Mild Blast Traumatic Brain Injury Research Articles

Mitochondrial Dysfunction after Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug.

Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11 psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2 days post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared with its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated a mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. Although there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

SAT270 Parity Increases Corticosterone Response To Restraint-induced Stress After Mild Blast Traumatic Brain Injury In Mice

Abstract Disclosure: S. Anisowicz: None. M. Bodemeier Loayza Careaga: None. T. Wu: None. Background: Traumatic brain injury (TBI) is a common problem worldwide, with an estimated incidence of 69 million injuries per year. In the US military, one of the most common forms of TBI during operational deployments after Sep 11, 2001 was the blast TBI, thought to be responsible for over 80% of TBI sustained in theater. One consequence of TBI is dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. HPA axis dysregulation is linked to increased risk for psychiatric disorders. Furthermore, prior research has shown that TBI may dysregulate the HPA axis in a sex-dependent manner. Throughout a female’s life span, there are several sentinel events of hormonal consequence, including pubarche, menopause, and parity, which are known to be times of changes in risks for psychiatric disorders. Objectives: The role of parity on TBI response has not yet been studied, though parity has been shown to decrease fear-related behaviors and decreased corticosterone load in multiparous mice when compared to nulliparous (NP) controls. Our objective is to determine if parity alters corticosterone (CORT) response to restraint, a mild psychological stressor, in mice exposed to mild blast TBI (mbTBI). Methods: One hundred thirteen NP or primiparous (PP) C57Bl6/J mice were randomly assigned to receive sham or mbTBI. Among those that received mbTBI (19.2 ± 0.12 psi), 32 were NP and 24 were PP. Among sham mice, 32 were NP and 26 were PP. All mice received isoflurane anesthesia prior to sham or mbTBI treatment. At 7-8 days after mbTBI, half the mice within each treatment group were subjected to a mild 20-min restraint before being anesthetized by CO2 followed by collection of trunk blood. Serum was harvested and analyzed for CORT concentrations by ELISA (Enzo Life Sciences). Results: All mice that received mbTBI had a longer (p<0.05) righting time compared to those that did not. There was no main effect of parity in the righting time (p>0.1). PP mice who experienced mbTBI demonstrated a greater (p<0.05) CORT response to restraint (157.3 ± 21 pg/mL) when compared to NP mice (95.9 ± 7.2 pg/mL). CORT response to restraint did not differ (p>0.1) between NP and PP mice who did not experience mbTBI (96.1 ± 7.6 vs 109.2 ± 16 pg/mL). Conclusions: Our data indicates that mbTBI alters HPA axis reactivity in PP mice compared to NP mice, increasing the CORT response to restraint induced stress. Parity alone did not alter CORT response to restraint stress or baseline CORT levels. The results of our finding highlight the importance of parity as a factor in an individual’s lifespan. Presentation: Saturday, June 17, 2023

Repetitive, but Not Single, Mild Blast TBI Causes Persistent Neurological Impairments and Selective Cortical Neuronal Loss in Rats.

Exposure to repeated mild blast traumatic brain injury (mbTBI) is common in combat soldiers and the training of Special Forces. Evidence suggests that repeated exposure to a mild or subthreshold blast can cause serious and long-lasting impairments, but the mechanisms causing these symptoms are unclear. In this study, we characterise the effects of single and tightly coupled repeated mbTBI in Sprague-Dawley rats exposed to shockwaves generated using a shock tube. The primary outcomes are functional neurologic function (unconsciousness, neuroscore, weight loss, and RotaRod performance) and neuronal density in brain regions associated with sensorimotor function. Exposure to a single shockwave does not result in functional impairments or histologic injury, which is consistent with a mild or subthreshold injury. In contrast, exposure to three tightly coupled shockwaves results in unconsciousness, along with persistent neurologic impairments. Significant neuronal loss following repeated blast was observed in the motor cortex, somatosensory cortex, auditory cortex, and amygdala. Neuronal loss was not accompanied by changes in astrocyte reactivity. Our study identifies specific brain regions particularly sensitive to repeated mbTBI. The reasons for this sensitivity may include exposure to less attenuated shockwaves or proximity to tissue density transitions, and this merits further investigation. Our novel model will be useful in elucidating the mechanisms of sensitisation to injury, the temporal window of sensitivity and the evaluation of new treatments.

Сhanges of trace elements in the cerebellum and their influence on the rats behavior in elevated plus maze in the acute period of mild blast-induced brain injury

BackgroundIn connection with the widespread use of explosive devices in military conflicts, in particular in Ukraine, is relevant to detect the biometals changes in the cerebellum and determine the presence of their influence on the behavior changes of rats in the elevated plus maze in the acute period of a mild blast-traumatic brain injury (bTBI). MethodsThe selected rats were randomly divided into 3 groups: Group I - Experimental with bTBI (with an excess pressure of 26–36 kPa), Group II - Sham and Group III - Intact. Behavior studies was in the elevated plus maze. Brain spectral analysis was with using of energy dispersive X-ray fluorescence analysis, after obtaining the quantitative mass fractions of biometals, the ratios of Cu/Fe, Cu/Zn, Zn/Fe were calculated and the data between the three groups were compared. ResultsThe results showed an increase in mobility in the experimental rats, which indicates functional disorders of the cerebellum in the form of maladaptation in space. Changes in cognitive activity also is an evidence of cerebellum suppression, which is indicated by changes in vertical locomotor activity. Grooming time was shortened. We established a significant increase in Cu/Fe and Zn/Fe ratios in the cerebellum, a decrease in Cu/Zn. ConclusionsChanges in the Cu/Fe, Cu/Zn, and Zn/Fe ratios in the cerebellum correlate with impaired locomotor and cognitive activity in rats in the acute posttraumatic period. Accumulation of Fe on the 1st and 3rd day leads to disturbance of the Cu and Zn balance on the 7th day and starts a "vicious cycle" of neuronal damage. Cu/Fe, Cu/Zn, and Zn/Fe imbalances are secondary factors in the pathogenesis of brain damage as a result of primary bTBI.

Timing matters: Sex differences in inflammatory and behavioral outcomes following repetitive blast mild traumatic brain injury

BackgroundRepetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction at multiple timepoints. MethodsIn this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood–brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. At the one-month timepoint, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. ResultsRepetitive blast exposure resulted in both similar (e.g., increased IL-6), and disparate (e.g., IL-10 increase only in females) patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited adverse behavioral outcomes that lasted at least one-month. DiscussionRepresenting a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

Does Blast Mild Traumatic Brain Injury Have an Impact on PTSD Severity? A Systematic Review and Meta-Analysis

Blast mild traumatic brain injury (mTBI) is a unique injury in the military population and post-traumatic stress disorder (PTSD) is shown to be linked with it. The main purpose of the systematic review was to understand the impact of blast mTBI on PTSD symptom severity. We systematically searched Pubmed, Web of Science, Embase (Ovid), APAPsycINFO (Ovid) and Medline (R) and In-Process, In-Data-Review and Other Non-Indexed Citations (Ovid). Data extraction and quality assessment was completed using the AXIS tool. Statistical analysis was undertaken to determine differences between blast mTBI and the control group (no blast and no TBI in military personnel) and a meta-analysis using the random effects model was used to calculate between-study heterogeneity and variance through I2 and Tau2, respectively. Additionally, the likelihood of PTSD, analysed using the average PTSD Checklist (PCL) score, was also determined based. Statistically higher PCL scores were found in the blast mTBI group compared to control groups, but high heterogeneity was found between the studies (p < 0.001, I2 = 84%, Tau2 = 0.44). Furthermore, all studies reported that blast mTBI had probable PTSD, but this was not the case for the control group. Blast mTBI appears to impact on PTSD symptom severity and the likelihood of developing PTSD, which healthcare professionals need to be aware of. The high heterogeneity present in the studies means that caution must be exercised when interpreting the data from this study. However, future studies require more well-defined, high-quality studies to answer the question of how blast mTBI affects PTSD symptom severity.

Age aspect of neurophysiological diagnostics of post-concussion syndrome in patients with mild blast traumatic brain injury

Introduction. It is generally accepted that age influences neuropsychological and neurophysiological findings due to a decrease in memory and attention in older age groups as a result of diseases and damage to the central nervous system of various origins. This should be taken into account when dealing with patients who underwent mild blast traumatic brain injury (mbTBI), and focus on standard characteristics considering the age factor. Purpose: to investigate the influence of the age factor on the characteristics of cognitive evoked potentials in patients with post-concussion syndrome (PCS) in the long-term period of mbTBI. Materials and methods. The study involved 41 patients with PCS aged 18-45 years (study group) and 30 healthy subjects (control group). The patients were in the late period of trauma (from 6 months to 3 years). The age distribution of patients in the study group was the following: 6 patients under 30 years old, 18 patients aged 31-40 years, 17 patients over 40 years old. Neuropsychological testing was performed according to the Montreal Cognitive Assessment Scale. Quantitative electroencephalography was performed according to standard parameters (sensitivity ‒ 70 μV/cm, time constant ‒ 0.1 s, filter ‒ 40 Hz). The results. Neurophysiological testing using the CEP P300 method allows us to verify the dysfunction of brain activity in the form of attention and memory disorders in patients with PCS as a result of mbTBI in the chronic period of damage. Exceeding the upper limit of the age norm of P2 and P3 latency components of CEP P300 is statistically significantly associated with the presence of cognitive impairment in patients with PCS. Conclusions. The CEP P300 method can be recommended for the use in the complex diagnostics of cognitive disorders in patients with PCS in the subacute and chronic periods of the injury. In the clinical interpretation of latency characteristics of CEP P300 components, it is reasonable to focus on standard parameters, including age factor.

Resilience of females to acute blood–brain barrier damage and anxiety behavior following mild blast traumatic brain injury

Low-level blast exposure can result in neurological impairment for military personnel. Currently, there is a lack of experimental data using sex as a biological variable in neurovascular outcomes following blast exposure. To model mild blast traumatic brain injury (mbTBI), male and female rats were exposed to a single 11 psi static peak overpressure blast wave using the McMillan blast device and cohorts were then euthanized at 6 h, 24 h, 7 d and 14 d post-blast followed by isolation of the amygdala. After mbTBI, animals experience immediate bradycardia, although no changes in oxygen saturation levels or weight loss are observed. Male mbTBI animals displayed significantly higher levels of anxiety-like behavior (open field and elevated plus maze) compared to male sham groups; however, there was no anxiety phenotype in female mbTBI animals. Blast-induced neurovascular damage was explored by measuring expression of tight junction (TJ) proteins (zonula occludens-1 (ZO-1), occludin and claudin-5), glial fibrillary acidic protein (GFAP) and astrocyte end-feet coverage around the blood–brain barrier (BBB). Western blot analysis demonstrates that TJ protein levels were significantly decreased at 6 h and 24 h post-mbTBI in male rats, but not in female rats, compared to sham. Female animals have decreased GFAP at 6 h post-mbTBI while male animals display decreased GFAP expression at 24 h post-mbTBI. By 7 d post-mbTBI, there were no significant differences in TJ or GFAP levels between groups in either sex. At 24 h post-mbTBI, vascular integrity and astrocytic end-feet coverage around the BBB was significantly decreased in males following mbTBI. These results demonstrate that loss of GFAP expression may be due to astrocytic damage at the BBB. Our findings also demonstrate sex differences in acute vascular and behavioral outcomes after single mbTBI. Female animals display a lack of BBB pathology after mbTBI corresponding to improved acute neuropsychological outcomes as compared to male animals.

Evaluation of Doppler and electroencephalographic changes in patients with postconcussion syndrome due to mild blast traumatic brain injury

Mild blast traumatic brain injury (mbTBI) often remains undiagnosed and untreated due to lack of treatment of patient, imperfect screening tools, unclear diagnostic criteria, and lack of means to objectify or visualize the injury. Objective: to investigate Doppler and electroencephalographic changes in patients with postconcussion syndrome (PCS) due to mbTBI and the possibility of their use to objectify the injury. Materials and methods. The study involved 115 male participants of hostilities in the East Ukraine (main group) with a diagnosis of "PCS after previous mbTBI" and 30 healthy individuals (control group). Patients were in the long-term period of injury (from 6 months to 3 years). After collecting complaints and history data, the neurological status and the state of cognitive functions were examined. Neuropsychological testing according to the Montreal cognitive assessment score was carried out. Ultrasound duplex scanning with color Doppler mapping of neck and head vessels and transcranial duplex scanning were performed. Quantitative electroencephalography was performed according to standard parameters (sensitivity - 70 μV / cm, time constant - 0.1 s, filter - 40 Hz). Results. In patients with PCS after mbTBI, transcranial duplex scanning can detect changes in vascular resistance in the intracranial vessels of both the carotid and vertebrobasilar basins (mostly reduced resistance values), as well as signs of venous discirculation in the basal veins of the brain, quantitative electroencephalography – changes in the frequency and topic of the α-rhythm, a decrease in its amplitude, frequency-spatial inversion, the presence of signs of dysfunction of nonspecific brain structures, according to spectral analysis – a decrease in α-power, an increase in β-power, activity in θ- and δ-bands. Conclusions. Detected Doppler and electroencephalographic changes may persist in the long-term period of mbTBI. They should be taken into account in the differential diagnosis of post-traumatic stress disorder.

Neurological and neuropsychological characteristics of postconcussion syndrome following blast mild traumatic brain injury

A common complication of blast mild traumatic brain injury (mTBI) is postconcussion syndrome (PCS), the diagnostic criteria of which are based on the patient's subjective complaints. Creation of reliable tools for clinical signs of blast mild TBI objectification is of great priority. Objective: using a comprehensive neurological and neuropsychological examination to determine the characteristics of clinical signs of blast mild TBI in the long-term period to assess the correlation with the data of neurophysiological and radiological studies. Materials and methods. The study involved 115 male participants of hostilities in the East of Ukraine (main group) with a diagnosis of " PCS after previous blast mTBI " and 30 healthy individuals (control group). Patients were in the long-term period of injury (from 6 months to 3 years). After collecting complaints and medical history data, the neurological status and the state of cognitive functions were examined. The latter were studied using the questionnaire "Cicerone". Neuropsychological testing according to the Montreal Cognitive Assessment score (MoCA) was carried out. The Hospital Anxiety and Depression Scale (HADS) was also used, and to objectify asthenic disorders - the Asthenic State Scale (ASS). Results. Assessment of the severity of cognitive impairment using the questionnaire "Cicerone" allowed identifying three clinical variants of PCS: 1) with cognitive impairment in combination with affective disorders (44,3 ± 9,1) % of patients), 2) with a predominance of affective disorders (23,5 ± 7,7) % of patients), 3) moderate and mild disorders of the cognitive and affective spectrum in combination with moderate autonomic disorders ((32,2 ± 8,5) % of patients). In 43,5% of cases, according to the MoCA scale, a decrease in cognitive impairment was found for memorization (memory), attention, delayed recall, total score. According to the HADS scale, the distribution of patients was as follows: clinically significant anxiety was noted in (9,6%) patients, depression - in (11,3%) patients, combination of clinically significant anxiety with depression - in (5,2%) patients, subclinical symptoms of anxiety of various severity - in (55,7%) patients. The phenomena of asthenia due to fatigue with mood swings, loss of the ability to concentrate for a long time on mental and physical tasks occurred in all patients with PCS. Factors with a probably higher risk of cognitive impairment were identified: 1) complaints of extreme fatigue and headache, 2) neurological signs in the form of pyramidal insufficiency, brisk tendon reflexes, 3) anxiety level according to the HADS scale. They can be considered as predictors of detection of cognitive deficit in patients with PCS as a result of blast mild TBI. Conclusions. Comprehensive neurological and neuropsychological examination is an effective tool for diagnosing cognitive changes in PCS as a result of blast mild TBI.

Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes

ABSTRACT Background Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets. Methods This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured. Results In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways. Discussion Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.

Repeated blast mild traumatic brain injury and oxycodone self-administration produce interactive effects on neuroimaging outcomes.

Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra-hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.

Cognitive evoked potentials in the diagnosis of post-concussion syndrome due to blast mild traumatic brain injury

Hostilities in the East of Ukraine are characterized by the use of new weapons, including rocket artillery, rocket-propelled grenades and landmines. This has led to an increase in the number of victims with blast mild traumatic brain injury (BMTBI) and the need to provide them with effective assistance and rehabilitation. An important task is to improve the BMTBI diagnosis by specifying the objective criteria for structural and functional disorders of the central nervous system. This will improve the prognosis of the course of BMTBI in the injured and the treatment program, including personalized, to prevent the development of persistent neurological deficit. Objective: to investigate the possibilities of the cognitive evoked potentials (CEP) method for the objective diagnosis of cognitive disorders in post-concussion syndrome (PCS) BMTBI. Materials and methods. The study involved 115 men with PCS (main group) and 30 healthy individuals (control group). The cognitive functions of the study participants were studied using the questionnaire "Cicerone". The neurophysiological method for assessing the functional state of the brain involved the registration of CEP, event-related (P300 CEP). Results. The selection of a subgroup of patients with PCS, characterized by a predominance of cognitive impairments, allowed us to trace the relationship between the results of neurophysiological studies with the cognitive indicators of patients with BMTBI. P300 latency indices are inversely proportional to cognitive assessment the questionnaire "Cicerone" and statistically significantly depend on the severity of cognitive impairment. Conclusions. The CEP P300 method can be an effective means of objectifying the degree of cognitive impairment in patients with PCS due to BMTBI.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows. Specifically, many peripheral measures of auditory function either recover or exhibit subclinical deficits, masking deficits in processing complex, real-world stimuli that may recover differently. Thus, examining the acute time course and pattern of neurophysiological impairment using appropriate stimuli is critical to better understanding and intervening in bTBI-induced auditory system impairments. Here, we compared auditory brainstem response, middle-latency auditory-evoked potentials, and envelope following responses. Stimuli were clicks, tone pips, amplitude-modulated tones in quiet and in noise, and speech-like stimuli (iterated rippled noise pitch contours) in adult male rats subjected to mild blast and sham exposure over the course of 2 mo. We found that blast animals demonstrated drastic threshold increases and auditory transmission deficits immediately after blast exposure, followed by substantial recovery during the window of 7-14 days postblast, although with some deficits remaining even after 2 mo. Challenging conditions and speech-like stimuli can better elucidate mild bTBI-induced auditory deficit during this period. Our results suggest multiphasic recovery and therefore potentially different time windows for treatment, and deficits can be best observed using a small battery of sound stimuli.NEW & NOTEWORTHY Few studies on blast-induced hearing deficits go beyond simple sounds and sparsely track postexposure. Therefore, the recovery arc for potential therapies and real-world listening is poorly understood. Evidence suggested multiple recovery phases over 2 mo postexposure. Hearing thresholds largely recovered within 14 days and partially explained recovery. However, midlatency responses, responses to amplitude modulation in noise, and speech-like pitch sweeps exhibited extended changes, implying persistent central auditory deficits and the importance of subclinical threshold shifts.

Psychosocial impairment following mild blast-induced traumatic brain injury in rats

Traumatic brain injury (TBI) is associated with increased risk for mental health disorders, impacting post-injury quality of life and societal reintegration. TBI is also associated with deficits in psychosocial processing, defined as the cognitive integration of social and emotional behaviors, however little is known about how these deficits manifest and their contributions to post-TBI mental health.In this pre-clinical investigation using rats, a single mild blast TBI (mbTBI) induced impairment of psychosocial processing in the absence of confounding physical polytrauma, post-injury motor deficits, affective abnormalities, or deficits in non-social behavior. Impairment severity correlated with acute upregulations of a known oxidative stress metabolite, 3-hydroxypropylmercapturic acid (3-HPMA), in urine. Resting state fMRI alterations in the acute post-injury period implicated key brain regions known to regulate psychosocial behavior, including orbitofrontal cortex (OFC), which is congruent with our previous report of elevated acrolein, a marker of neurotrauma and 3-HPMA precursor, in this region following mbTBI. OFC of mbTBI-exposed rats demonstrated elevated mRNA expression of metabotropic glutamate receptors 1 and 5 (mGluR1/5) and injection of mGluR1/5-selective agonist in OFC of uninjured rats approximated mbTBI-induced psychosocial processing impairment, demonstrating a novel role for OFC in this psychosocial behavior. Furthermore, OFC may serve as a hotspot for TBI-induced disruption of psychosocial processing and subsequent mental health disorders.

Blast mild traumatic brain injury is associated with increased myopia and chronic convergence insufficiency

While chronic visual symptom complaints are common among Veterans with a history of mild traumatic brain injury (mTBI), research is still ongoing to characterize the pattern of visual deficits that is most strongly associated with mTBI and specifically, the impact of blast-related mTBI on visual functioning. One area that has not been well explored is the potential impact of blast mTBI on refractive error. While myopic shifts have been documented following head injuries in civilian populations, posttraumatic myopic shifts have not been explored in participants with military mTBI. This study investigated the impact of blast mTBIs on a range of visual function measures including distance acuity and refractive error, in a well-characterized cohort of thirty-one Post-9/11 veterans for whom detailed clinical interviews regarding military and TBI history were available. Seventeen participants had a history of blast-related mTBI (blast mTBI + group) while 14 did not (blast mTBI- group). Results show an increased frequency of convergence insufficiency and myopia in the blast mTBI + group relative to the blast mTBI- group. Linear regression analyses further show that deficits in distance acuity and refractive error are associated with the number of blast mTBIs during military service but not the number of non-blast mTBIs or the number of lifetime non-blast TBIs and cannot be accounted for by PTSD. These results are consistent with long-lasting damage following blast mTBI to subcortical visual structures that support both vergence movements and the accommodative functions needed to see clearly objects at varying distances.

Repetitive blast mild traumatic brain injury increases ethanol sensitivity in male mice and risky drinking behavior in male combat veterans.

Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. Both single and repetitive blast-mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH-induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption "front-loading" (e.g., a higher rate of consumption during an initial 2-h acute phase of a 24-h alcohol access period and decreased total daily intake) during an intermittent 2-bottle choice condition. Examination of AUDIT-C scores in Iraq/Afghanistan Veterans revealed an optimal 3-cluster solution: "low" (low intake and low frequency), "frequent" (low intake and high frequency), and "risky" (high intake and high frequency), where Veterans with a history of blast-mTBI displayed a shift in cluster assignment from "frequent" to "risky," as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. Together, these results offer new insight into how blast-mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast-mTBI.

Effects of Selective Serotonin Reuptake Inhibitors on Depression-Like Behavior in a Laser-Induced Shock Wave Model.

Primary blast injury can result in depression-like behavior in the long-term. However, the effects of the selective serotonin reuptake inhibitor (SSRI) on the depression induced by mild blast traumatic brain injury (bTBI) in the long-term remain unclear. We generated a mouse model of mild bTBI using laser-induced shock wave (LISW) and administered an SSRI to mice by oral gavage for 14 days after LISW exposure. This study aimed to investigate the mechanisms of SSRI-mediated alleviation of depression-like behavior induced by mild bTBI. Animals were divided into three groups: sham, LISW-Vehicle, and LISW-SSRI. LISW was applied to the head of anesthetized mice at 0.5 J/cm2. Twenty-eight days after the LISW, mice in the LISW-SSRI group exhibited reduced depression-like behavior, a significant increase in the number of cells co-stained for 5-bromo-2'-deoxyuridine (Brd-U) and doublecortin (DCX) in the dentate gyrus (DG) as well as increased brain-derived neurotrophic factor (BDNF) and serotonin levels in the hippocampus compared to the sham and LISW-Vehicle groups. Additionally, levels of phosphorylated cAMP response element binding protein (pCREB) in the DG were significantly decreased in the LISW-Vehicle group compared to that in the sham group. Importantly, pCREB levels were not significantly different between LISW-SSRI and sham groups suggesting that SSRI treatment may limit the downregulation of pCREB induced by mild bTBI. In conclusion, recovery from depression-like behavior after mild bTBI may be mediated by hippocampal neurogenesis induced by increased BDNF and serotonin levels as well as the inhibition of pCREB downregulation in the hippocampus.

Abstract 17234: Elevated Atherosclerotic Biomarkers in Mice With Mild Blast Traumatic Brain Injury and Chronic Variable Stress

Introduction: Traumatic brain injury (TBI) and stress are significant health concerns that have atherosclerotic cardiovascular disease (ASCVD) effects. Stress and injury can elevate neurochemicals and hormones in the brain that lead to dysfunction of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system increasing inflammation, which plays a role in the development of ASCVD. Animal models can provide a method of separating mild TBI (mTBI) from models of chronic stress. Hypothesis: We hypothesize that mild blast TBI (mbTBI) and chronic variable stress (CVS) will result in elevated ASCVD biomarkers in mice. Methods: Frozen hearts from C57BL/6J mice (8 weeks, N=16, 8 male/8 randomly cycling female) were obtained through an IACUC approved study. The C57BL/6J mice were part of a mild blast TBI (mbTBI) study utilizing a blast chamber to receive a short duration shock wave (<10 msec, mean peak pressure of blast waves 19.9 psi). A group was subjected to CVS for two weeks prior to the blast, plus one week after blast. All groups were followed for four weeks. Western Blots with relative expression (normalized) were performed using an infrared imaging system. ERK1, ERK2, Galactein 3, Endothelin-1, BDNF, NT-Pro-BNP, and NRG1. ANOVA with Tukey HSD correction and descriptive statistics were performed using SPSS with significance by α of 0.05. Results: ERK1: mbTBI and CVS (p<0.05). CVS +mbTBI to CVS (0.015)( p<0.05 ), compared to mbTBI (0.017). ERK2: mbTBI sham = 0.009, CVS only = 0.008, mbTBI only = 0.008 and CVS + mbTBI = 0.012. Galectin-3 (Gal-3): CVS only = 0.144, CVS+mbTBI = 0.168, mbTBI (0.114) to sham (0.111) ( p<0.05 ). NT-Pro-BNP: CVS+mbTBI = 0.168, sham 0.076. mbTBI alone (0.077) and CVS alone (0.078). NRG1: mbTBI (0.195) and mbTBI with CVS (0.178). CVS only group (0.157). ET-1: mbTBI sham = 0.068, CVS only = 0.080 mbTBI only = 0.084 and CVS+mbTBI = 0.134. BDNF: CVS only = 0.053, CVS+mbTBI = 0.069. Sham group (0.047), mbTBI (0.038). Conclusion: Our results on proteins related to a broad spectrum of vascular growth, innervation, function, inflammation and markers of atherosclerotic plaque development suggest that mbTBI and/or chronic stress may increase risk for developing early ASCVD.

Neuropsychiatric Outcomes in UK Military Veterans With Mild Traumatic Brain Injury and Vestibular Dysfunction.

To estimate the frequency of vestibular dysfunction following blunt, blast, and combined blunt and blast mild traumatic brain injury (mTBI) and thereon assess the long-term impact of vestibular dysfunction on neurobehavioral function and disability independently of comorbid psychiatric symptoms. Combat Stress residential and Veterans' Outreach drop-in centers for psychological support. One hundred sixty-two help-seeking UK military veterans. Self-reported frequency and severity of mTBI (using the Ohio State TBI Identification Method), Vertigo Symptom Scale, PTSD Checklist for DSM-5, Kessler Psychological Distress Scale (K10), Neurobehavioral Symptom Inventory, Headache Impact Test (HIT6), Memory Complaints Inventory, World Health Organization Disability Assessment Schedule II short version (WHODAS 2.0). Seventy-two percent of the sample reported 1 or more mTBIs over their lifetime. Chi-square analyses indicated that vestibular disturbance, which affected 69% of participants, was equally prevalent following blunt (59%) or blast (47%) injury and most prevalent following blunt and blast combined (83%). Mediation analysis indicated that when posttraumatic stress disorder, depression, and anxiety were taken into account, vestibular dysfunction in participants with mTBI was directly and independently associated with increased postconcussive symptoms and functional disability. Vestibular dysfunction is common after combined blunt and blast mTBI and singularly predictive of poor long-term mental health. From a treatment perspective, vestibular rehabilitation may provide relief from postconcussive symptoms other than dizziness and imbalance.