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INTRODUCTION: Posttraumatic nightmares (PTNs) are common among service members with a history of combat or mission-related trauma and are associated with decreased well-being. Unfortunately, beyond establishing an association between mental health symptoms and PTNs, the existing literature fails to provide a more comprehensive understanding of factors associated with PTNs. The effectiveness of current recommended treatments is frequently debated, with the literature varying in levels of support. Treatment of PTN is complicated, given their association with a number of mental health difficulties including posttraumatic stress disorder (PTSD), anxiety, and depression. The present study sought to better delineate the association of these difficulties with PTNs, in an effort to inform and improve treatments for the nation's service members. MATERIALS AND METHODS: This study utilized de-identified data collected during standard procedures for an interdisciplinary intensive outpatient program for service members with a history of traumatic brain injury and/or psychological health conditions (N = 1,550). Study analyses were performed under a Walter Reed National Military Medical Center institutional review board-approved protocol. Three cross-sectional forward likelihood ratio logistic regressions predicting the presence of PTNs were conducted while controlling for the alpha-blocker prazosin, as it is recommended for the treatment of PTSD-associated nightmares. Separate models were created for posttraumatic stress symptoms (PTSS), depression, and anxiety because of multicollinearity concerns. Additional variables considered for inclusion were psychological symptoms (e.g., suicide ideation, postconcussive symptoms), satisfaction with life, sleep (e.g., pain that disrupts sleep, early awakenings, sleepiness), demographics (e.g., sex, race/ethnicity, marital status, age), and military characteristics (e.g., rank, branch, special operator status, time in service). RESULTS: PTSS (odds ratio [OR]: 1.13), anxiety (OR: 1.19), and depression (OR: 1.19) were associated with increased odds of PTNs when controlling for prazosin. Each of the final models accounted for a significant amount of variance in the presence/absence of PTN. The included variables differed across models. The PTSS model included pain that disrupted sleep, postconcussive symptoms, special operator status, and early awakenings. The anxiety model included postconcussive symptoms, pain that disrupted sleep, special operator status, and prazosin use. The depression model included postconcussive symptoms, pain that disrupted sleep, special operator status, difficulty falling asleep within 30 min, and prazosin use. Although most variables were associated with an increased odds of PTNs, postconcussive symptoms in the PTSS model and special operator status in all 3 models were associated with decreased odds of PTNs. These findings are illustrated in Tables 2 to 4. CONCLUSIONS: Findings support the association of PTSS, anxiety, and depression to PTNs, and, importantly, suggest that other factors may be equally or more important in understanding PTNs. Notably, increased odds of PTNs were observed among patients with pain that disrupts their sleep. The cross-sectional nature of the study allows examination of these co-occurring symptoms as they would present in the clinic, potentially informing assessment and treatment strategies; however, it precludes consideration of temporal relationships. Results highlight the importance of considering comorbid symptoms and relevant military characteristics to gain a more complete understanding of PTNs. Future research utilizing longitudinal methods are needed to inform the temporal/causal aspects of these relationships.

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INTRODUCTION: To address the military gap in the standardized collection of lifetime blast exposures across clinical and research endeavors, researchers at the National Intrepid Center of Excellence (NICoE) completed a quality improvement project that utilized systematic, iterative focus groups that leveraged the input from various stakeholders including subject matter experts, clinical providers, and service members (SMs) to develop a comprehensive, self-report blast exposure inventory that could be completed within 5-10 minutes. This manuscript outlines the process of the development of this inventory. MATERIALS AND METHODS: This project included three phases of focus groups that occurred at the NICoE between August 2020 and March 2021 to collect feedback and input from relevant military stakeholders. The study team utilized related assessments available in the literature, together with clinical experience with the NICoE patient population, to inform the development of an initial draft inventory. Phase 1 consisted of blast injury research subject matter experts who had extensive experience researching and providing clinical care to SMs exposed to blast. Phase 2 consisted of NICoE clinicians across numerous clinical specialties. Phase 3 included current active duty patients in the NICoE intensive outpatient program. RESULTS: Following completion of the focus groups, a lifetime blast exposure inventory was developed in the form of a single page table including incoming, outgoing, training, and operational exposures and broken down by levels of weapon systems as well as breaching and explosive ordnance disposal exposures. In addition, select questions related to the first and most recent blast exposures and experience as an instructor for explosive ordnance disposal- and breaching-related training were included. CONCLUSIONS: Researchers at the NICoE developed a self-report blast exposure inventory through a quality improvement project that included active, ongoing participation and feedback of clinical experts and military SMs. The end result is a brief, single page inventory that can be administered within 5-10 minutes. Although additional research is needed to refine and validate the inventory, the project team believes that the tool begins to address a long-standing gap in the DoD in the standardized collection of lifetime blast exposures.

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Posttraumatic nightmares commonly occur after a traumatic experience. Despite significant deleterious effects on well-being and their role in posttraumatic stress disorder, posttraumatic nightmares remain understudied. The neuroanatomical structures of the amygdala, medial prefrontal cortex, hippocampus, and anterior cingulate cortex constitute the AMPHAC model (Levin and Nielsen, 2007), which is implicated in the neurophysiology of disturbing dreams of which posttraumatic nightmares is a part. However, this model has not been investigated using neuroimaging data. The present study sought to determine whether there are structural differences in the AMPHAC regions in relation to the occurrence of posttraumatic nightmares. Data were obtained from treatment-seeking male active duty service members (N = 351). Posttraumatic nightmares were not significantly related to gray matter volume, cortical surface area, or cortical thickness of any the AMPHAC regions when controlling for age and history of mild traumatic brain injury. Although the present analyses do not support an association between structural measures of AMPHAC regions and posttraumatic nightmares, we suggest that functional differences within and/or between these brain regions may be related to the occurrence of posttraumatic nightmares because functional and structural associations are distinct. Future research should examine whether functional differences may be associated with posttraumatic nightmares.

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Mild (mTBI) traumatic brain injury (TBI) accounts for the majority of all TBI cases. Evidence has suggested that patients with mTBI can suffer from long-lasting cognitive deficits, persistent symptoms, and decreased quality of life. Sleep disorders are commonly observed after TBI, with the prevalence rate of sleep disturbances in persons with TBI being much higher than that in the general population. Poor sleep quality can impair cognitive functions in the general population. This effect of sleep disturbances may impede the recovery processes in the population with TBI. The objective of this study is to add to our understanding of the relationship between self-reported sleep problems and other post-concussion symptoms and look at the association between early sleep problems and long-term outcomes in mTBI. Post-concussion symptoms, neurocognitive functions, level of global outcomes, and rating of satisfaction of life were assessed in 64 patients with mTBI. The results revealed that the presence of sleep disturbances co-occur with an increased level of overall post-concussion symptoms at the subacute stage of mTBI, particularly with symptoms including poor concentration, memory problems, and irritability. In addition, sleep disturbance at the subacute stage is associated with persistent poor concentration and memory problems, as well as worse neurocognitive function, slower overall recovery, and lower satisfactory of life at the long term. Our findings suggest that sleep disturbance can be a prognostic factor of long-term outcomes after mTBI. Early interventions to improve sleep quality can have potential benefits to facilitate the recovery process from mTBI.

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BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is the result of global hypoxic-ischemic brain injury in neonates due to asphyxia during birth and is one of the most common causes of severe, long-term neurologic deficits in children. Methods: Resting state fMRI (rs-fMRI) was used to assess potential functional disruptions in the primary and association motor areas in HIE neonates (n = 16) compared to healthy controls (n = 11). RESULTS: Results demonstrate reduced intra-hemispheric resting state functional connectivity (rs-FC) between primary motor regions (upper extremity and facial motor regions) as well as reduced inter-hemispheric rs-FC in the HIE group. In addition, HIE neonates demonstrated increased rs-FC between motor regions and frontal, temporal and parietal cortices but decreased rs-FC with the cerebellum. DISCUSSION: These preliminary results provide initial evidence for the disruption of functional communication with the motor network in neonates with HIE. Further studies are necessary to both validate these findings in a larger dataset as well as to determine if rs-fMRI measurements collected at birth may have the potential to serve as a prognostic marker in addition to the traditional combination of clinical measurements and conventional MRI.

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Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic interrelationships in service members with and without persistent PTSD symptoms after mTBI by using 18F-fluorodeoxyglucose (FDG) positron emission tomography. Methods: Service members (n = 408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic interrelationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic interrelationships between age-matched PTSD-absent (n = 204) and PTSD-present (n = 204) groups were evaluated. Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in the PTSD-present group had stronger metabolic interrelationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared with the PTSD-absent group. For the top-down control, the PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala. Discussion: Our results suggest altered metabolic interrelationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD. Impact statement This is the first 18F-fluorodeoxyglucose positron emission tomography study to investigate brain metabolic interrelationships in service members with persistent post-traumatic stress disorder (PTSD) symptoms after mild traumatic brain injury (mTBI). We identified that the temporo-limbic metabolic system was associated with post-concussive and hyperarousal symptoms. Further, brain metabolic interrelationships in the cortico-limbic circuitry were altered in mTBI subjects with significant PTSD symptoms compared with those without them.

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INTRODUCTION: Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are common conditions among military personnel that frequently co-occur. This study investigated relationships between self-reported blast exposure, mTBI history, and current post-traumatic stress (PTS) symptoms in a population of active duty service members (n = 202) from the Intensive Outpatient Program at the National Intrepid Center of Excellence. MATERIALS AND METHODS: Participants were divided into four mTBI groups (0, 1, 2, and 3+) and four blast exposure groups (0-10, 11-100, 101-1,000, and 1,000+). Self-reported lifetime mTBI and blast history were obtained via the Ohio State University TBI Identification Method. PTSS severity was obtained via the PTSD Checklist-Civilian version (PCL-C). Several secondary measures of depression, anxiety, chronic mTBI symptoms, and sleep were also assessed. RESULTS: The total PCL-C scores differed significantly between mTBI groups, with significant differences detected between the 0/1 mTBI groups and the 3+ mTBI groups. Similar group differences were noted across the three PCL-C subgroup scores (avoidance, re-experiencing, and hyperarousal); however, when comparing the proportion of group participants meeting DSM-IV criteria for each symptom cluster, significant differences between mTBI groups were only noted for avoidance (P = .002). No group differences were noted in PTS symptom severity or distribution between blast groups. CONCLUSIONS: This study demonstrates an association between lifetime mTBI history and PTS symptom severity and distribution but failed to identify the significant group in self-reported symptoms between the blast exposure groups. Results suggest that additional research is needed to understand the neurobiological mechanism behind these associations and the need for the development of precise assessment tools that are able to more accurately quantify significant lifetime sub-concussive and blast exposures experienced by service members in training and combat operations.

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Objective: To investigate early brain volumetric changes from acute to 6 months following mild traumatic brain injury (mTBI) in deep gray matter regions and their association with patient 6-month outcome.Methods: Fifty-six patients with mTBI underwent MRI and behavioral evaluation at acute (<10 days) and approximately 1 and 6 months post injury. Regional volume changes were investigated in key gray matter regions: thalamus, hippocampus, putamen, caudate, pallidum, and amygdala, and compared with volumes from 34 healthy control subjects. In patients with mTBI, we further assessed associations between longitudinal regional volume changes with patient outcome measures at 6 months including post-concussive symptoms, cognitive performance, and overall satisfaction with life.Results: Reduction in thalamic and hippocampal volumes was observed at 1 month among patients with mTBI. Such volume reduction persisted in the thalamus until 6 months. Changes in thalamic volumes also correlated with multiple symptom and functional outcome measures in patients at 6 months.Conclusion: Our results indicate that the thalamus may be differentially affected among patients with mTBI, resulting in both structural and functional deficits with subsequent post-concussive sequelae and may serve as a biomarker for the assessment of efficacy of novel therapeutic interventions.

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Mild traumatic brain injury (mTBI) is one of the most common neurological disorders for which a subset of patients develops persistent postconcussive symptoms. Previous studies discovered abnormalities and disruptions in the brain functional networks of mTBI patients principally using static functional connectivity measures which assume that neural communication across the brain is static during resting state conditions. In this study, we examine the differences in dynamic neural communication between mTBI and control participants through the application of a combination of dynamic functional analysis and graph theoretic algorithms. Resting state functional magnetic resonance imaging data was obtained on 47 mTBI patients at the acute stage of injury and 30 demographically matched healthy control participants. Results show unique alterations in both the static and dynamic functional connectivity at the acute stage in mTBI patients who suffer persistent symptoms (≥6 months after injury). In addition, mTBI patients with postconcussion syndrome demonstrated a unique allocation of time in various brain states compared to both control participants and mTBI patients with favorable outcomes. These findings suggest that global damage to the overall communication across the brain in the acute stage may contribute to chronic mTBI symptoms. Dynamic functional analysis is a powerful tool that provides insights into the brain states and the innovative analysis methodology utilized may hold the potential to delineate patients predisposed to poor outcomes upon early presentation following injury.

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BACKGROUND: Functional magnetic resonance imaging (fMRI) presents the ability to selectively protect functionally significant regions of the brain when primary brain tumors are treated with radiation therapy. Previous research has focused on task-based fMRI of language and sensory networks; however, there has been limited investigation on the inclusion of resting-state fMRI into the design of radiation treatment plans. METHODS AND MATERIALS: In this pilot study of 9 patients with primary brain tumors, functional data from the default mode network (DMN), a network supporting cognitive functioning, was obtained from resting-state fMRI and retrospectively incorporated into the design of radiation treatment plans. We compared the dosimetry of these fMRI DMN avoidance treatment plans with standard of care treatment plans to demonstrate feasibility. In addition, we used normal tissue complication probability models to estimate the relative benefit of fMRI DMN avoidance treatment plans over standard of care treatment plans in potentially reducing memory loss, a surrogate for cognitive function. RESULTS: On average, we achieved 20% (P = 0.002) and 12% (P = 0.002) reductions in the mean and maximum doses, respectively, to the DMN without compromising the dose coverage to the planning tumor volume or the dose-volume constraints to organs at risk. Normal tissue complication probability models revealed that when the fMRI DMN was considered during radiation treatment planning, the probability of developing memory loss was lowered by more than 20%. CONCLUSION: In this pilot study, we demonstrated the feasibility of including rs-MRI data into the design of radiation treatment plans to spare cognitively relevant brain regions during radiation therapy. These results lay the groundwork for future clinical trials that incorporate such treatment planning methods to investigate the long-term behavioral impact of this reduction in dose to the cognitive areas and their neural networks that support cognitive performance.

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