2025 Theses Doctoral

Determining the impact of the interval between repetitive low-level blast exposures on functional deficits in the hippocampus

Kim, Carolyn Yijae

Traumatic brain injury (TBI) is a significant cause of death and disability worldwide. Although mTBI (mTBI) accounts for the majority of TBIs, frequent underdiagnosis increases the likelihood of repeated injuries. TBI has also been a major concern for the United States military over the past decade. Previous research largely focused on moderate and mild blast TBIs (bTBIs) that modeled shock waves from improved explosive devices (IEDs), but there is growing concern that repeated exposure to shock waves of lower intensities also may be capable of inflicting neurocognitive deficits. Concern is particularly relevant during training exercises where large numbers of trainees, and particularly trainers, may experience repeated exposures. Current training protocols impose a 4 psi (28 kPa) limit on individual overpressure exposures but fail to account for the cumulative and temporal dynamics of repetitive low-level blast exposures. To improve such guidelines, we must better understand how repetitive low-level blasts over time lead to neurocognitive deficits. In this thesis, we modified our existing shock tube apparatus to develop a new Level 0 blast exposure representative of firing heavy weapons. This dissertation investigated how the number of blasts, inter-blast interval (IBI), and number of sessions interact to influence the neurophysiological and molecular consequences of repetitive low-level blast.

In Aim 1, we utilized this new Level 0 blast exposure to develop tolerance criteria for repetitive low-level blasts with a 5 min IBI. We observed that repetitive low-level blast exposure had a dose-response effect on long-term potentiation (LTP), the cellular correlate for learning, with 3 blast exposures resulting in significant LTP deficits at 24 h after blast. Overall, LTP deficits spontaneously recovered between 48 and 72 h after blast. Increasing the IBI to 1 or 2 days largely attenuated LTP deficits.

In Aim 2, we investigated the molecular mechanisms of blast-induced LTP deficits. Although evoked stimulus-response parameters were unaltered by blast, spontaneous network characteristics, including spike duration, spike amplitude, and connectivity coefficient, were elevated in a delayed manner. Expression of the anti-inflammatory cytokine interleukin-10 (IL-10) exhibited a biphasic pattern after blast exposure, characterized by initial suppression at 3 h after blast followed by overexpression 24 h after blast. Treatment with progesterone, a potent anti-inflammatory agent, both attenuated LTP deficits and increased early IL-10 expression to prevent the delayed overexpression of IL-10. Blast also induced a minor deficit in the synaptic protein postsynaptic density protein 95 (PSD-95) and slight increases in expression of inflammatory markers.

In Aim 3, we increased blast quantity, varied same-day IBIs, and introduced multiple sessions of repetitive blast to better understand how the complex interplay of these parameters drives mechanisms of blast-induced LTP deficits. Surprisingly, a single session of 6 blast exposures with a 1 h IBI produced significantly greater LTP deficits than when delivered with a shorter 30 min IBI. This phenomenon persisted when the 6 blasts were instead split over 2 sessions of triple blast. Both IBI and number of sessions affected the expression of synaptic proteins and inflammatory proteins in a nonlinear fashion that did not consistently correlate with LTP outcomes.

Overall, this dissertation has demonstrated that repetitive low-level blasts with same-day IBIs can significantly impair synaptic plasticity depending on the timing of blast exposures. These findings have provided foundational data to expand upon the tolerance criteria for repetitive blast exposures by improving our understanding of how the number of blasts, IBI, and number of sessions drive blast-induced molecular mechanisms of injury. Ultimately, the insights from these studies can inform the development of safer training protocols to establish occupational exposure limits designed to prevent neurological impairments and long-term health consequences.