Twenty Years of Blast-Induced Neurotrauma: Current State of Knowledge

Blast-induced neurotrauma (BINT) is an important injury paradigm of neurotrauma research. This short communication summarizes the current knowledge of BINT. We divide the BINT research into several broad categories—blast wave generation in laboratory, biomechanics, pathology, behavioral outcomes, repetitive blast in animal models, and clinical and neuroimaging investigations in humans. Publications from 2000 to 2023 in each subdomain were considered. The analysis of the literature has brought out salient aspects. Primary blast waves can be simulated reasonably in a laboratory using carefully designed shock tubes. Various biomechanics-based theories of BINT have been proposed; each of these theories may contribute to BINT by generating a unique biomechanical signature. The injury thresholds for BINT are in the nascent stages. Thresholds for rodents are reasonably established, but such thresholds (guided by primary blast data) are unavailable in humans. Single blast exposure animal studies suggest dose-dependent neuronal pathologies predominantly initiated by blood–brain barrier permeability and oxidative stress. The pathologies were typically reversible, with dose-dependent recovery times. Behavioral changes in animals include anxiety, auditory and recognition memory deficits, and fear conditioning. The repetitive blast exposure manifests similar pathologies in animals, however, at lower blast overpressures. White matter irregularities and cortical volume and thickness alterations have been observed in neuroimaging investigations of military personnel exposed to blast. Behavioral changes in human cohorts include sleep disorders, poor motor skills, cognitive dysfunction, depression, and anxiety. Overall, this article provides a concise synopsis of current understanding, consensus, controversies, and potential future directions.


Introduction
Blast-induced neurotrauma (BINT) has been identified as a signature wound during conflicts in Iraq and Afghanistan. 1,24][5] Since then, significant efforts have been made to understand BINT.In the past 20 years, *$900 million USD has been spent on research funding related to BINT. 6In this short communication, we summarize (Fig. 1) the current knowledge, consensus, controversies, and FIG. 1. Schematic depicting the current state of knowledge of BINT in various subdomains.The text color for each aspect in individual subdomains is commensurate with the degree of understanding.Greencolored text indicates significant, unequivocal findings in the literature.Gray-colored text indicates that the findings are equivocal.Red-colored text indicates a lack of substantial literature.For example, in the ''behavioral animal models'' subdomain, unequivocal findings are reported in the literature for various behavioral outcomes observed because of exposure to the blast demonstrating/exuberating consensus across investigations.However, findings regarding temporal recovery of the behavioral outcomes are equivocal (or confounding), indicating a lack of consensus.There is a lack of substantial literature regarding the relationship between external mechanical insult and behavioral outcomes and the correlation between observed pathology and behavioral outcomes.Future work in each subdomain should focus on aspects highlighted using gray-and red-colored texts.BINT, blast-induced neurotrauma; BOP, blast overpressure; CTE, chronic traumatic encephalopathy; PPE, personal protective equipment.potential future directions.Additional details regarding this short communication are provided in the section Transparency, Rigor, and Reproducibility Summary at the end of the article.

Blast Wave and Its Generation in a Laboratory
An explosion is termed as a rapid expansion of gases, generally occurring because of the detonation of explosives. 7Explosion creates a pressure pulse in the surrounding medium (e.g., air) that propagates at supersonic speed, generating an (almost) instantaneous rise in pressure known as a shock front.The rarefaction wave, generated because of the overexpansion of explosive gases or reflections from the ground, catches with the shock front, causing a decay in the pressure profile.At a sufficiently longer distance from the explosion, a blast wave takes the form of the Friedlander wave 8 (or so-called free-field blast wave).The free-field blast wave is characterized by an instantaneous rise in pressure followed by a non-linear decay.Broadly, the blast wave implied in BINT is a free-field blast wave referred to as a ''primary blast'' in BINT literature.
0][11][12][13][14][15] It has been shown, in these investigations, that shock tubes can generate primary blast waves in some form.7][18][19][20][21][22][23][24][25][26][27][28] The blast wave evolves considerably along the length of the shock tube, 17,18,21 based on the design of the shock tube. 22,24,25,27It has also been demonstrated that the blast wave profile and specimen placement location critically affect biomechanical loading 16,23,28 and injury outcome. 28It is difficult to generate similar blast wave profiles across various shock tubes.Thus, it is crucial to report the blastrelated measurements rigorously.1]27 There is a lack of standard protocol for the blast measurements (i.e., incident blast overpressure [BOP], reflected overpressure, and intracranial pressure [ICP]).[31][32] As a result, correlating BOP with the biomechanical response (e.g., ICP) and comparing data across various investigations become challenging. 33We have collected and analyzed the experimental data from the literature across various models (head surrogates, post-mortem human subjects [PMHS], and rat). 33Our analysis (Supplementary Fig. S1) suggests that, for a given model, a reasonable correlation can be established between reflected overpressure measured on the surface of the head (generally at the point of initial impact location) and ICP measured in the brain.Hence, in addition to the measurement of BOP, it is advisable to measure reflected overpressures at a few locations on the surface of the head.
Blast-induced head acceleration [43][44][45][46] was observed as a dominant mechanism in several investigations using rodents.In these investigations, head acceleration alone led to diffuse axonal injury (DAI) pathology and memory deficits.Further, there is evidence of DAI in veterans with histories of blast exposure. 69-72Thus, there is a need to investigate the effect of blast-induced head acceleration and blast DAI pathology using primates, rodents, PMHS, and CHHM, given that it may offer significant new insights.9][50] However, additional experimental investigations explicitly focused on CSF cavitation, biomechanical cascade, and BINT are needed to corroborate these findings fully.
Injury thresholds for BINT are in the nascent stages.A few investigations 73,74 suggest that incident BOP of *145 kPa is a threshold for mild BINT in rodents.Animal-to-human scaling 75 has been attempted; however, robust thresholds for BINT in humans remain unavailable.Biofidelic, three-dimensional CHHM 34,35,37,39,55,57,58 may eventually provide threshold values, provided significant clinical data and associated field measurements in humans become available.The use of blast dosimeter 76 to characterize blast exposure in military and law enforcement personnel will be a promising step.
The role of helmets and goggles in blast protection is a critical issue.Numerous investigations suggest that these accessories only marginally mitigate or have an adverse effect under certain situations (e.g., a gap between the head and helmet, 40,[77][78][79] with visor and high-density foam pads, 80 with better linking of the helmet with the head, 56 excessive compression of foam pads). 81,82Particularly, negative ICPs and brain strains have been shown to increase with these accessories. 56,80Carefully constructed strategies will be required to address the challenges associated with personal protective equipment (PPE).
In summary, reasonable progress has been made in each subdomain of BINT as discussed above.Pathology in rodents is most widely understood, followed by behavioral outcomes.Significant literature also exists on BINT mechanisms and the use of shock tubes for simulating primary blast waves.Clinical data in humans, exclusive to blast, are limited.Definitive injury thresholds for BINT in humans remain unavailable.Contemporary investigations of repetitive blast in targeted cohorts, exposed to primary blast, are encouraging.Future interdisciplinary research within and across various subdomains of BINT will probably lead to further progress and tangible outcomes.

Transparency, Rigor, and Reproducibility Summary
This short communication is not a detailed review of various subdomains (Fig. 1) of BINT.Rather, it is a broad overview of the present state of knowledge in each subdomain.For a few subdomains, review articles 51,52,89,100, 146,168,212,213 are already available in the literature.Nonetheless, we have extensively gone through the literature in each subdomain.Relevant literature in each subdomain was considered while writing the manuscript; specifically, publications from 2000 to 2023 were included.Various search terms, such as ''blast + rodent,'' ''blast + human,'' ''blast + imaging,'' ''blast + behavior,'' ''blast + TBI,'' ''blast + shock tube,'' and ''blast + biomechanical,'' were used.The search items are a few sample search terms only.For blast wave generation and biomechanics subdomains, the corresponding author has been an active researcher for over a decade.Data collected and analyzed during this period were also considered during investigation and writing.