIMBIC under Awards No. W81XWH1920067 and W81XWH1320095, and by the U.S. Department of Veterans Affairs Awards No. I01 CX002097, I01 CX002096, I01 HX003155, I01 RX003444, I01 RX003443, I01 RX003442, I01 CX001135, I01 CX001246, I01 RX001774, I01 RX 001135, I01 RX 002076, I01 RX 001880, I01 RX 002172, I01 RX 002173, I01 RX 002171, I01 RX 002174, I01 CX001820, and I01 RX 002170. Dr. Pugh was supported by VA Health Services Research and Development Service Research Career Scientist Award, 1 IK6 HX002608; RCS 17-297. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of the University of Utah gave ethical approval for this work. IRB of the Richmond VA gave ethical approval for this work. IRB of the Houston VA gave ethical approval for this work. IRB of the Tampa VA gave ethical approval for this work. IRB of the Portland VA gave ethical approval for this work. IRB of the Minneapolis VA gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available upon reasonable request to the LIMBIC-CENC consortium.