Traumatic brain injury and sleep in military and veteran populations: A literature review.

BACKGROUND: Traumatic brain injury (TBI) is a hallmark of wartime injury and is related to numerous sleep wake disorders (SWD), which persist long term in veterans. Current knowledge gaps in pathophysiology have hindered advances in diagnosis and treatment. OBJECTIVE: We reviewed TBI SWD pathophysiology, comorbidities, diagnosis and treatment that have emerged over the past two decades. METHODS: We conducted a literature review of English language publications evaluating sleep disorders (obstructive sleep apnea, insomnia, hypersomnia, parasomnias, restless legs syndrome and periodic limb movement disorder) and TBI published since 2000. We excluded studies that were not specifically evaluating TBI populations. RESULTS: Highlighted areas of interest and knowledge gaps were identified in TBI pathophysiology and mechanisms of sleep disruption, a comparison of TBI SWD and post-traumatic stress disorder SWD. The role of TBI and glymphatic biomarkers and management strategies for TBI SWD will also be discussed. CONCLUSION: Our understanding of the pathophysiologic underpinnings of TBI and sleep health, particularly at the basic science level, is limited. Developing an understanding of biomarkers, neuroimaging, and mixed-methods research in comorbid TBI SWD holds the greatest promise to advance our ability to diagnose and monitor response to therapy in this vulnerable population.

Internet-Guided Cognitive Behavioral Therapy for Insomnia Among Patients With Traumatic Brain Injury: A Randomized Clinical Trial.

Importance: Many military service members and veterans report insomnia after sustaining traumatic brain injury (TBI). Limitations of first-line treatment, cognitive-behavioral therapy for insomnia (CBT-I), include availability of qualified clinicians, low completion rates, and cost. Objective: To investigate the feasibility and efficacy of internet-guided CBT-I (eCBT-I) in military service members and veterans with insomnia and a history of TBI. Design, Setting, and Participants: This randomized clinical trial of fully remote internet-based interventions and evaluations was conducted from September 1, 2020, to June 30, 2021, with 3 months of follow-up. Participants included a volunteer sample of military service members and veterans aged 18 to 64 years with a history of mild TBI/concussion and at least moderately severe insomnia defined as an insomnia severity index (ISI) score of greater than 14 and Pittsburgh Sleep Quality Index of greater than 4. Self-reported race, ethnicity, and educational level were generally representative of the US military. Data were analyzed from October 21, 2021, to April 29, 2024. Intervention: Internet-based CBT-I delivered over 6 weekly lesson modules with assigned homework activities. Main Outcomes and Measures: The prespecified primary outcome measure was change in ISI score over time. Prespecified secondary outcome measures included self-reported measures of depression symptoms, posttraumatic stress disorder (PTSD) symptoms, sleep quality, migraine impact, and fatigue. Results: Of 204 people screened, 125 were randomized 3:1 to eCBT-I vs online sleep education, and 106 completed baseline evaluations (83 men [78.3%]; mean [SD] age, 42 [12] years). Of these, 22 participants (20.8%) were Hispanic or Latino and 78 (73.6%) were White. Fifty participants completed postintervention evaluations, and 41 completed the 3-month follow-up. Baseline mean (SD) ISI scores were 19.7 (4.0) in those randomized to eCBT-I and 18.9 (5.0) in those randomized to sleep education. After intervention, mean (SD) ISI scores were 13.7 (5.6) in those randomized to eCBT-I and 16.6 (5.7) in those randomized to sleep education. The difference in the extent of reduction in ISI scores between groups was 3.5 (95% CI,-6.5 to -0.4 [P = .03]; Cohen d, -0.32 [95% CI, -0.70 to -0.04]). In the eCBT-I group, the extent of insomnia improvement correlated with the extent of depressive symptom improvement (Spearman ρ = 0.68 [P < .001]), PTSD symptoms (ρ = 0.36 [P = .04]), sleep quality (ρ = 0.54 [P = .001]), and fatigue impact (ρ = -0.58 [P < .001]) but not migraine-related disability. Conclusions and Relevance: The findings of this randomized clinical trial suggest that fully remote eCBT-I was moderately feasible and effective for self-reported insomnia and depression symptoms in military service members and veterans with a history of TBI. There is great potential benefit for eCBT-I due to low availability and cost of qualified CBT-I clinicians, although optimization of completion rates remains a challenge. Future studies may use home-based objective sleep assessments and should increase study retention. Trial Registration: ClinicalTrials.gov Identifier: NCT04377009.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury.

Importance: Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. Objective: To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Design, Setting, and Participants: This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Exposures: Remote history of mTBI. Main Outcomes and Measures: White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. Results: A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (ß = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (ß = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (ß = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (ß = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (ß = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (ß = 1.2 × 10-3; P = .02). Conclusions and Relevance: In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

Association of Biomarkers of Neuronal Injury and Inflammation With Insomnia Trajectories After Traumatic Brain Injury: A TRACK-TBI Study.

BACKGROUND AND OBJECTIVES: Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories. METHODS: Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics. RESULTS: Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers. DISCUSSION: Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

Subcortical functional connectivity and its association with walking performance following deployment related mild TBI.

Introduction: The relation between traumatic brain injury (TBI), its acute and chronic symptoms, and the potential for remote neurodegenerative disease is a priority for military research. Structural and functional connectivity (FC) of the basal ganglia, involved in motor tasks such as walking, are altered in some samples of Service Members and Veterans with TBI, but any behavioral implications are unclear and could further depend on the context in which the TBI occurred. Methods: In this study, FC from caudate and pallidum seeds was measured in Service Members and Veterans with a history of mild TBI that occurred during combat deployment, Service Members and Veterans whose mild TBI occurred outside of deployment, and Service Members and Veterans who had no lifetime history of TBI. Results: FC patterns differed for the two contextual types of mild TBI. Service Members and Veterans with deployment-related mild TBI demonstrated increased FC between the right caudate and lateral occipital regions relative to both the non-deployment mild TBI and TBI-negative groups. When evaluating the association between FC from the caudate and gait, the non-deployment mild TBI group showed a significant positive relationship between walking time and FC with the frontal pole, implicated in navigational planning, whereas the deployment-related mild TBI group trended towards a greater negative association between walking time and FC within the occipital lobes, associated with visuo-spatial processing during navigation. Discussion: These findings have implications for elucidating subtle motor disruption in Service Members and Veterans with deployment-related mild TBI. Possible implications for future walking performance are discussed.

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).

Association Between Insomnia and Mental Health and Neurocognitive Outcomes Following Traumatic Brain Injury.

We previously described five trajectories of insomnia (each defined by a distinct pattern of insomnia severity over 12 months following traumatic brain injury [TBI]). Our objective in the present study was to estimate the association between insomnia trajectory status and trajectories of mental health and neurocognitive outcomes during the 12 months after TBI. In this study, participants included N = 2022 adults from the Federal Inter-agency Traumatic Brain Injury Repository database and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The following outcome measures were assessed serially at 2 weeks, and 3, 6, and 12 months post-injury: Insomnia Severity Index, Patient Health Questionnaire, Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Patient Reported Outcomes Measurement Information System-Pain, and Quality of Life After Brain Injury-Overall Scale. Neurocognitive performance was assessed at 2 weeks, and 6 and 12 months using the Wechsler Adult Intelligence Scales Processing Speed Index and the Trails Making Test Parts A and B. Results indicated that greater insomnia severity was associated with greater abnormality in mental health, quality of life, and neuropsychological testing outcomes. The pattern of insomnia over time tracked the temporal pattern of all these outcomes for all but a very small number of participants. Notably, severe insomnia at 3 or 6 months post-TBI was a risk factor for poor recovery at 12 months post-injury. In conclusion, in this well-characterized sample of individuals with TBI, insomnia severity generally tracked severity of depression, pain, PTSD, quality of life, and neurocognitive outcomes over 12 months post-injury. More intensive sleep assessment is needed to elucidate the nature of these relationships and to help inform best strategies for intervention.

Traumatic Brain Injury, Sleep, and Melatonin-Intrinsic Changes with Therapeutic Potential.

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity in the United States and is associated with numerous chronic sequelae long after the point of injury. One of the most common long-term complaints in patients with TBI is sleep dysfunction. It is reported that alterations in melatonin follow TBI and may be linked with various sleep and circadian disorders directly (via cellular signaling) or indirectly (via free radicals and inflammatory signaling). Work over the past two decades has contributed to our understanding of the role of melatonin as a sleep regulator and neuroprotective anti-inflammatory agent. Although there is increasing interest in the treatment of insomnia following TBI, a lack of standardization and rigor in melatonin research has left behind a trail of non-generalizable data and ambiguous treatment recommendations. This narrative review describes the underlying biochemical properties of melatonin as they are relevant to TBI. We also discuss potential benefits and a path forward regarding the therapeutic management of TBI with melatonin treatment, including its role as a neuroprotectant, a somnogen, and a modulator of the circadian rhythm.

A randomized sham-controlled clinical trial of a novel wearable intervention for trauma-related nightmares in military veterans.

STUDY OBJECTIVES: Persistent nightmares are common among individuals exposed to trauma and are especially prevalent among veterans. While behavioral and pharmacological interventions are available, they have demonstrated limited efficacy. Innovations in wearable technology provide a potential avenue to match or exceed these existing treatments by directly targeting nightmare physiology. METHODS: We conducted a randomized, sham-controlled study to determine the efficacy of a novel wearable device-based application in 65 veterans with impaired sleep secondary to trauma-related nightmares. Changes in measures of sleep quality, posttraumatic stress disorder/depression symptoms, and quality of life across the 30-day trial were compared between the Active and Sham systems. RESULTS: Both groups demonstrated statistically significant within-person improvement on all measures. While the Active system was generally associated with stronger magnitude of improvement, none of the comparisons of individual measures across conditions reached statistical significance. However, a post-hoc analysis excluding participants with low frequency of usage demonstrated significantly better improvement in perceived sleep quality with the Active device than Sham. CONCLUSIONS: Overall, these results provide preliminary evidence that a wearable device may improve self-reported sleep quality for veterans reporting frequent trauma-related nightmares, especially in compliant users. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken) (TNT/NW); URL: https://www.clinicaltrials.gov/ct2/show/NCT04040387; Identifier: NCT04040387. CITATION: Davenport ND, Werner JK. A randomized sham-controlled clinical trial of a novel wearable intervention for trauma-related nightmares in military veterans. J Clin Sleep Med. 2023;19(2):361-369.

Methodology of the INVestigating traIning assoCiated blasT pAthology (INVICTA) study.

BACKGROUND: Subconcussive blast exposure during military training has been the subject of both anecdotal concerns and reports in the medical literature, but prior studies have often been small and have used inconsistent methods. METHODS: This paper presents the methodology employed in INVestigating traIning assoCiated blasT pAthology (INVICTA) to assess a wide range of aspects of brain function, including immediate and delayed recall, gait and balance, audiologic and oculomotor function, cerebral blood flow, brain electrical activity and neuroimaging and blood biomarkers. RESULTS: A number of the methods employed in INVICTA are relatively easy to reproducibly utilize, and can be completed efficiently, while other measures require greater technical expertise, take longer to complete, or may have logistical challenges. CONCLUSIONS: This presentation of methods used to assess the impact of blast exposure on the brain is intended to facilitate greater uniformity of data collection in this setting, which would enable comparison between different types of blast exposure and environmental circumstances, as well as to facilitate meta-analyses and syntheses across studies.

An examination of volumetric and cortical thickness correlates of posttraumatic nightmares in male active duty service members.

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.

Association Between Traumatic Brain Injury and Subsequent Cardiovascular Disease Among Post-9/11-Era Veterans.

Importance: Traumatic brain injury (TBI) was common among US service members deployed to Iraq and Afghanistan. Although there is some evidence to suggest that TBI increases the risk of cardiovascular disease (CVD), prior reports were predominantly limited to cerebrovascular outcomes. The potential association of TBI with CVD has not been comprehensively examined in post-9/11-era veterans. Objective: To determine the association between TBI and subsequent CVD in post-9/11-era veterans. Design, Setting, and Participants: This was a retrospective cohort study conducted from October 1, 1999, to September 30, 2016. Participants were followed up until December 31, 2018. Included in the study were administrative data from the US Department of Veterans Affairs and the Department of Defense from the Long-term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. Participants were excluded if dates did not overlap with the study period. Data analysis was conducted between November 22, 2021, and June 28, 2022. Exposures: History of TBI as measured by diagnosis in health care records. Main Outcomes and Measures: Composite end point of CVD: coronary artery disease, stroke, peripheral artery disease, and cardiovascular death. Results: Of the 2 530 875 veterans from the consortium, after exclusions, a total of 1 559 928 veterans were included in the analysis. A total of 301 169 veterans (19.3%; median [IQR] age, 27 [23-34] years; 265 217 male participants [88.1]) with a TBI history and 1 258 759 veterans (80.7%; median [IQR] age, 29 [24-39] years; 1 012 159 male participants [80.4%]) without a TBI history were included for analysis. Participants were predominately young (1 058 054 [67.8%] <35 years at index date) and male (1 277 376 [81.9%]). Compared with participants without a history of TBI, diagnoses of mild TBI (hazard ratio [HR], 1.62; 95% CI, 1.58-1.66; P < .001), moderate to severe TBI (HR, 2.63; 95% CI, 2.51-2.76; P < .001), and penetrating TBI (HR, 4.60; 95% CI, 4.26-4.96; P < .001) were associated with CVD in adjusted models. In analyses of secondary outcomes, all severities of TBI were associated with the individual components of the composite outcome except penetrating TBI and CVD death. Conclusions and Relevance: Results of this cohort study suggest that US veterans with a TBI history were more likely to develop CVD compared with veterans without a TBI history. Given the relatively young age of the cohort, these results suggest that there may be an increased burden of CVD as these veterans age and develop other CVD risk factors. Future studies are needed to determine if the increased risk associated with TBI is modifiable.

Targeted dietary interventions to reduce pain in persistent post-traumatic headache among service members: Protocol for a randomized, controlled parallel-group trial.

INTRODUCTION: Post-traumatic headache (PTH) is common after traumatic brain injury (TBI), especially among active-duty service members (SMs), affecting up to 35% of patients with chronic TBI. Persistent PTH is disabling and frequently unresponsive to treatment and is often migrainous. Here, we describe a trial assessing whether dietary modifications to increase n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and reduce n-6 linoleic acid (LA), will alter nociceptive lipid mediators and result in clinical improvements in persistent PTH. METHODS: This prospective, randomized, controlled trial tests the efficacy, safety, and biochemical effects of targeted, controlled alterations in dietary n-3 and n-6 fatty acids in 122 adult SMs and military healthcare beneficiaries with diagnosed TBI associated with actively managed persistent frequent (>8 /month) PTH with migraine. Following a 4-week baseline, participants are randomized to one of two equally intensive dietary regimens for 12 additional weeks: 1) increased n-3 EPA + DHA with low n-6 LA (H3L6); 2) usual US dietary content of n-3 and n-6 fatty acids (Control). During the intervention, participants receive diet arm-specific study oils and foods sufficient for 75% of caloric needs and comprehensive dietary counseling. Participants complete daily headache diaries throughout the intervention. Clinical outcomes, including the Headache Impact Test (HIT-6), headache hours per day, circulating blood fatty acid levels, and bioactive metabolites, are measured pre-randomization and at 6 and 12 weeks. Planned primary analyses include pre-post comparisons of treatment groups on clinical measures using ANCOVA and mixed-effects models. Similar approaches to explore biochemical and exploratory clinical outcomes are planned. CLINICALTRIALS: gov registration: NCT03272399.

Central disorders of hypersomnolence: diagnostic discrepancies between military and civilian sleep centers.

STUDY OBJECTIVES: The majority of active-duty service members obtain insufficient sleep, which can influence diagnostic evaluations for sleep disorders, including disorders of hypersomnolence. An incorrect diagnosis of hypersomnia may be career ending for military service or lead to inappropriate medical care. This study was conducted to assess the rates at which narcolepsy (Nc) and idiopathic hypersomnia (IH) are diagnosed by military vs civilian sleep disorders centers. METHODS: This retrospective study utilized claims data from the Military Health System Data Repository. The analyses compared diagnostic rates of military personnel by provider type-either civilian provider or military provider-from January 1, 2016 to December 31, 2019. Three diagnostic categories for Nc and IH: Nc or IH, Nc only, and IH only, were assessed with multivariate logistic regression models. RESULTS: We found that among service members evaluated for a sleep disorder, the odds ratios of a positive diagnosis at a civilian facility vs a military facility for Nc or IH was 2.1, for Nc only was 2.1, and IH only was 2.0 over the 4-year period. CONCLUSIONS: Civilian sleep specialists were twice as likely to diagnose central disorders of hypersomnolence compared to military specialists. Raising awareness about this discrepancy is critical given the occupational and patient care-related implications of misdiagnoses. CITATION: Thomas CL, Vattikuti S, Shaha D, et al. Central disorders of hypersomnolence: diagnostic discrepancies between military and civilian sleep centers. J Clin Sleep Med. 2022;18(10):2433-2441.

Sensory Phenotypes for Balance Dysfunction After Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Recent team-based models of care use symptom subtypes to guide treatments for individuals with chronic effects of mild traumatic brain injury (mTBI). However, these subtypes, or phenotypes, may be too broad, particularly for balance (e.g., 'vestibular subtype'). To gain insight into mTBI-related imbalance we 1) explored whether a dominant sensory phenotype (e.g., vestibular impaired) exists in the chronic mTBI population, 2) determined the clinical characteristics, symptomatic clusters, functional measures, and injury mechanisms that associate with sensory phenotypes for balance control in this population, and 3) compared the presentations of sensory phenotypes between individuals with and without previous mTBI. METHODS: A secondary analysis was conducted on the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium. Sensory ratios were calculated from the Sensory Organization Test, and individuals were categorized into one of eight possible sensory phenotypes. Demographic, clinical, and injury characteristics were compared across phenotypes. Symptoms, cognition, and physical function were compared across phenotypes, groups, and their interaction. RESULTS: Data from 758 Service Members and Veterans with mTBI and 172 with no lifetime history of mTBI were included. Abnormal visual, vestibular, and proprioception ratios were observed in 29%, 36%, and 38% of people with mTBI, respectively, with 32% exhibiting more than one abnormal sensory ratio. Within the mTBI group, global outcomes (p<0.001), self-reported symptom severity (p<0.027), and nearly all physical and cognitive functioning tests (p<0.027) differed across sensory phenotypes. Individuals with mTBI generally reported worse symptoms than their non-mTBI counterparts within the same phenotype (p=0.026), but participants with mTBI in the Vestibular-Deficient phenotype reported lower symptom burdens than their non-mTBI counterparts [e.g., mean(SD) Dizziness Handicap Inventory = 4.9(8.1) for mTBI vs. 12.8(12.4) for non-mTBI, group*phenotype interaction p<0.001]. Physical and cognitive functioning did not differ between groups after accounting for phenotype. DISCUSSION: Individuals with mTBI exhibit a variety of chronic balance deficits involving heterogeneous sensory integration problems. While imbalance when relying on vestibular information is common, it is inaccurate to label all mTBI-related balance dysfunction under the 'vestibular' umbrella. Future work should consider specific classification of balance deficits, including specific sensory phenotypes for balance control.

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

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

Clinical features of dementia cases ascertained by ICD coding in LIMBIC-CENC multicenter study of mild traumatic brain injury.

OBJECTIVE: Describe dementia cases identified through International Classification of Diseases (ICD) coding in the Long-term Impact of Military-relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) multicenter prospective longitudinal study (PLS) of mild traumatic brain injury (mTBI). DESIGN: Descriptive case series using cross-sectional data. METHODS: Veterans Affairs (VA) health system data including ICD codes were obtained for 1563 PLS participants through the VA Informatics and Computing Infrastructure (VINCI). Demographic, injury, and clinical characteristics of Dementia positive and negative cases are described. RESULTS: Five cases of dementia were identified, all under 65 years old. The dementia cases all had a history of blast-related mTBI and all had self-reported functional problems and four had PTSD symptomatology at the clinical disorder range. Cognitive testing revealed some deficits especially in the visual memory and verbal learning and memory domains, and that two of the cases might be false positives. CONCLUSIONS: ICD codes for early dementia in the VA system have specificity concerns, but could be indicative of cognitive performance and self-reported cognitive function. Further research is needed to better determine links to blast exposure, blast-related mTBI, and PTSD to early dementia in the military population.

Sleep quality: A common thread linking depression, post-traumatic stress, and post-concussive symptoms to biomarkers of neurodegeneration following traumatic brain injury.

OBJECTIVE: Following mild traumatic brain injury (mTBI), many individuals suffer from persistent post-concussive, depressive, post-traumatic stress, and sleep-related symptoms. Findings from self-report scales link these symptoms to biomarkers of neurodegeneration, although the underlying pathophysiology is unclear. Each linked self-report scale includes sleep items, raising the possibility that despite varied symptomology, disordered sleep may underlie these associations. To isolate sleep effects, we examined associations between post-mTBI biomarkers of neurodegeneration and symptom scales according to composite, non-sleep, and sleep components. METHODS: Plasma biomarkers and self-report scales were obtained from 143 mTBI-positive warfighters. Pearson's correlations and regression models were constructed to estimate associations between total, sleep, and non-sleep scale items with biomarker levels, and with measured sleep quality. RESULTS: Symptom severity positively correlated with biomarker levels across scales. Biomarker associations were largely unchanged when sleep items were included, excluded, or considered in isolation. Pittsburgh Sleep Quality Index demonstrated strong correlations with sleep and non-sleep items of all scales. CONCLUSION: The congruency of associations raises the possibility of a common pathophysiological process underlying differing symptomologies. Given its role in neurodegeneration and mood dysregulation, sleep physiology seems a likely candidate. Future longitudinal studies should test this hypothesis, with a focus on identifying novel sleep-related therapeutic targets.