Review Effects of Low-Level Blast on Neurovascular Health and Cerebral Blood Flow: Current Findings and Future Opportunities in Neuroimaging, 2024

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Effects of Low-Level Blast on Neurovascular Health and Cerebral Blood Flow: Current Findings and Future Opportunities in Neuroimaging
Kilgore, Madison O.; Hubbard, W. Brad

Low-level blast (LLB) exposure can lead to alterations in neurological health, cerebral vasculature, and cerebral blood flow (CBF). The development of cognitive issues and behavioral abnormalities after LLB, or subconcussive blast exposure, is insidious due to the lack of acute symptoms. One major hallmark of LLB exposure is the initiation of neurovascular damage followed by the development of neurovascular dysfunction. Preclinical studies of LLB exposure demonstrate impairment to cerebral vasculature and the blood–brain barrier (BBB) at both early and long-term stages following LLB. Neuroimaging techniques, such as arterial spin labeling (ASL) using magnetic resonance imaging (MRI), have been utilized in clinical investigations to understand brain perfusion and CBF changes in response to cumulative LLB exposure.

In this review, we summarize neuroimaging techniques that can further our understanding of the underlying mechanisms of blast-related neurotrauma, specifically after LLB. Neuroimaging related to cerebrovascular function can contribute to improved diagnostic and therapeutic strategies for LLB. As these same imaging modalities can capture the effects of LLB exposure in animal models, neuroimaging can serve as a gap-bridging diagnostic tool that permits a more extensive exploration of potential relationships between blast-induced changes in CBF and neurovascular health.

Future research directions are suggested, including investigating chronic LLB effects on cerebral perfusion, exploring mechanisms of dysautoregulation after LLB, and measuring cerebrovascular reactivity (CVR) in preclinical LLB models.

Link | PDF (International Journal of Molecular Sciences)

 

[SNT Gatchaman]

As the field of blast-induced neurotrauma, blast TBI, and LLB progress, it is important to understand the alignment of clinical and preclinical findings. One area of investigation in the field is the examination of neurovascular, neurovascular unit (NVU), and blood–brain barrier (BBB) outcomes. The NVU describes cellular interactions with the blood vessels of the brain. The NVU includes vascular cells (including endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (including astrocytes, microglia, and oligodendroglia), and neurons. The cell-to-cell communication is vital for maintaining BBB integrity and regulating CBF.

Based on blood biomarkers in military personnel with a history of blast exposure, it is clear that BBB damage is an important factor. Chronic alterations in markers of BBB integrity have been observed among Veterans with mbTBI [mild blast traumatic brain injury]. In a study by Meabon et al., blood plasma levels of vascular endothelial growth factor-A (VEGF-A), a factor contributing to BBB permeability, were elevated in Veterans who, on average, were 5.5 years removed from the last sustained mbTBI. Notably, changes in VEGF are particularly vulnerable to both single and repeated LLB exposure in preclinical models, indicating that damage to the NVU and, consequently, the BBB is an important prognostic and therapeutic target in service members exposed to repeated LLB.

Neuroimaging is an important translational link and may provide an avenue for prognostication for long-term outcomes in Veterans with a history of blast exposure. [...] Diffusion tensor imaging (DTI) is an essential diagnostic tool to assess microstructural changes following blast exposure. DTI acquires information on axonal health by generating different parameters, including fractional anisotropy (FA) and radial diffusivity (RD), to determine the directionality of water diffusion along axons.

Veterans with a history of blast exposure not only showed a similar graded association via DTI but also demonstrated a more rapid decline in white matter integrity with age compared to unexposed individuals, indicating that cumulative blast exposure may contribute to an accelerated aging process.

 

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As previously mentioned, service members with a high occupational risk of LLB are more vulnerable to developing PTSD. Interestingly, imaging studies have shown that CBF in specific brain regions is altered in individuals at various stages of PTSD onset. [...] Studies have shown that the onset of PTSD correlates with CBF alterations as early as three months after a traumatic event, and changes in CBF have been observed in Veterans who have experienced both military-conflict-related trauma and early-life trauma.

Consequently, exploring the effects of chronic LLB exposure on PTSD-related outcomes is particularly imperative for Veterans, as PTSD symptoms can persist for decades and, in some cases, have a delayed onset, starting at a minimum of 6 months following the traumatic event.

Neurovascular pathology is a well-established outcome of blast-induced TBI. Military service members exposed to blast exhibit vascular dysfunction, including vasospasm, hypotension, and altered cerebral perfusion. While the cellular underpinnings of vascular dysfunction in military LLB exposure are not fully understood, clinical studies have shown, via neuroimaging, that alterations in CBF could underlie neurological symptoms, such as PTSD.

Despite the limited preclinical research on LLB effects on CBF, evidence shows that blast exposure impairs neurovascular health, including alterations in acute cerebral perfusion and ongoing BBB permeability.

LLB is hypothesized to accelerate neurovascular-associated age-related processes, including cerebrovascular dysfunction and progression of neurodegenerative disease

 

[SNT Gatchaman]

See also —

The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma (2024)
Elder, Gregory A.; Gama Sosa, Miguel A.; De Gasperi, Rita; Perez Garcia, Georgina; Perez, Gissel M.; Abutarboush, Rania; Kawoos, Usmah; Zhu, Carolyn W.; Janssen, William G. M.; Stone, James R.; Hof, Patrick R.; Cook, David G.; Ahlers, Stephen T.

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable.

Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood–brain barrier permeability, and glymphatic flow.

Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.

Link | PDF (International Journal of Molecular Sciences)

 

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Distinct Functional MRI Connectivity Patterns and Cortical Volume Variations Associated with Repetitive Blast Exposure in Special Operations Forces Members (2025)
Andrea Diociasi; Mary A. Iaccarino; Scott Sorg; Emily J. Lubin; Caroline Wisialowski; Amol Dua; Can Ozan Tan; Rajiv Gupta

BACKGROUND
Special operations forces members often face multiple blast injuries and have a higher risk of traumatic brain injury. However, the relationship between neuroimaging markers, the cumulative severity of injury, and long-term symptoms has not previously been well-established in the literature.

PURPOSE
To determine the relationship between the frequency of blast injuries, persistent clinical symptoms, and related cortical volumetric and functional connectivity (FC) changes observed at brain MRI in special operations forces members.

MATERIALS AND METHODS
A cohort of 220 service members from a prospective study between January 2021 and May 2023 with a history of repetitive blast exposure underwent psychodiagnostics and a comprehensive neuroimaging evaluation, including structural and resting-state functional MRI (fMRI). Of these, 212 met the inclusion criteria. Participants were split into two datasets for model development and validation, and each dataset was divided into high-and low-exposure groups based on participants’ exposure to various explosives. Differences in FC were analyzed using a general linear model, and cortical gray matter volumes were compared using the Mann-Whitney U test. An external age-and sex-matched healthy control group of 212 participants was extracted from the SRPBS Multidisorder MRI Dataset for volumetric analyses. A multiple linear regression model was used to assess correlations between clinical scores and FC, while a logistic regression model was used to predict exposure group from fMRI scans.

RESULTS
In the 212 participants (mean age, 43.0 years ± 8.6 [SD]; 160 male [99.5%]) divided into groups with low or high blast exposure, the high-exposure group had higher scores for the Neurobehavioral Symptom Inventory (NSI) (t = 3.16, P < .001) and Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5) (t = 2.72, P = .01). FC differences were identified in the bilateral superior and inferior lateral occipital cortex (LOC) (P value range, .001–.04), frontal medial cortex (P < .001), left superior frontal gyrus (P < .001), and precuneus (P value range, .02–.03). Clinical scores from NSI and PCL-5 were inversely correlated with FC in the LOC, superior parietal lobule, precuneus, and default mode networks (r = −0.163 to −0.384; P value range, <.001 to .04). The high-exposure group showed increased cortical volume in regions of the LOC compared with healthy controls and the low-exposure group (P value range, .01–.04). The predictive model helped accurately classify participants into high-and low-exposure groups based on fMRI data with 88.00% sensitivity (95% CI: 78.00, 98.00), 67% specificity (95% CI: 53.00, 81.00), and 73% accuracy (95% CI: 60.00, 86.00).

CONCLUSION
Repetitive blast exposure leads to distinct alterations in FC and cortical volume, which correlate with neurobehavioral symptoms. The predictive model suggests that even in the absence of observable anatomic changes, FC may indicate blast-related trauma.

Link | PDF (Radiology) [Open Access]