Military-related mild traumatic brain injury: clinical characteristics, advanced neuroimaging, and molecular mechanisms

Abstract

Mild traumatic brain injury (mTBI) is a significant health burden among military service members. Although mTBI was once considered relatively benign compared to more severe TBIs, a growing body of evidence has demonstrated the devastating neurological consequences of mTBI, including chronic post-concussion symptoms and deficits in cognition, memory, sleep, vision, and hearing. The discovery of reliable biomarkers for mTBI has been challenging due to under-reporting and heterogeneity of military-related mTBI, unpredictability of pathological changes, and delay of post-injury clinical evaluations. Moreover, compared to more severe TBI, mTBI is especially difficult to diagnose due to the lack of overt clinical neuroimaging findings. Yet, advanced neuroimaging techniques using magnetic resonance imaging (MRI) hold promise in detecting microstructural aberrations following mTBI. Using different pulse sequences, MRI enables the evaluation of different tissue characteristics without risks associated with ionizing radiation inherent to other imaging modalities, such as X-ray-based studies or computerized tomography (CT). Accordingly, considering the high morbidity of mTBI in military populations, debilitating post-injury symptoms, and lack of robust neuroimaging biomarkers, this review (1) summarizes the nature and mechanisms of mTBI in military settings, (2) describes clinical characteristics of military-related mTBI and associated comorbidities, such as post-traumatic stress disorder (PTSD), (3) highlights advanced neuroimaging techniques used to study mTBI and the molecular mechanisms that can be inferred, and (4) discusses emerging frontiers in advanced neuroimaging for mTBI. We encourage multi-modal approaches combining neuropsychiatric, blood-based, and genetic data as well as the discovery and employment of new imaging techniques with big data analytics that enable accurate detection of post-injury pathologic aberrations related to tissue microstructure, glymphatic function, and neurodegeneration. Ultimately, this review provides a foundational overview of military-related mTBI and advanced neuroimaging techniques that merit further study for mTBI diagnosis, prognosis, and treatment monitoring.

Fig. 1. A conceptual framework for the study of military-related mTBI.

Pre-injury and injury factors influence the clinical presentation of mTBI patients. In military settings, prior combat exposure and history of TBI influence post-injury clinical presentation and outcome. Important injury factors in military combat settings include the mechanism of injury (blast vs. blunt), type of blast-related injury (refer to Table 2), duration of LOC, and use of uniform gear (blast pressure sensors, cameras). Big data analytics of post-injury factors, clinical symptoms, blood-based biomarkers, genetic biomarkers, and advanced neuroimaging enable a more personalized medicine approach for the proper diagnosis, prognosis, and treatment of military-related mTBI. A culmination of various factors and multi-modal diagnostic, prognostic, and treatment approaches can influence post-injury outcomes. Figure inspired by and adapted from Polinder et al. [193].

Fig. 2. Structural MRI.

T1 (A, B) and T2 (C) weighted images are two main types of image contrast used to characterize tissue and structures in MRI. A and B show images from a T1w MPRAGE sequence. A is a traditional T1w MPRAGE that clearly delineates the white and gray matter structures in the brain as shown in this axial image. White matter is brighter than gray matter on T1 weighted images. B is produced from the newer MPRAGE PROMO (PROspective MOtion correction) sequence, which provides the utility of reducing motion artefacts which can be problematic in some patients. C is produced from the T2w fast spin echo sequence that complements the T1w images. Fluid is bright on T2w images as demonstrated by the bright CSF in the ventricles (arrow). Gray and white matter are reversed with white matter being darker on T2w images.

Fig. 3. T2 FLAIR and SWI images.

T2 FLAIR is a technique that accentuates the white matter hyper-intensities while nulling the signal from CSF (A, B). On T2 FLAIR sequences, the white matter is dark, the gray matter is bright, and the CSF in the ventricles is dark. This technique allows for subtle white matter hyperintensities to be detectable even in areas close to the ventricles. Susceptibility-weighted imaging (SWI) is a gradient echo technique that takes advantage of both phase and magnitude effects to accentuate the presence of ferromagnetic, paramagnetic, and diamagnetic compounds (C, D). Thus, SWI is used to identify microbleeds, blood products, and calcium. C is a standard SWI image and D. is from a patient with a small hemorrhage (red arrow) that is seen as a dark ring.

Fig. 4. Diffusion multi-shell MRI techniques.

Standard diffusion techniques utilize a single b-value to measure water movement in the brain along the white matter tracts, usually underestimating the restriction in the voxel. Multi-shell techniques utilize multiple b-values and can improve the ability to detect features of the cellular environment and better estimate the white fiber tracts within a voxel. A shows a multi-shell axial image acquired at 3 T. B shows an FA map from a 3 T GE MR 750 scanner. C is a zoomed in tractography view of the centrum semioval from the same patient showing the white matter pathways that can be seen with conventional 3 T MR scanner using the multi-shell diffusion technique. Note the complex fiber angles in the close-up view. D shows a NODDI orientation dispersion index (ODI) map, with lighter colors representing values closer to 1. E shows a NODDI intra-cellular volume fraction (ICVF) map, with lighter colors representing values closer to 1. F shows a NODDI isometric volume fraction (ISOVF) map, with red colors representing values closer to 1.