Impact of Prior Brain Injury on Concussion Recovery in Military Personnel: Evaluation of Timing Between Concussions.

OBJECTIVE: To evaluate the potential impact of timing between the current and the most recent previous concussions on symptom severity among acutely concussed active duty military Service members (SMs). SETTING: Three military installations. PARTICIPANTS: Eighty-four SMs aged 18 to 44 years who sustained a concussion within 72 hours of enrollment. No previous concussion within 1 year preenrollment. DESIGN: Longitudinal study with enrollment within 72 hours of injury, and follow-up at 1 week and 1 month postinjury. MAIN MEASURES: Lifetime concussion history (yes/no) and recency of the latest concussion (no history, relatively more recent [1 to <6 years ago], and more remote [6+ years ago]) from the current concussion using the Ohio State University Traumatic Brain Injury Identification Method-Interview Form. Symptom severity (total and by categories: cognitive, affective, somatosensory, vestibular) at all time points using the Neurobehavioral Symptoms Inventory. RESULTS: Concussion history assessed as having any previous concussion was not found significantly related to symptom severity (total or by categories) following a current concussion. However, when timing between concussion was taken into account, time since previous concussion was significantly related to symptomatology, whereby those with relatively more recent previous concussion had greater total symptoms within 72 hours of injury and at 1 week postinjury (though not at 1 month) than those with more remote previous concussion (≤72 hours: difference = 15.4, 95% CI = 1.8 to 29.1; 1 week: difference = 15.2, 95% CI = 1.2 to 29.2) or no history (≤72 hours: difference = 11.6, 95% CI = 0.4 to 22.8; 1 week: difference = 13.9, 95% CI = 2.4 to 25.4). When evaluated by symptom category, this relationship was particularly important on affective and somatosensory symptoms. CONCLUSION: In recently concussed active duty SMs, the timing between the current and previous concussions may be an important factor in determining prognosis. Clinical assessment of concussion history that accounts for the timing of the most recent event may be necessary to identify patients who may require a more conservative plan of care and more gradual return to activity in the acute recovery stage.

Profile Analysis of the Neurobehavioral and Psychiatric Symptoms Following Combat-Related Mild Traumatic Brain Injury: Identification of Subtypes.

OBJECTIVE: To explore the taxonomy of combat-related mild traumatic brain injury (mTBI) based on symptom patterns. PARTICIPANTS: Up to 1341 military personnel who experienced a combat-related mTBI within 2 years of evaluation. MEASURES: Neurobehavioral Symptom Inventory and PTSD Checklist-Civilian Version (PCL-C). RESULTS: Cluster analysis revealed the following 4 subtypes: primarily psychiatric (posttraumatic stress disorder) group, a cognitive group, a mixed symptom group, and a good recovery group. The posttraumatic stress disorder cluster (21.9% of the sample) reported symptoms related to hyperarousal and dissociation/depression with few complaints related to cognition or headaches. The cognitive group (21.5% of the sample) had primarily cognitive and headache complaints with few mood symptoms. The mixed profile cluster included 18.6% of the sample and was characterized by a combination of mood complaints (hyperarousal and dissociation/depression), cognitive complaints, and headaches. The largest cluster (37.8% of the sample) had an overall low symptom profile and was labeled the "good recovery" group. CONCLUSIONS: The results support a unique taxonomy for combat-related mTBI. The clinical differences among these subtypes indicate a need for unique treatment resources and programs.

Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration.

Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound.

Feasibility of At-Home Serial Testing Using Over-the-Counter SARS-CoV-2 Tests With a Digital Smartphone App for Assistance: Longitudinal Cohort Study.

BACKGROUND: The ongoing SARS-CoV-2 pandemic necessitates the development of accurate, rapid, and affordable diagnostics to help curb disease transmission, morbidity, and mortality. Rapid antigen tests are important tools for scaling up testing for SARS-CoV-2; however, little is known about individuals' use of rapid antigen tests at home and how to facilitate the user experience. OBJECTIVE: This study aimed to describe the feasibility and acceptability of serial self-testing with rapid antigen tests for SARS-CoV-2, including need for assistance and the reliability of self-interpretation. METHODS: A total of 206 adults in the United States with smartphones were enrolled in this single-arm feasibility study in February and March 2021. All participants were asked to self-test for COVID-19 at home using rapid antigen tests daily for 14 days and use a smartphone app for testing assistance and to report their results. The main outcomes were adherence to the testing schedule, the acceptability of testing and smartphone app experiences, and the reliability of participants versus study team's interpretation of test results. Descriptive statistics were used to report the acceptability, adherence, overall rating, and experience of using the at-home test and MyDataHelps app. The usability, acceptability, adherence, and quality of at-home testing were analyzed across different sociodemographic, age, and educational attainment groups. RESULTS: Of the 206 enrolled participants, 189 (91.7%) and 159 (77.2%) completed testing and follow-up surveys, respectively. In total, 51.3% (97/189) of study participants were women, the average age was 40.7 years, 34.4% (65/189) were non-White, and 82% (155/189) had a bachelor's degree or higher. Most (n=133/206, 64.6%) participants showed high testing adherence, meaning they completed over 75% of the assigned tests. Participants' interpretations of test results demonstrated high agreement (2106/2130, 98.9%) with the study verified results, with a κ score of 0.29 (P<.001). Participants reported high satisfaction with self-testing and the smartphone app, with 98.7% (157/159) reporting that they would recommend the self-test and smartphone app to others. These results were consistent across age, race/ethnicity, and gender. CONCLUSIONS: Participants' high adherence to the recommended testing schedule, significant reliability between participants and study staff's test interpretation, and the acceptability of the smartphone app and self-test indicate that self-tests for SARS-CoV-2 with a smartphone app for assistance and reporting is a highly feasible testing modality among a diverse population of adults in the United States.

The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology.

The possibility of mass exposure to nerve agents by a terrorist attack necessitates the availability of antidotes that can be effective against nerve agent toxicity even when administered at a relatively long latency after exposure, because medical assistance may not be immediately available. Nerve agents induce status epilepticus (SE), which can cause brain damage or death. Antagonists of kainate receptors that contain the GluK1 (formerly known as GluR5) subunit (GluK1Rs) are emerging as a new potential treatment for SE and epilepsy from animal research, whereas clinical trials to treat pain have shown that the GluK1/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] is safe and well tolerated. Therefore, we tested whether LY293558 is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure, in rats. LY293558 stopped seizures induced by soman and reduced the total duration of SE, monitored by electroencephalographic recordings within a 24 h-period after exposure. In addition, LY293558 prevented neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area on both days 1 and 7 after soman exposure and reduced neuronal degeneration in the CA1, CA3, and hilar hippocampal regions, entorhinal cortex, amygdala, and neocortex on day 1 after exposure and in the CA1, CA3, amygdala, and neocortex on day 7 after exposure. It also prevented the delayed loss of glutamic acid decarboxylase-67 immuno-stained BLA interneurons on day 7 after exposure. LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration.

Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis.

An episode of status epilepticus (SE), if left untreated, can lead to death, or brain damage with long-term neurological consequences, including the development of epilepsy. The most common first-line treatment of SE is administration of benzodiazepines (BZs). However, the efficacy of BZs in terminating seizures is reduced with time after the onset of SE; this is accompanied by a reduced efficacy in protecting the hippocampus against neuronal damage, and is associated with impaired function and internalization of hippocampal GABA(A) receptors. In the present study, using Fluoro-Jade C staining, we found that administration of diazepam to rats at 3 h after the onset of kainic acid-induced SE, at a dose sufficient to terminate SE, had no protective effect on the hippocampus, but produced a significant reduction in neuronal degeneration in the amygdala, piriform cortex, and endopiriform nucleus, examined on days 7-9 after SE. Thus, in contrast to the hippocampus, the amygdala and other limbic structures are responsive to neuroprotection by BZs after prolonged SE, suggesting that GABA(A) receptors are not significantly altered in these structures during SE.

Activity Level and Type During Post-acute Stages of Concussion May Play an Important Role in Improving Symptoms Among an Active Duty Military Population.

Background: Previous research demonstrates that early rest and gradual increases in activity after concussion can improve symptoms; however, little is known about the intensity and type of activity during post-acute time periods-specifically months post-injury-that may promote optimal recovery in an active duty service member (SM) population. Objective: The objectives of this study were to investigate how activity level and type at the post-acute stages of concussion (at 1 and 3 month[s] post-injury) impact subsequent symptoms among SMs, and how this relationship might differ by the level of symptoms at the time of injury. Methods: Participants included 39 SMs ages 19-44 years from 3 military installations who were enrolled within 72 h after sustaining a concussion. Linear regression was used to evaluate whether the association between activity level at 1 or 3 month(s) post-injury (as measured by a multi-domain Activity Questionnaire) and subsequent symptoms at 3 and/or 6 months (as measured by the Neurobehavioral Symptom Inventory) varied by the level of symptoms at acute stages of concussion. Partial correlation was used to evaluate relationships that did not differ by acute symptom level. Symptoms at the time of activity assessment (1 or 3 month[s]) were accounted for in all models, as well as activity level at acute stages of concussion. Results: Greater physical and vestibular/balance activity at 1 month were significantly correlated with lower symptoms at 3 months, but not at 6 months post-injury. There were no significant associations found between activity (total or by type) at 3 months and symptoms at 6 months. The association between activity level at either 1 or 3 months and subsequent symptoms at 3 and/or 6 months did not differ by the level of acute symptoms. Conclusion: The intensity and type of activities in which SMs engage at post-acute stages of concussion may impact symptom recovery. Although low levels of activity have been previously shown to be beneficial during the acute stage of injury, higher levels of activity may provide benefit at later stages. These findings provide support for the importance of monitoring and managing activity level beyond the acute stage of concussion.

Use of the Progressive Return to Activity Guidelines May Expedite Symptom Resolution After Concussion for Active Duty Military.

BACKGROUND: Clinical recommendations for concussion management encourage reduced cognitive and physical activities immediately after injury, with graded increases in activity as symptoms resolve. Empirical support for the effectiveness of such recommendations is needed. PURPOSE: To examine whether training medical providers on the Defense and Veterans Brain Injury Center's Progressive Return to Activity Clinical Recommendation (PRA-CR) for acute concussion improves patient outcomes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study was conducted from 2016 to 2018 and compared patient outcomes before and after medical providers received an educational intervention (ie, provider training). Patients, recruited either before or after intervention, were assessed at ≤72 hours, 1 week, 1 month, 3 months, and 6 months after a concussion. The participant population included 38 military medical providers and 106 military servicemembers with a diagnosed concussion and treated by one of the military medical providers: 58 patient participants received care before the intervention (ie, provider training) and 48 received care after intervention. The primary outcome measure was the Neurobehavioral Symptom Inventory. RESULTS: The patients seen before and after the intervention were predominantly male (89.7% and 93.8%, respectively) of military age (mean ± SD, 26.62 ± 6.29 years and 25.08 ± 6.85 years, respectively) and a mean ± SD of 1.92 ± 0.88 days from injury. Compared with patients receiving care before intervention, patients receiving care after intervention had smaller increases in physical activities (difference in mean change; 95% CI, 0.39 to 6.79) and vestibular/balance activities (95% CI, 0.79 to 7.5) during the first week of recovery. Although groups did not differ in symptoms at ≤72 hours of injury (d = 0.22; 95% CI, -2.21 to 8.07), the postintervention group reported fewer symptoms at 1 week (d = 0.61; 95% CI, 0.52 to 10.92). Postintervention patients who completed the 6-month study had improved recovery both at 1 month (d = 1.55; 95% CI, 5.33 to 15.39) and 3 months after injury (d = 1.10; 95% CI, 2.36 to 11.55), but not at 6 months (d = 0.35; 95% CI, 5.34 to 7.59). CONCLUSION: Training medical providers on the PRA-CR for management of concussion resulted in expedited recovery of patients.

Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy.

Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE), which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays a major role in the initial pathological and pathophysiological damage. This initial damage is followed by a latent period, during which there is no seizure activity, yet a number of pathophysiological and structural alterations are taking place in key brain regions, that culminate in the expression of epilepsy. The process by which affected/injured neurons that have survived the acute insult, along with well-preserved neurons are progressively forming hyperexcitable, epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms of epileptogenesis is crucial for the development of therapeutic interventions that will prevent the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a temporal lobe structure that is most well known for its central role in emotional behavior, also plays a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients, and in animal models of TLE. In addition, because a derangement in the balance between glutamatergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic neuronal circuits, we also review the information available on the role of the glutamatergic and GABAergic systems in epileptogenesis and epilepsy in the amygdala.

A Comparison of Four Computerized Neurocognitive Assessment Tools to a Traditional Neuropsychological Test Battery in Service Members with and without Mild Traumatic Brain Injury.

OBJECTIVE: Computerized neurocognitive assessment tools (NCATS) are often used as a screening tool to identify cognitive deficits after mild traumatic brain injury (mTBI). However, differing methodology across studies renders it difficult to identify a consensus regarding the validity of NCATs. Thus, studies where multiple NCATs are administered in the same sample using the same methodology are warranted. METHOD: We investigated the validity of four NCATs: the ANAM4, CNS-VS, CogState, and ImPACT. Two NCATs were randomly assigned and a battery of traditional neuropsychological (NP) tests administered to healthy control active duty service members (n = 272) and to service members within 7 days of an mTBI (n = 231). Analyses included correlations between NCAT and the NP test scores to investigate convergent and discriminant validity, and regression analyses to identify the unique variance in NCAT and NP scores attributed to group status. Effect sizes (Cohen's f2) were calculated to guide interpretation of data. RESULTS: Only 37 (0.6%) of the 5,655 correlations calculated between NCATs and NP tests are large (i.e. r ≥ 0.50). The majority of correlations are small (i.e. 0.30 > r ≥ 0.10), with no clear patterns suggestive of convergent or discriminant validity between the NCATs and NP tests. Though there are statistically significant group differences across most NCAT and NP test scores, the unique variance accounted for by group status is minimal (i.e. semipartial R2 ≤ 0.033, 0.024, 0.062, and 0.011 for ANAM4, CNS-VS, CogState, and ImPACT, respectively), with effect sizes indicating small to no meaningful effect. CONCLUSION: Though the results are not overly promising for the validity of the four NCATs we investigated, traditional methods of investigating psychometric properties may not be appropriate for computerized tests. We offer several conceptual and methodological considerations for future studies regarding the validity of NCATs.

Use of a multi-level mixed methods approach to study the effectiveness of a primary care progressive return to activity protocol after acute mild traumatic brain injury/concussion in the military.

The large number of U.S. service members diagnosed with concussion/mild traumatic brain injury each year underscores the necessity for clear and effective clinical guidance for managing concussion. Relevant research continues to emerge supporting a gradual return to pre-injury activity levels without aggravating symptoms; however, available guidance does not provide detailed standards for this return to activity process. To fill this gap, the Defense and Veterans Brain Injury Center released a recommendation for primary care providers detailing a step-wise return to unrestricted activity during the acute phase of concussion. This guidance was developed in collaboration with an interdisciplinary group of clinical, military, and academic subject matter experts using an evidence-based approach. Systematic evaluation of the guidance is critical to ensure positive patient outcomes, to discover barriers to implementation by providers, and to identify ways to improve the recommendation. Here we describe a multi-level, mixed-methods approach to evaluate the recommendation incorporating outcomes from both patients and providers. Procedures were developed to implement the study within complex but ecologically-valid settings at multiple military treatment facilities and operational medical units. Special consideration was given to anticipated challenges such as the frequent movement of military personnel, selection of appropriate design and measures, study implementation at multiple sites, and involvement of multiple service branches (Army, Navy, and Marine Corps). We conclude by emphasizing the need to consider contemporary approaches for evaluating the effectiveness of clinical guidance.

Test-retest reliability of four computerized neurocognitive assessment tools in an active duty military population.

Computerized neurocognitive assessment tools (NCATs) are increasingly used for baseline and post-concussion assessments. To date, NCATs have not demonstrated strong test-retest reliabilities. Most studies have used non-military populations and different methodologies, complicating the determination of the utility of NCATs in military populations. The test-retest reliability of four NCATs (Automated Neuropsychological Assessment Metrics 4 [ANAM4], CNS-Vital Signs, CogState, and Immediate Post-Concussion Assessment and Cognitive Test [ImPACT]) was investigated in a healthy active duty military sample. Four hundred and nineteen Service Members were randomly assigned to take one NCAT and 215 returned after approximately 30 days for retest. Participants deemed to have inadequate effort during one or both testing sessions, according to the NCATs scoring algorithms, were removed from analyses. Each NCAT had at least one reliability score (intraclass correlation) in the "adequate" range (.70-.79), only ImPACT had one score considered "high" (.80-.89), and no scores met "very high" criteria (.90-.99). However, overall test-retest reliabilities in four NCATs in a military sample are consistent with reliabilities reported in the literature and are lower than desired for clinical decision-making.

RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures.

BACKGROUND: Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown. OBJECTIVE: We investigated the mechanism by which RDX induces seizures. METHODS AND RESULTS: By screening the affinity of RDX for a number of neurotransmitter receptors, we found that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric acid type A (GABA(A)) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents. In extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges. CONCLUSIONS: These results suggest that binding to the GABA(A) receptor convulsant site is the primary mechanism of seizure induction by RDX and that reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism of RDX action with respect to seizure induction can guide therapeutic strategies, allow more accurate development of safe thresholds for exposures, and help prevent the development of new explosives or other munitions that could pose similar health risks.

Higher susceptibility of the ventral versus the dorsal hippocampus and the posteroventral versus anterodorsal amygdala to soman-induced neuropathology.

Nerve agents are acetylcholinesterase inhibitors, exposure to which causes brain damage, primarily by inducing intense seizure activity. Knowledge of the brain regions that are most vulnerable to nerve agent-induced brain damage can facilitate the development of drugs targeting the protection of these regions. Both the amygdala and the hippocampus have been shown to suffer significant damage after nerve agent exposure, but the amygdala appears to be the more severely affected structure. However, damage in the amygdala has generally been compared with damage in the dorsal hippocampus, whereas there is evidence that the ventral hippocampus is significantly more susceptible to seizures than the dorsal region and, therefore, it may also be more susceptible to nerve agent-induced neuropathology. Here, we report that after status epilepticus induced by soman administration to rats, neuronal degeneration as assessed by Fluoro-Jade C staining was more extensive in the ventral than the dorsal hippocampal subfields, 1 day after soman exposure. Seven days later, the difference between dorsal and ventral regions was not statistically significant. In the amygdala, soman-induced neurodegeneration was more severe in the posteroventral regions of the lateral, basolateral, and medial nuclei compared to the anterodorsal regions of these nuclei. In contrast, the basomedial nucleus was more severely affected in the anterodorsal region. The extent of neurodegeneration in the amygdala was not significantly different from that in the ventral hippocampus. However, when compared with the whole hippocampus, the amygdala displayed more severe neurodegeneration, on both day 1 and day 7 after soman exposure. Testing the protective efficacy of drugs against nerve agent-induced brain damage should include examination of the ventral hippocampus and the posteroventral regions of the amygdala, as these areas are most vulnerable to nerve agent-induced neurodegeneration.

Primary brain targets of nerve agents: the role of the amygdala in comparison to the hippocampus.

Exposure to nerve agents and other organophosphorus acetylcholinesterases used in industry and agriculture can cause death, or brain damage, producing long-term cognitive and behavioral deficits. Brain damage is primarily caused by the intense seizure activity induced by these agents. Identifying the brain regions that respond most intensely to nerve agents, in terms of generating and spreading seizure activity, along with knowledge of the physiology and biochemistry of these regions, can facilitate the development of pharmacological treatments that will effectively control seizures even if administered when seizures are well underway. Here, we contrast the pathological (neuronal damage) and pathophysiological (neuronal activity) findings of responses to nerve agents in the amygdala and the hippocampus, the two brain structures that play a central role in the generation and spread of seizures. The evidence so far suggests that exposure to nerve agents causes significantly more damage in the amygdala than in the hippocampus. Furthermore, in in vitro brain slices, the amygdala generates prolonged, seizure-like neuronal discharges in response to the nerve agent soman, at a time when the hippocampus generates only interictal-like activity. In vivo experiments are now required to confirm the primary role that the amygdala seems to play in nerve agent-induced seizure generation.