Mild traumatic brain injury in the Veteran population is frequently comorbid with pain, post-traumatic stress disorder, and/or depression. However, not everyone exposed to mild traumatic brain injury experiences these comorbidities and it is unclear what factors contribute to this variability. The objective of this study was to identify comorbidity phenotypes among Post-9/11 deployed Veterans with no or mild traumatic brain injury and examine the association of comorbidity phenotypes with adverse outcomes. We found that Veterans with mild traumatic brain injury (n = 93,003) and no brain injury (n = 434,378) were mean age of 32.0 (SD 9.21) on entering Department of Veterans Health Administration care, were predominantly Caucasian non-Hispanic (64.69%), and served in the Army (61.31%). Latent class analysis revealed five phenotypes in each subcohort; Moderately Healthy and Mental Health phenotypes were common to both. The Healthy phenotype was found only in no brain injury. Unique phenotypes in mild traumatic brain injury included Moderately Healthy+Decline, Polytrauma, and Polytrauma+Improvement. There was substantial variation in adverse outcomes. The Polytrauma+Improvement phenotype had the lowest likelihood of adverse outcomes. There were no differences between Moderately Healthy+Decline and Polytrauma phenotypes. Phenotypes of comorbidity vary significantly by traumatic brain injury status including divergence in phenotypes (and outcomes) over time in the mild traumatic brain injury subcohort. Understanding risk factors for the divergence between Polytrauma vs. Polytrauma+Improvement and Moderately Healthy vs. Moderately Healthy+Decline, will improve our ability to proactively mitigate risk, better understand the early patterns of comorbidity that are associated with neurodegenerative sequelae following mild traumatic brain injury, and plan more patient-centered care.

Traumatic brain injury (TBI) is common among military personnel and the civilian population and is often followed by a heterogeneous array of clinical, cognitive, behavioral, mood, and neuroimaging changes. Unlike many neurological disorders that have a characteristic abnormal central neurologic area(s) of abnormality pathognomonic to the disorder, a sufficient head impact may cause focal, multifocal, diffuse or combination of injury to the brain. This inconsistent presentation makes it difficult to establish or validate biological and imaging markers that could help improve diagnostic and prognostic accuracy in this patient population. The purpose of this manuscript is to describe both the challenges and opportunities when conducting military-relevant TBI research and introduce the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Military Brain Injury working group. ENIGMA is a worldwide consortium focused on improving replicability and analytical power through data sharing and collaboration. In this paper, we discuss challenges affecting efforts to aggregate data in this patient group. In addition, we highlight how "big data" approaches might be used to understand better the role that each of these variables might play in the imaging and functional phenotypes of TBI in Service member and Veteran populations, and how data may be used to examine important military specific issues such as return to duty, the late effects of combat-related injury, and alteration of the natural aging processes.

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.