The Impact of the COVID-19 Pandemic on Mental Health, Occupational Functioning, and Professional Retention Among Health Care Workers and First Responders.

BACKGROUND: The COVID-19 pandemic has greatly affected front-line health care workers (HCW) and first responders (FR). The specific components of COVID-19 related occupational stressors (CROS) associated with psychiatric symptoms and reduced occupational functioning or retention remain poorly understood. OBJECTIVES: Examine the relationships between total and factored CROS, psychiatric symptoms, and occupational outcomes. DESIGN: Observational, self-report, single time-point online assessment. PARTICIPANTS: A total of 510 US HCW (N = 301) and FR (N = 200) with occupational duties affected by the COVID-19 pandemic. MAIN OUTCOMES AND MEASURES: CROS were assessed using a custom 17-item questionnaire. Post-traumatic stress disorder (PTSD), depression, insomnia, and generalized anxiety symptoms were assessed using the PTSD Checklist-5 (PCL5), Patient Health Questionnaire-9 (PHQ9), Insomnia Severity Index (ISI), and General Anxiety Disorder-7 (GAD7). Respondents' likelihood of leaving current field and occupational functioning were assessed with 2-item PROMIS subscales. Relationships were modeled using multivariable regression. Open-ended responses were coded using rapid template analysis. RESULTS: CROS total scores correlated significantly with all four psychiatric symptom domains (R's = .42-.53), likelihood of leaving one's current occupation (R = .18), and trouble doing usual work (R = .28), all p's < .001. Half of HCW indicated a decreased likelihood of staying in their current occupation as a result of the pandemic. CROS were fit to a 3-factor model consisting of risk, demoralization, and volume factors. All CROS factors were associated with psychiatric symptom burden, but demoralization was most prominently associated with psychiatric symptoms and negative occupational outcomes. Among psychiatric symptoms, PTSD symptoms were most strongly associated with negative occupational outcomes. Open-ended statements emphasized lack of protection and support, increased occupational demands, and emotional impact of work duties. CONCLUSIONS AND RELEVANCE: These results demonstrate potentially treatable psychiatric symptoms in HCW and FR experiencing CROS, impacting both wellbeing and the health care system. Mitigating CROS, particularly by addressing factors driving demoralization, may improve HCW and FR mental health, occupational functioning, and retention.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Posttraumatic Stress Disorder Treatment Effects on Cardiovascular Physiology: A Systematic Review and Agenda for Future Research.

Posttraumatic stress disorder (PTSD) is linked to both altered physiological functioning and poorer cardiovascular health outcomes, including an increased risk for cardiovascular disease and cardiovascular-related mortality. An important question is whether interventions for PTSD might ameliorate the risk for poorer health by improving cardiovascular physiological intermediaries. To begin to characterize the literature addressing this question, we conducted a systematic review of empirical studies examining the impact of PTSD interventions on cardiovascular physiological intermediaries, including blood pressure (BP), heart rate (HR), cardiac impedance, and subclinical atherosclerosis. Outcomes included both tonic (i.e., resting) cardiovascular functioning and cardiovascular reactivity (CVR). A total of 44 studies met the inclusion criteria. There was mixed evidence regarding whether PTSD treatment improved tonic cardiovascular functioning. There was stronger evidence that PTSD treatments reduced CVR to trauma-related stressors, particularly for higher-quality studies of cognitive behavioral interventions. No studies examined cardiac impedance or subclinical atherosclerosis. The studies had a high degree of heterogeneity in the populations sampled and interventions tested. Moreover, they generally included small sample sizes and lacked control conditions. Interventions for PTSD may improve cardiovascular physiological outcomes, particularly CVR to trauma cues, although additional methodologically rigorous studies are needed. We outline changes to future research that would improve the literature regarding this important question, including the more frequent use of control groups and larger sample sizes.

Retrospective and Prospective Memory Among OEF/OIF/OND Veterans With a Self-Reported History of Blast-Related mTBI.

OBJECTIVES: To evaluate prospective and retrospective memory abilities in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans with and without a self-reported history of blast-related mild traumatic brain injury (mTBI). METHODS: Sixty-one OEF/OIF/OND Veterans, including Veterans with a self-reported history of blast-related mTBI (mTBI group; n=42) and Veterans without a self-reported history of TBI (control group; n=19) completed the Memory for Intentions Test, a measure of prospective memory (PM), and two measures of retrospective memory (RM), the California Verbal Learning Test-II and the Brief Visuospatial Memory Test-Revised. RESULTS: Veterans in the mTBI group exhibited significantly lower PM performance than the control group, but the groups did not differ in their performance on RM measures. Further analysis revealed that Veterans in the mTBI group with current PTSD (mTBI/PTSD+) demonstrated significantly lower performance on the PM measure than Veterans in the control group. PM performance by Veterans in the mTBI group without current PTSD (mTBI/PTSD-) was intermediate between the mTBI/PTSD+ and control groups, and results for the mTBI/PTSD- group were not significantly different from either of the other two groups. CONCLUSIONS: Results suggest that PM performance may be a sensitive marker of cognitive dysfunction among OEF/OIF/OND Veterans with a history of self-reported blast-related mTBI and comorbid PTSD. Reduced PM may account, in part, for complaints of cognitive difficulties in this Veteran cohort, even years post-injury. (JINS, 2018, 24, 324-334).

Untangling PTSD and TBI: Challenges and Strategies in Clinical Care and Research.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) can result from similar injuries and can result in similar symptoms, such as problems with sleep, concentration, memory, and mood. Although PTSD and persistent sequelae due to a TBI (PST) have generally been viewed as pragmatically confounded but conceptually separable entities, we examine emerging evidence emphasizing the breadth of overlap in both clinical presentation and underlying pathophysiology between PST and PTSD. RECENT FINDINGS: New evidence underscores the poor specificity of symptoms to etiology and emphasizes the potential, after both physical brain injury and traumatic stress, for changes in each of the three interacting systems that coordinate the body's response to the experience or expectation of major injury-the immune, endocrine, and neuromodulatory neurotransmitter systems. A view of PTSD and PST sharing common pathophysiologic elements related to the CNS response to acute injury or threat carries important implications for research and clinical care.

Two-dimensional electronic spectroscopy using incoherent light: theoretical analysis.

Electronic energy transfer in photosynthesis occurs over a range of time scales and under a variety of intermolecular coupling conditions. Recent work has shown that electronic coupling between chromophores can lead to coherent oscillations in two-dimensional electronic spectroscopy measurements of pigment-protein complexes measured with femtosecond laser pulses. A persistent issue in the field is to reconcile the results of measurements performed using femtosecond laser pulses with physiological illumination conditions. Noisy-light spectroscopy can begin to address this question. In this work we present the theoretical analysis of incoherent two-dimensional electronic spectroscopy, I((4)) 2D ES. Simulations reveal diagonal peaks, cross peaks, and coherent oscillations similar to those observed in femtosecond two-dimensional electronic spectroscopy experiments. The results also expose fundamental differences between the femtosecond-pulse and noisy-light techniques; the differences lead to new challenges and new opportunities.

Poorer prospective memory performance is associated with reduced time monitoring among OEF/OIF/OND Veterans with a history of blast-related mild traumatic brain injury.

Objective:Prospective memory (PM) or "remembering to remember" has been shown to be reduced in Veterans with histories of mild traumatic brain injury (mTBI), particularly on tasks with high strategic demands such as recalling time-based information in the absence of external cues. This study examined whether time monitoring during a PM task was reduced in Veterans with a history of mTBI and was associated with time-based PM performance. Method:Veterans with a history of mTBI (n = 49) and Veterans without a history of TBI (n = 16) completed the Memory for Intentions Screening Test (MIST) as a measure of PM during which their time monitoring (i.e. number of clock checks) was recorded. Results:Adjusting for age, education, depression, and PTSD symptoms, negative binomial regression revealed that the mTBI group checked the clock less frequently compared to the control group (Cohen's d = 0.84, p = 0.005). Within the mTBI group, less frequent time monitoring across the entire MIST task was associated with poorer time-based MIST performance (rs = .57, p < 0.001), but not with event-based MIST (rs = .04, p = 0.768). Conclusions:Veterans with a history of mTBI evidenced significantly reduced time monitoring during a PM task compared to Veterans without a history mTBI, which was associated with strategically-demanding PM. Current findings provide that mTBI-associated difficulties with strategic aspects of PM may be due to reduced time monitoring. Future studies are needed to determine if reduced time monitoring also contributes to mTBI-associated PM difficulties in the real-world (e.g. medication non-adherence).

The relative contribution of COVID-19 infection versus COVID-19 related occupational stressors to insomnia in healthcare workers.

Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burden and occupational attrition during the COVID-19 pandemic. Identifying contributory factors can inform prevention and mitigation measures. Here, we explore the potential contributions of occupational stressors vs COVID-19 infection to insomnia symptoms in US healthcare workers.Patients/Methods: An online self-report survey was collected between September 2020 and July 2022 from N = 594 US healthcare workers, with longitudinal follow-up up to 9 months. Assessments included the Insomnia Severity Index (ISI), the PTSD Checklist for DSM-5 (PCL-5), and a 13-item scale assessing COVID-19 related occupational stressors. Results: Insomnia was common (45% of participants reported at least moderate and 9.2% reported severe symptoms at one or more timepoint) and significantly associated with difficulty completing work-related tasks, increased likelihood of occupational attrition, and thoughts of suicide or self-harm (all p<.0001). In multivariable regression with age, gender, and family COVID-19 history as covariates, past two-week COVID-related occupational stressors, peak COVID-related occupational stressors, and personal history of COVID-19 infection were all significantly related to past two-week ISI scores (ß = 1.7 ± 0.14SE, ß = 0.08 ± 0.03, and ß = 0.69 ± 0.22 respectively). Although similar results were found for the PCL-5, when ISI and PCL-5 items were separated by factor, COVID-19 infection was significantly related only to the factor consisting of sleep-related items. Conclusions: Both recent occupational stress and personal history of COVID-19 infection were significantly associated with insomnia in healthcare workers. These results suggest that both addressing occupational stressors and reducing rate of COVID-19 infection are important to protect healthcare workers and the healthcare workforce.

A randomized controlled clinical trial of prazosin for alcohol use disorder in active duty soldiers: Predictive effects of elevated cardiovascular parameters.

BACKGROUND: Excessive noradrenergic signaling contributes to aversive symptoms of alcohol withdrawal that interfere with abstinence or reductions in harmful use. METHODS: To address this aspect of alcohol use disorder, 102 active-duty soldiers participating in command-mandated Army outpatient alcohol treatment were randomized to also receive the brain-penetrant alpha-1 adrenergic receptor antagonist prazosin or placebo for 13 weeks. Primary outcomes were scores on the Penn Alcohol Craving Scale (PACS), standard drink units (SDUs) per day averaged over each week, % days of any drinking per week, and % days of heavy drinking per week. RESULTS: PACS declines did not differ significantly between the prazosin and placebo groups in the overall sample. In the subgroup with comorbid PTSD (n = 48), PACS declines were significantly greater in the prazosin than in the placebo condition (p < 0.05). Baseline alcohol consumption was markedly reduced by the pre-randomization outpatient alcohol treatment program, but the addition of prazosin treatment produced a greater slope of decline in SDUs per day compared to placebo (p = 0.01). Preplanned subgroup analyses were performed in soldiers with elevated baseline cardiovascular measures consistent with increased noradrenergic signaling. In soldiers with elevated standing heart rate (n = 15), prazosin reduced SDUs per day (p = 0.01), % days drinking (p = 0.03), and % days heavy drinking (p = 0.001) relative to placebo. In soldiers with elevated standing systolic blood pressure (n = 27), prazosin reduced SDUs per day (p = 0.04) and tended to reduce % days drinking (p = 0.056). Prazosin also reduced depressive symptoms and the incidence of emergent depressed mood more than placebo (p = 0.05 and p = 0.01, respectively). During the final 4 weeks of prazosin vs. placebo treatment that followed completion of Army outpatient AUD treatment, alcohol consumption in soldiers with elevated baseline cardiovascular measures increased in those receiving placebo but remained suppressed in those receiving prazosin. CONCLUSIONS: These results extend reports that higher pretreatment cardiovascular measures predict beneficial effects of prazosin, which may be useful for relapse prevention in patients with AUD.

The relative contribution of COVID-19 infection versus COVID-19 related occupational stressors to insomnia in healthcare workers.

Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burden and occupational attrition during the COVID-19 pandemic. Identifying contributory factors can inform prevention and mitigation measures. Here, we explore the potential contributions of occupational stressors vs COVID-19 infection to insomnia symptoms in US healthcare workers. Patients/Methods: An online self-report survey was collected between September 2020 and July 2022 from N=594 US healthcare workers, with longitudinal follow-up up to 9 months. Assessments included the Insomnia Severity Index (ISI), the PTSD Checklist for DSM-5 (PCL-5), and a 13-item scale assessing COVID-19 related occupational stressors. Results: Insomnia was common (45% of participants reported at least moderate and 9.2% reported severe symptoms at one or more timepoint) and significantly associated with difficulty completing work-related tasks, increased likelihood of occupational attrition, and thoughts of suicide or self-harm (all p<.0001). In multivariable regression with age, gender, and family COVID-19 history as covariates, past two-week COVID-related occupational stressors, peak COVID-related occupational stressors, and personal history of COVID-19 infection were all significantly related to past two-week ISI scores (ß=1.7±0.14SE, ß=0.08±0.03, and ß=0.69±0.22 respectively). Although similar results were found for the PCL-5, when ISI and PCL-5 items were separated by factor, COVID-19 infection was significantly related only to the factor consisting of sleep-related items. Conclusions: Both recent occupational stress and personal history of COVID-19 infection were significantly associated with insomnia in healthcare workers. These results suggest that both addressing occupational stressors and reducing rates of COVID-19 infection are important to protect healthcare workers and the healthcare workforce.

The Relative Effects of Prazosin on Individual PTSD Symptoms: Evidence for Pathophysiologically-Related Clustering.

BACKGROUND: The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α1-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined. METHODS: In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple comparisons. RESULTS: Prazosin showed the largest effect for distressing dreams, anhedonia, difficulty falling or staying asleep, difficulty concentrating, and hypervigilance. These items were also (a) of higher baseline severity in the underlying population, and (b) more related in how they fluctuated at the level of individual subjects. Covariance analysis did not support a clear cutoff between highly prazosin responsive items and those showing a smaller, not statistically significant response. CONCLUSIONS: In this data set, twice daily prazosin substantially reduced not only nightmares and sleep disruption, but the majority of hyperarousal symptoms, with some evidence of efficacy for avoidance symptoms. The relationship of baseline symptom distribution to which symptoms showed significant response to prazosin reinforces the possibility that differences in a clinical trial's participant populations may significantly influence trial outcome. The pattern of symptom endorsement at the level of individual subjects was consistent with prazosin-responsive items sharing a common pathophysiologic mechanism.

Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice.

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Optimizing Aggregated N-Of-1 Trial Designs for Predictive Biomarker Validation: Statistical Methods and Theoretical Findings.

Background and Significance: Parallel-group randomized controlled trials (PG-RCTs) are the gold standard for detecting differences in mean improvement across treatment conditions. However, PG-RCTs provide limited information about individuals, making them poorly optimized for quantifying the relationship of a biomarker measured at baseline with treatment response. In N-of-1 trials, an individual subject moves between treatment conditions to determine their specific response to each treatment. Aggregated N-of-1 trials analyze a cohort of such participants, and can be designed to optimize both statistical power and clinical or logistical constraints, such as allowing all participants to begin with an open-label stabilization phase to facilitate the enrollment of more acutely symptomatic participants. Here, we describe a set of statistical simulation studies comparing the power of four different trial designs to detect a relationship between a predictive biomarker measured at baseline and subjects' specific response to the PTSD pharmacotherapeutic agent prazosin. Methods: Data was simulated from 4 trial designs: (1) open-label; (2) open-label + blinded discontinuation; (3) traditional crossover; and (4) open label + blinded discontinuation + brief crossover (the N-of-1 design). Designs were matched in length and assessments. The primary outcome, analyzed with a linear mixed effects model, was whether a statistically significant association between biomarker value and response to prazosin was detected with 5% Type I error. Simulations were repeated 1,000 times to determine power and bias, with varied parameters. Results: Trial designs 2 & 4 had substantially higher power with fewer subjects than open label design. Trial design 4 also had higher power than trial design 2. Trial design 4 had slightly lower power than the traditional crossover design, although power declined much more rapidly as carryover was introduced. Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open label titration phase may provide superior power over open label or open label and blinded discontinuation designs, and similar power to a traditional crossover design, in detecting an association between a predictive biomarker and the clinical response to the PTSD pharmacotherapeutic prazosin. This is achieved while allowing all participants to spend the first 8 weeks of the trial on open-label active treatment.

Effect of blast-related mTBI on the working memory system: a resting state fMRI study.

Reduced working memory is frequently reported by Veterans with a history of blast-related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory.

Chronic elevation of plasma vascular endothelial growth factor-A (VEGF-A) is associated with a history of blast exposure.

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.

Inhibition shapes sex selectivity in the mouse accessory olfactory bulb.

Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhibition resulted in a shift in many neurons' stimulus selectivities. Finally, we found that a behavioral response (pregnancy block) evoked by the presence of unfamiliar male urine could be suppressed by the addition of female urine to the stimulus, demonstrating that this system displays a behavioral opponency consistent with neural inhibition. Together, these results indicate that laterally connected inhibitory circuitry in the accessory olfactory bulb plays an important role in shaping neural selectivity for natural stimuli.

Variables associated with subjective cognitive change among Iraq and Afghanistan war Veterans with blast-related mild traumatic brain injury.

Introduction: This study investigated variables associated with subjective decline in executive function among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) following a history of blast-related mild traumatic brain injury (mTBI). Method: Fifty-six male U.S. Veterans (MAge = 35.3 ± 8.8 years) with a history of blast-related mTBI (6.6 ± 3.2 years post injury) completed a battery of self-report questionnaires and neuropsychological measures. Participants rated current and retrospectively estimated pre-mTBI executive function difficulties on the Frontal Systems Behavior Scale (FrSBe). A difference score (post- minus pre-mTBI ratings) was the dependent variable (∆FrSBe). Linear regression models examined variables predicting ∆FrSBe, including: pre-injury characteristics (education, premorbid intelligence), injury-related characteristics (number of blast exposures, losses of consciousness), post-injury clinical symptoms (PTSD Checklist-Military version; Pittsburgh Sleep Quality Index), and post-injury neuropsychological performances on executive function measures (Trail Making Test Part B; Controlled Oral Word Association Test; Auditory Consonant Trigrams; Wisconsin Card Sorting Test). Results: While 11% of participants had a clinically elevated pre-injury FrSBe total score, 82% had a clinically elevated post-injury FrSBe total score. Only self-reported PTSD symptom severity independently predicted perceived change in executive function. Conclusions: Many OEF/OIF/OND Veterans with a history of blast-related mTBI experience subjective decline in executive function following injury. Perceived executive function decline was associated with higher PTSD symptom severity, aligning with previous research associating PTSD with cognitive complaints. Results did not support a correspondence between perceived cognitive change and neuropsychological performances.

Fatigue - but not mTBI history, PTSD, or sleep quality - directly contributes to reduced prospective memory performance in Iraq and Afghanistan era Veterans.

OBJECTIVE: Memory problems that affect daily functioning are a frequent complaint among Veterans reporting a history of repetitive mild traumatic brain injury (mTBI), especially in cohorts with comorbid PTSD. Here, we test the degree to which subjective sleep impairment and daytime fatigue account for the association of PTSD and self-reported mTBI history with prospective memory. METHOD: 82 Veterans with and without personal history of repeated blast-related mTBI during deployment were administered the Clinician Administered PTSD Scale (CAPS), Memory for Intentions Test (MIST), Patient Health Questionnaire-9 (PHQ-9), Neurobehavioral Symptom Inventory (NSI), and the Pittsburgh Sleep Quality Index (PSQI). Relationships between self-reported mTBI, PTSD, self-reported poor sleep and daytime fatigue, and MIST performance were modeled using partial least squares structural equation modeling (PLS-SEM). RESULTS: Reported daytime fatigue was strongly associated with poorer prospective memory performance. Poor subjective sleep quality was strongly and positively associated with reported daytime fatigue, but had no significant direct effect on prospective memory performance. PTSD diagnosis and self-reported mTBI history were only associated with prospective memory via their impact on subjective sleep quality and daytime fatigue. CONCLUSIONS: Results suggest that daytime fatigue may be a mediating factor by which both mTBI and PTSD can interfere with prospective memory. Additional attention should be given to complaints of daytime fatigue, independent of subjective sleep quality, in the clinical care of those with a self-reported history of mTBI, and/or PTSD. Further research into whether interventions that decrease daytime fatigue lead to improvement in prospective memory and subjective cognitive functioning is warranted.

Evidence for altered brain reactivity to norepinephrine in Veterans with a history of traumatic stress.

BACKGROUND: Increases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). This increased signaling may result from increased norepinephrine (NE) release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. METHODS: Using a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF). CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS), which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS) and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]). Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. RESULTS: Fifty-two Veterans met criteria for a history of trauma exposure; of these, 36 met criteria for PTSD. CSF NE levels were not significantly different in Veterans with a history of trauma compared to those without, nor in Veterans with PTSD as compared to those without. Veterans with a history of trauma and who were not using the medication prazosin demonstrated a significantly more positive correlation between CSF NE and behavioral symptom expression than Veterans who had not experienced traumatic stress. No relationship between CSF NE and behavioral symptom expression was found in Veterans who had experienced traumatic stress and were taking prazosin at the time of the assessments. CONCLUSIONS: These results are consistent with increased central nervous system responsiveness to noradrenergic signaling in individuals with a history of traumatic exposure, raising the possibility that there may be long-lasting physiologic effects of trauma-exposure that exist independently of whether an individual meets criteria for PTSD at any given point in time. Exploration of the mechanism by which brain responsiveness to NE is modulated following trauma holds the possibility of finding new strategies for both preventing and treating PTSD.