Hallmark Of Posttraumatic Stress Disorder Research Articles

Does enhanced memory of disgust vs. fear images extend to involuntary memory?

ABSTRACT People remember disgusting stimuli better than fearful stimuli, but do disgust’s memory-enhancing effects extend to involuntary memory? This question is important because disgust reactions occur following trauma, and trauma-related involuntary memories are a hallmark of Posttraumatic Stress Disorder (PTSD) symptoms. In two experiments, we presented participants (n = 88 Experiment 1; n = 106 Experiment 2) with disgust, fear, and neutral images during an attention-monitoring task. Participants then completed an undemanding vigilance task, responding any time an image involuntarily came to mind. We measured the frequency and characteristics of these involuntary memories (e.g. emotional intensity) immediately after encoding and over a 24-hour delay (Experiment 2 only). Our main findings were mixed: participants experienced similarly frequent (Experiment 2) – or more (Experiment 1) – disgust as fear involuntary memories. Therefore, when controlling for memory-enhancing confounds (e.g. distinctiveness), in-laboratory disgust memory enhancement does not extend to involuntary memory. Disgust memories were more emotionally intense than fear memories over the 24-hour delay– but not immediately after encoding – suggesting disgust elicits additional consolidation processes to fear. Participants paid more attention towards the disgust images, but the attention did not account for the memory of disgust. In sum, disgust and fear have both similar and distinct cognitive effects.

Objective Sleep Effciency Is Negatively Associated with Resting Heart Rate in Young Trauma-Exposed Women with Poor Sleep

Introduction: Women are twice as likely as men to develop post-traumatic stress disorder (PTSD), a debilitating mental health disorder caused by a traumatic event that can lead to a higher risk of developing cardiovascular disease (CVD). Sleep is currently recognized as an essential component of cardiovascular health by the American Heart Association. Further, a large epidemiological study empirically set the cut-off point for normal sleep effciency (SE) at 83%, differentiating good sleep from poor sleep. Trauma-provoked sleep disturbances such as disruptive nocturnal behaviors and nightmares are a hallmark of PTSD. Yet, the impact of sleep disturbances on cardiovascular biomarkers such as blood pressure (BP) and heart rate (HR) in young trauma-exposed women is unknown. Therefore, the aim of our study was to investigate how objectively recorded sleep measures are associated with HR and BP in these young trauma-exposed women. We hypothesized that sleep quality will predict HR and/or BP, independently of the severity of trauma symptoms. Methods: We recruited 93 trauma-exposed young women (18-40 years). During the in-person visit, we measured BP and HR using an automated vital signs monitor. Additionally, we assessed trauma symptom severity using the PTSD checklist for DSM-5 (PCL5). After the laboratory visit, we sent participants home with a sleep watch (Philips Respironics) for 7 consecutive days, to quantify the percentage of time spent asleep while in bed. Given that a minimum of 83% SE is considered effcient sleep, we separated our data into two groups based on SE [good effciency (SE >83%, n= 42) and poor effciency (SE <83%, n= 51)]. Results: Participants’ mean age and body mass index were 26 ± 7 years and 25.7 ± 6.6 kg/m2 respectively. Pearson correlations revealed a negative correlation between resting HR and SE (r= -0.486, p< 0.001) and HR and age (r= -0.246, p= 0.085) in the SE <83% group. In contrast, there was no correlation between resting HR and SE (r= 0.025, p= 0.861) in the SE >83% group. Therefore, we conducted further analysis in the SE >83% group only. We observed a negative correlation between HR and the trauma symptoms subcluster of hyperarousal (r= -0.285, p= 0.045) in this poor SE group. Next, we ran a multiple linear regression predicting HR with SE, age, and the subclusters of hyperarousal and intrusion (affected by disruptive nocturnal behaviors and nightmares) as predictors. The model predicting HR was significant (R2= 0.366, p< 0.001) and SE remained the strongest predictor (β= -0.458, p= 0.001) even when controlling for age, and trauma symptom subclusters, followed by age (β= -0.263, p= 0.037). Conclusion: Our analyses reveal that sleep effciency in trauma-exposed women is a strong predictor of resting HR, even when controlling for age and trauma symptoms subclusters of intrusion and hyperarousal. These findings suggest that in the context of trauma, it is the reduction in sleep effciency that has the greatest impact on resting heart rate, and ultimately mental health-associated CVD. K01HL161027 and UMN CTSI UL1TR002494 No Disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Validation of the Italian version of the Neuroception of Psychological Safety Scale (NPSS)

Research on the neuroscience of fear in both humans and non-humans has suggested that a lack of acquisition of safety cues might be a biological hallmark of posttraumatic stress disorder (PTSD). Danger perception, and in particular, feeling as one's own life is in danger, is thought to represent a major predictor of PTSD. Persistent danger perception is concurrently associated with a persistence of lack of safety. However, despite several research efforts, no validated psychometric tools exist regarding psychological safety as a unique core construct in the domain of a soothing-contentment system. By including social, compassionate, and bodily components, the Neuroception of Psychological Safety Scale (NPSS), neurophysiologically rooted in the polyvagal theory, aims to specifically assess psychological safety. Originally developed in English, we employed a rather large non clinical sample to validate our Italian translation of the NPSS (n = 338) and the scale was found to retain a three-factor structure. In light of its positive moderate correlations with the Unconditional Self-Kindness Scale (ρ = 0.376) and the Self-Compassion Scale-Short-Form (ρ = 0.481), good convergent validity and robust psychometric properties were shown by the NPSS. The Subjective Traumatic Outlook Questionnaire (ρ = −0.283) and the three subscales of the Body Perception Questionnaire-22—Body Awareness (ρ = −0.103), Supradiaphragmatic Reactivity (ρ = −0.234), and Body Awareness/Subdiaphragmatic Reactivity (ρ = −0.146)—were found to have weak negative correlations with the NPSS, which further demonstrated its good discriminant validity. Eventually, the NPSS was found to show good test-retest reliability (intraclass correlation coefficient = 0.922; three-week time interval), and its usage is fostered in clinical and research contexts where the evaluation of psychological safety is of relevance.

Sleep Disturbances Associated With Posttraumatic Stress Disorder.

Sleep disturbances, namely insomnia and recurrent nightmares, are ubiquitous following trauma exposure and are considered hallmarks of posttraumatic stress disorder (PTSD). Other sleep disorders frequently co-occur with PTSD. This article describes research examining sleep problems most common in PTSD, including prevalence and clinical characteristics. Sleep disturbances are often robust to trauma-focused treatment; thus, evidence for psychological and pharmacological interventions for insomnia and nightmares in PTSD are discussed. Given the high prevalence of sleep problems in PTSD, more work is needed to empirically study putative mechanisms linking trauma exposure and sleep, as well as how to best target these symptoms in patients with PTSD.

0673 Sleep in PTSD: A Subjective Concern

Abstract Introduction Sleep complaints are a hallmark of posttraumatic stress disorder (PTSD). Prior studies examining sleep abnormalities in PTSD are inconsistent, with some reporting objective sleep changes including associated obstructive sleep apnea (OSA), possibly due to moderating variables including advancing age, traumatic brain injury (TBI), and medications. We sought to compare sleep disorders and objective and subjective sleep metrics in service members with and without PTSD while controlling for these potential confounders. Methods Case-controlled observational cohort study performed at an academic military sleep center. Detailed sleep history, sleep-related questionnaires, trauma history, and video-polysomnography was performed. Patients with a history of TBI, abnormal neuroimaging, or psychoactive medication use (antidepressants, antipsychotics, anxiolytics) were excluded. Results Patients (N=169, 124 males) were active duty service members (median age 37.1 years) reporting a sleep complaint. Of these, 43 (25.4%) had PTSD vs 126 (74.6%) without PTSD. In patients with PTSD vs no PTSD, there was no significant difference in the rate of OSA, mean total sleep time, sleep efficiency, mean apnea-hypopnea index, sleep stage percentage, or any other polysomnogram (PSG) variable. Stage N3 sleep was non-significantly increased in patients with PTSD (18% vs 14%, p=0.078). Subjective sleepiness was similar between those with and without PTSD (Epworth Sleepiness Score 12.9 vs 11.9, p=0.35). However, subjective insomnia symptoms (Insomnia Severity Index 20.4 vs 15.2, p< 0.0001) and perceived sleep quality (Pittsburgh Sleep Quality Index 15.4 vs 11.1, p< 0.0001) were worse in those with PTSD vs no PTSD. Conclusion In a relatively young active duty cohort with no history of psychoactive medication use or TBI, patients with PTSD had more subjective sleep complaints than those without PTSD but objective sleep parameters, including PSG variables and OSA rate, did not differ significantly. The higher stage N3 (slow wave) sleep percentage, though not statistically significant, suggests that PTSD patients sleep better in a monitored sleep lab than in their habitual sleeping environment. Support (if any)

Potential Utility of Cannabidiol in Stress-Related Disorders.

Background: The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic-pituitary-adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD). Methods: This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models. Conclusion: Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.

Trauma-induced human glucocorticoid receptor expression increases predict subsequent HPA-axis blunting in a prospective longitudinal design

One of the hallmarks of post-traumatic stress disorder (PTSD) is abnormalities in the HPA-axis. This includes alterations in its negative feedback regulation. Although altered glucocorticoid receptor (GR) mRNA expression is thought to play a crucial role herein, direct longitudinal evidence in humans is lacking to support this assumption. The current prospective longitudinal study assessed the consequence of repeated trauma exposure on GR mRNA expression from saliva samples in early-career police recruits (n = 112) by assessing them before and after trauma exposure. We did not observe a relationship between change in GR mRNA expression and development of PTSD symptom severity. However, the more traumatic events were experienced during police training the stronger GR mRNA expression was increased. Moreover, increases in GR mRNA expression were associated with blunted HPA-axis stress-reactivity at follow-up compared to baseline. This study provides the first longitudinal evidence of a dose-response relationship between trauma and human GR mRNA expression (extracted from saliva) changes; therefore, replication is warranted. Our finding might contribute a possible explanatory framework for blunted HPA-axis function associated with PTSD.

T-lymphocyte tyrosine hydroxylase regulates TH17 T-lymphocytes during repeated social defeat stress

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which results in deleterious changes to psychological and physical health. Patients with PTSD are especially susceptible to life-threatening co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (TH17) lymphocyte-driven inflammation. While the exact mechanism of this increased inflammation is unknown, overactivity of the sympathetic nervous system is a hallmark of PTSD. Neurotransmitters of the sympathetic nervous system (i.e., catecholamines) can alter T-lymphocyte function, which we have previously demonstrated to be partially mitochondrial redox-mediated. Furthermore, we have previously elucidated that T-lymphocytes generate their own catecholamines, and strong associations exist between tyrosine hydroxylase (TH; the rate-limiting enzyme in the synthesis of catecholamines) and pro-inflammatory interleukin 17A (IL-17A) expression within purified T-lymphocytes in a rodent model of psychological trauma. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive TH17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (THT-KO) were subjected to psychological trauma utilizing repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor-α (TNFα), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (TH17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of THT-KO animals. When activated ex vivo, secretion of IL-17A and IL-22 by THT-KO T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, THT-KO T-lymphocytes were still able to polarize to TH17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed THT-KO T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and TH17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced TH17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.

Posttraumatic stress and prenatal care adequacy among Black/African American women

Black/African American women with trauma histories experience a disproportionate burden of adverse perinatal outcomes. One mechanism for this association is inadequate prenatal care, as avoidant symptoms are a hallmark of posttraumatic stress disorder (PTSD). The objective of this study is to examine the association between PTSD symptoms and adequacy of prenatal care among Black/African American women. This retrospective cohort study included all pregnant women who self-identified as Black/African American and were referred to a hospital’s integrated mental health program between 2017-2021. All participants completed a PTSD Checklist -Civilian Version (PCL-C) as a part of an initial mental health evaluation. The EHR was reviewed to codify adequacy of prenatal care, which was assessed in three ways: late initiation of prenatal care (defined as gestational age at the first prenatal visit > 12 weeks), the ratio of no-show to attended prenatal visits, and the Adequacy of Prenatal Care Utilization (APNCU) Index. Bivariable analyses were performed. A propensity score for a positive PTSD screen was generated using confounders generated from a directed acyclic graph. This propensity score was included in multivariable models to control for imbalance across the exposure. Of the 111 women who met inclusion criteria, 57 (51%) screened positive on the PCL-C. Sample characteristics, stratified by a positive screen, are shown in Table 1. PCL-C score was associated with late initiation of prenatal care, the ratio of no-show to attended prenatal visits, and non-adequate prenatal care defined by the APNCU index (Table 2). The associations between late initiation of care and non-adequate APNCU index persisted in multivariable analyses. In this sample of pregnant Black/African American women with an identified mental health condition, PTSD symptoms were associated with inadequate prenatal care. The high prevalence of PTSD symptoms and the association with prenatal care emphasizes the importance of future research focused on trauma-related interventions for Black/African-American women.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Beyond Neuropsychiatric Manifestations of Systemic Lupus Erythematosus: Focus on Post-traumatic Stress Disorder and Alexithymia.

To deepen the comprehension of the role of specific psychological conditions in the pathogenesis and in the treatment of systemic lupus erythematosus (SLE). Specifically, the present comprehensive review aims at examining the association between SLE, alexithymia (AT)-a personality construct referring to the inability to identify, describe, and express sensations, emotions, and physical state-and post-traumatic stress disorder (PTSD), to infer potential biological relationships between these psychopathological issues and disease course, and to draw up a research agenda on gray areas of these topics. Whereas several studies document the presence of neuropsychiatric symptoms in patients with SLE, psychological distress, alexithymia, and post-traumatic manifestations are usually neglected by healthcare professionals and poorly investigated in research contexts. However, the interplay of these aspects, which affect physiologic stress coping mechanisms, potentially plays an important role in SLE pathogenesis. In particular, research documents that cytokine repertoire pattern alteration and hypothalamic-pituitary-adrenal axis impairment leading to inflammation and pain represent the main links between emotional health and immunity. AT and PTSD seem to be common in patients with SLE and account for multiple aspects of SLE-related morbidity. Furthermore, abnormal processing of stressful stimuli as hallmarks of PTSD and AT might promote neuroendocrine dysfunction and dysregulated immunity, thus contributing to the pathogenesis of SLE. A comprehensive, multidisciplinary clinical approach, based on a cooperation between immunologists, rheumatologists, neurologists, and mental health professionals, is crucial to promote patients' global health.

Propranolol rescued secondary trauma induced by immediate extinction

<p id="p00005">One hallmark of posttraumatic stress disorder (PTSD) involves impairments in the ability to extinguish conditioned fear memory. Accumulating evidence suggests that extinction training that occurs shortly after fear conditioning is less effective than delayed extinction training in yielding long-term extinction memory, a phenomenon that is referred to as immediate extinction deficit (IED). However, unknown is whether the IED is just an aberration or continues to affect re-extinction. <p id="p00010">This study revealed that the early extinction intervention after severe trauma may not only fail to inhibit the fear response but also act as a secondary trauma which can continually damage the ability to extinguish fear memory. Propranolol may be a good candidate to repair such damage. Our findings improve our understanding of the pathogenesis of PTSD and outcomes of an early intervention and may be helpful for selecting appropriate and effective interventions after trauma exposure and avoid secondary trauma that is caused by the intervention itself. <p id="p00015">In Experiment 1, 32 Sprague-Dawley rats were randomly divided into four groups (Immediate-Extinction, Immediate-No Extinction, Delayed-Extinction, Delayed-No Extinction) and underwent a standard fear conditioning procedure in which they received five tone-footshock trials in chamber A. After either 1 h (immediate) or 24 h (delayed), half of the animals underwent 30 extinction trials (1^st extinction session) in chamber B where the tone was presented alone. The other half remained in chamber B without any tone or footshock (these animals served as a no-extinction control group). Twenty-four hours later, these rats underwent the 2^nd extinction session (re- extinction) in chamber B. Twenty-four hours after the 2^nd extinction session, the rats were once again returned to chamber B and tested for their fear response to four continuous tones. The fear response was assessed by freezing behavior, and the effect of the 1^st extinction session was assessed by the average freezing response across the first four trials of the 2^nd extinction session. Compared with rats in the delayed extinction group, recently conditioned rats exhibited significantly higher levels of fear in the 2^nd extinction session, although an equivalent decline in freezing was observed in both groups across the 1^st extinction session, suggesting that immediate extinction failed to maintain fear suppression the next day. Furthermore, after undergoing two extinction training sessions, rats in the immediate extinction group exhibited no significant reduction of freezing compared with the non-extinguished control during the retention test, suggesting that the deficit reappeared during re-extinction. <p id="p00020">The aim of Experiment 2 was to investigate whether the deficit that was induced by immediate extinction could be rescued by the β-adrenergic receptor antagonist propranolol. In Experiment 2, 20 Sprague-Dawley rats underwent the same procedures as the immediate extinction groups in Experiment 1, with the exception that they received saline or propranolol (10 mg/kg, i.p.) within minutes after fear conditioning. We found that one injection of propranolol immediately after fear acquisition rescued the deficit of re-extinction but not immediate extinction.

NPY Released From GABA Neurons of the Dentate Gyrus Specially Reduces Contextual Fear Without Affecting Cued or Trace Fear.

Disproportionate, maladapted, and generalized fear are essential hallmarks of posttraumatic stress disorder (PTSD), which develops upon severe trauma in a subset of exposed individuals. Among the brain areas that are processing fear memories, the hippocampal formation exerts a central role linking emotional-affective with cognitive aspects. In the hippocampus, neuronal excitability is constrained by multiple GABAergic interneurons with highly specialized functions and an extensive repertoire of co-released neuromodulators. Neuropeptide Y (NPY) is one of these co-transmitters that significantly affects hippocampal signaling, with ample evidence supporting its fundamental role in emotional, cognitive, and metabolic circuitries. Here we investigated the role of NPY in relation to GABA, both released from the same interneurons of the dorsal dentate gyrus (DG), in different aspects of fear conditioning. We demonstrated that activation of dentate GABA neurons specifically during fear recall reduced cue-related as well as trace-related freezing behavior, whereas inhibition of the same neurons had no significant effects. Interestingly, concomitant overexpression of NPY in these neurons did not further modify fear recall, neither under baseline conditions nor upon chemogenetic stimulation. However, potentially increased co-release of NPY substantially reduced contextual fear, promoted extinction learning, and long-term suppression of fear in a foreground context–conditioning paradigm. Importantly, NPY in the dorsal DG was not only expressed in somatostatin neurons, but also in parvalbumin-positive basket cells and axoaxonic cells, indicating intense feedback and feedforward modulation of hippocampal signaling and precise curtailing of neuronal engrams. Thus, these findings suggest that co-release of NPY from specific interneuron populations of the dorsal DG modifies dedicated aspects of hippocampal processing by sharpening the activation of neural engrams and the consecutive fear response. Since inappropriate and generalized fear is the major impediment in the treatment of PTSD patients, the dentate NPY system may be a suitable access point to ameliorate PTSD symptoms and improve the inherent disease course.

Platelet serotonin concentration and trait aggression in veterans with post-traumatic stress disorder: a preliminary study

Animal and human studies suggest that aggressive behavior may be modulated by brain serotonergic system. Serotonergic (5-HT) dysfunction is associated with post-traumatic stress disorder (PTSD), but also with increased aggression and impulsivity, hallmarks of PTSD. The aim of the study was to investigate the association of platelet 5-HT concentration and various types of aggression and impulsivity in veterans with PTSD. A group of 42 male combat-related PTSD subjects entered the study. Four different aggression facets were measured by the Buss and Perry's Aggression Questionnaire (BPAQ). Verbal and physical types of impulsive aggressive behavior were measured by the subscales of the Žužul's Aggressiveness Inventory A-87. Impulsivity was determined using Eysenck's IVE questionnaire. PTSD severity was evaluated by Watson’s PTSD questionnaire. Platelet serotonin concentration was determined spectrofluorimetrically. Confounding variables were: age, body mass, alcohol use, comorbid depression, and tobacco use. Platelet 5-HT concentration and PTSD severity were independently associated only with impulsive types of aggression, as higher platelet 5-HT concentration and more severe PTSD were related to more impulsive aggression. These results strongly recommend distinguishing between specific types of aggression facets, and advise the importance of theory-based concepts of aggression facets when evaluating the biological correlates of aggression.

020 Sleep Quality Affects the Plasma Exosomal MicroRNA Expression Profile in Military Personnel with Traumatic Brain Injury

Abstract Introduction Disordered sleep is a critical issue facing the US military due to its negative impact on maintaining force readiness, health, and well-being. Traumatic brain injury (TBI) is highly prevalent among military personnel and commonly co-occurs with disturbed sleep: up to 89% of military service members with TBI report poor sleep quality. Disturbed sleep is a hallmark of post-traumatic stress disorder (PTSD), which often coexists with TBI, with upward of 90% of patients with PTSD reporting some form of sleep disturbance. The pathophysiological mechanisms underlying sleep disturbances in TBI patients remain elusive. Exosomal microRNA (exomiRs), which are implicated in intracellular communication, may provide novel insight into molecular networks related to sleep disturbances in TBI patients. Methods ExomiR was extracted from plasma samples of 108 post-9/11 military personnel, and veterans with a history of mild TBI enrolled in a multicenter prospective longitudinal study. ExomiR profiling analysis was conducted using nCounter Human v3 miRNA Expression Panel with 798 microRNA probes. Sleep quality was assessed using the global score on the Pittsburgh Sleep Quality Index (PSQI), and symptoms of PTSD were measured with the PTSD Checklist for DSM-5 (PCL-5). Generalized linear models and Spearman’s correlations were constructed to analyze the relationship between levels of exomiR and global PSQI score. Results We found 17 exomiR that were significantly (P &amp;lt; 0.05) associated with sleep quality and 11 exomiR significantly associated with PTSD symptoms. Two exomiR, has-miR-1268a and has-miR-139-5p, were significantly associated with both sleep quality and PTSD symptoms. The top three significant exomiR associated with sleep quality were hsa-miR-1250-5p (r = 0.2295, p = 0.0171), hsa-miR-3615(r = 0.2207, p = 0.0229), and hsa-miR-122-5p(r = 0.2069, p = 0.0132). Conclusion Overall, these findings suggest that analysis of exosomal miRNA expression may provide novel insights into the underlying pathobiology of sleep quality in military personnel with mild TBI, independent of PTSD symptoms. Further research is needed to understand the biological underpinnings of poor sleep quality in individuals with TBI and to determine causal links. Support (if any) Intramural Research Program at the NINR, Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01 CX001135.

Fear Potentiated Startle to Safety Cues is Related to Anxious Arousal in PTSD

The inability to inhibit fear is a hallmark of posttraumatic stress disorder (PTSD). Prior research has shown that hyperarousal symptoms of PTSD are related to greater fear-potentiated startle (FPS) to safe stimuli, particularly during the middle and late phases of fear acquisition. Factor analysis models of PTSD symptom structure have shown that hyperarousal symptoms can be separated into anxious and dysphoric arousal clusters. This study tested the hypothesis that anxious but not dysphoric arousal symptoms would be significantly related to FPS to safe stimuli (CS-) during middle and late fear acquisition.

Sympathetic Nerves Control Splenic T-Lymphocyte Inflammation and the Mitochondrial Redox Environment During Repeated Social Defeat Stress

Post-traumatic stress disorder (PTSD) is a devastating psychological disorder that increases the risk for autoimmune disease by >3 fold, with the exact etiology still unclear. A known hallmark of PTSD is increased sympathetic tone and norepinephrine (NE) outflow. We have previously demonstrated that exogenous NE induces a pro-inflammatory T-helper 17 (TH17) phenotype in T-lymphocytes through a mitochondrial superoxide-dependent manner. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation.

Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: a combined positron emission tomography and magnetic resonance imaging study in healthy individuals.

BackgroundUpregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control.MethodsThirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using pre-determined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest.ResultsThe strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = −0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05).LimitationsWe did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity.ConclusionOur data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Repetitive Blast Promotes Chronic Aversion to Neutral Cues Encountered in the Peri-Blast Environment.

Repetitive mild traumatic brain injury (mTBI) has been called the "signature injury" of military service members in the Iraq and Afghanistan wars and is highly comorbid with post-traumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Pre-clinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction-but only to the degree by which such models reflect the human experience. Avoidance of trauma reminders is a hallmark of PTSD. Here, we sought to understand whether a mouse model of blast reproduces this phenomenon, in addition to blast-induced physical injuries. Drawing on well-established work from the chronic stress and Pavlovian conditioning literature, we hypothesized that even while one is anesthetized during blast exposure, environmental cues encountered in the peri-blast environment could be conditioned to evoke aversion/dysphoria and re-experiencing of traumatic stress. Using a pneumatic shock tube that recapitulates battlefield-relevant open-field blast forces, we provide direct evidence that stress is inherent to repetitive blast exposure, resulting in chronic aversive/dysphoric-like responses to previous blast-paired cues. The results in this report demonstrate that, although both single and repetitive blast exposures produce acute stress responses (weight loss, corticosterone increase), only repetitive blast exposure also results in co-occurring aversive/dysphoric-like stress responses. These results extend appreciation of the highly complex nature of repetitive blast exposure; and lend further support for the potential translational relevance of animal modeling approaches currently used by multiple laboratories aimed at elucidating the mechanisms (both molecular and behavioral) of repetitive blast exposure.

Neuroimmune Contributions to T-Lymphocyte-Driven Inflammation in a Preclinical Model of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder, and PTSD patients have a >3 fold risk of developing comorbid autoimmune diseases. While the etiology of this increased risk remains unclear, a known hallmark of PTSD is increased sympathetic tone. Therefore, we hypothesized that sympathoexcitation in PTSD may be causally linked to inflammation and the predisposition to autoimmunity.

Neuroimmune Contributions to T‐lymphocyte‐Driven Inflammation in a Preclinical Model of Post‐traumatic Stress Disorder (PTSD)

Post‐traumatic stress disorder (PTSD) is a devastating psychological disorder with an idiopathic etiology. Interestingly, patients with PTSD have a &gt;3 fold risk of developing comorbid autoimmune diseases compared to matched controls, yet, the exact mechanisms underlying this risk remain unclear. A hallmark of PTSD is increased sympathetic tone, and previous work from our lab has shown that immune cells, primarily T‐lymphocytes, display an autoreactive phenotype when exposed to elevated levels of norepinephrine (NE). Therefore, we hypothesized that the sympathoexcitation observed in PTSD may be causally linked to T‐lymphocyte‐driven inflammation and the predisposition to autoimmune diseases. To test this hypothesis, we adapted a preclinical mouse model of PTSD known as social defeat stress. After validating the PTSD‐like behavioral phenotype of our trauma‐exposed mice, we investigated the neuroimmune interactions of T‐lymphocytes in the spleen that may govern the increased predilection for inflammatory diseases in PTSD patients. The spleen is a primary site of adaptive immune system activation, and is innervated exclusively by the sympathetic efferent splenic nerve. Trauma‐exposed animals exhibited a 2.5 fold increase in splenic catecholamines and 4.1 fold increase in splenic tyrosine hydroxylase (TH) content (p&lt;0.05) compared to controls. Additionally, purified splenic T‐lymphocytes from socially‐defeated mice showed elevations in the pro‐inflammatory cytokines interleukin 6 (IL‐6, 1.84 fold increase, p&lt;0.0001) and interleukin 17A (IL‐17A, 5.5 fold increase, p=0.0032). Importantly, TH content was tightly correlated with T‐lymphocyte IL‐6 and IL‐17A expression (R=0.43, p=0.0001 and R=0.87, p&lt;0.0001, respectively), suggesting a neuroimmune mechanism of pro‐inflammation. To test this, we performed targeted splenic denervation to deduce the contribution of the splenic nerve to T‐lymphocyte‐driven inflammation after psychological trauma. Denervation reduced splenic NE content by 80% (p&lt;0.0001), and persisted to at least 30 days after denervation. While splenic denervation did not alter the PTSD‐like behavioral changes after social defeat, denervation ameliorated the characteristic increase in gene expression of splenic T‐lymphocyte IL‐6 and IL‐17A after social defeat stress. Overall, our data suggest that psychological trauma results in altered inflammation through sympathetic modulation of splenic T‐lymphocytes. Further elucidation of this neuroimmune interaction will provide possible new biomarkers or therapeutic strategies to reduce the inflammatory‐driven morbidity and mortality of PTSD patients.Support or Funding InformationNIH R00HL123471, T32NS105594