modeling-highly-repetitive-low-level-blast-exposure-in-mice

Modeling Highly Repetitive Low-level Blast Exposure in Mice

Exposure to explosive blasts is a significant risk factor for brain trauma among exposed persons. Although the effects of large blasts on the brain are ...

United States Army Special Operations Command

University of Colorado School of Medicine

Special Operations Forces (SOF) Service members endure frequent exposures to blast and overpressure mechanisms given their high training tempo. The link between cumulative subconcussive blasts on short- and long-term neurological impairment is largely understudied. Neurodegenerative diseases such as brain dysfunction, cognitive decline, mild cognitive impairment, and dementia may develop with chronic exposures. This hypothesis remains unproven because of lack of ecologically valid occupational blast exposure surveillance among SOF Service members. The purpose of the study was to measure occupational blast exposures in a close quarter battle (CQB) training environment and to use those outcomes to develop a pragmatic cumulative blast exposure (CBE) estimate model. Four blast silhouettes equipped with a field-deployable wireless blast gauge system were positioned in breaching positions during CQB training scenarios. Silhouettes were exposed to flashbangs and three interior breaching charges (single strand roll-up interior charge, 300 grain (gr) explosive cutting tape (ECT), and Jelly charge). Mean blast measures were calculated for each silhouette for flashbangs ( = 93), single strand roll-up interior charge ( = 80), 300 gr ECT ( = 28), and Jelly charge ( = 71). Mean peak blast pressures per detonation are reported as follows: (1) flashbangs (1.97 pounds per square inch [psi]); (2) single strand roll-up interior charge (3.88 psi); (3) 300 gr ECT (2.78 psi); and (4) Jelly charge (1.89 psi). Pragmatic CBE estimates for SOF Service members suggest 36.8 psi, 184 psi, and 2760 psi may represent daily, weekly, and training cycle cumulative pressure exposures. Estimating blast exposures during routine CQB training can be determined from empirical measures taken in CQB environments. Factoring in daily, weekly, training cycle, or even career length may reasonably estimate cumulative occupational training blast exposures for SOF Service members. Future work may permit more granular exposure estimates based on operational blast exposures and those experienced by other military occupational specialties.

Cumulative Blast Exposure Estimate Model for Special Operations Forces Combat Soldiers.

Cumulative low-level blast exposure during military training may be a significant occupational hazard, increasing the risk of poor long-term outcomes in brain function. US Public Law 116-92 section 717 mandates that US Department of Defense agencies document the blast exposure of each Service member to help inform later disability and health care decisions. However, which empirical measures of training blast exposure, such as the number of incidents, peak overpressure, or impulse, best inform changes in the neurobehavioral symptoms reflecting brain health have not been established.

Cumulative Blast Impulse Is Predictive for Changes in Chronic Neurobehavioral Symptoms Following Low Level Blast Exposure during Military Training.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [F]fluorodeoxyglucose-positron emission tomography ([F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [F]FDG-uptake in Veterans with blast-mTBI versus control participants,  < 0.0001;  = 3.29 × 10 [Cohen's , 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [F]FDG-uptake correlated with the number of self-reported blast-mTBIs,  = 0.22;  < 0.0001. Greater [F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 ( < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls,  < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate  = 0.021; total effect estimate,  = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [F]FDG-uptake,  < 0.0001, with mTBI as a covariate. Increased left pallidum [F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [F]FDG-uptake in the left pallidum.

Increased [F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Cory McEvoy

United States Army Special Operations Command

Modeling Highly Repetitive Low-level Blast Exposure in Mice