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.

Traumatic Brain Injury and Early Onset Dementia in Post 9-11 Veterans.

OBJECTIVES: To assess traumatic brain injury (TBI)-related risks factors for early-onset dementia (EOD). BACKGROUND: Younger Post-9/11 Veterans may be at elevated risk for EOD due to high rates of TBI in early/mid adulthood. Few studies have explored the longitudinal relationship between traumatic brain injury (TBI) and the emergence of EOD subtypes. METHODS: This matched case-control study used data from the Veterans Health Administration (VHA) to identify Veterans with EOD. To address the low positive predictive value (PPV = 0.27) of dementia algorithms in VHA records, primary outcomes were Alzheimer's disease (AD) and frontotemporal dementia (FTD). Logistic regression identified conditions associated with dementia subtypes. RESULTS: The EOD cohort included Veterans with AD (n = 689) and FTD (n = 284). There were no significant demographic differences between the EOD cohort and their matched controls. After adjustment, EOD was significantly associated with history of TBI (OR: 3.05, 2.42-3.83), epilepsy (OR: 4.8, 3.3-6.97), other neurological conditions (OR: 2.0, 1.35-2.97), depression (OR: 1.35, 1.12-1.63) and cardiac disease (OR: 1.36, 1.1-1.67). CONCLUSION: Post-9/11 Veterans have higher odds of EOD following TBI. A sensitivity analysis across TBI severity confirmed this trend, indicating that the odds for both AD and FTD increased after more severe TBIs.

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.

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.

Advanced brain age in deployment-related traumatic brain injury: A LIMBIC-CENC neuroimaging study.

OBJECTIVE: To determine if history of mild traumatic brain injury (mTBI) is associated with advanced or accelerated brain aging among the United States (US) military Service Members and Veterans. METHODS: Eight hundred and twenty-two participants (mean age = 40.4 years, 714 male/108 female) underwent MRI sessions at eight sites across the US. Two hundred and one participants completed a follow-up scan between five months and four years later. Predicted brain ages were calculated using T1-weighted MRIs and then compared with chronological ages to generate an Age Deviation Score for cross-sectional analyses and an Interval Deviation Score for longitudinal analyses. Participants also completed a neuropsychological battery, including measures of both cognitive functioning and psychological health. RESULT: In cross-sectional analyses, males with a history of deployment-related mTBI showed advanced brain age compared to those without (t(884) = 2.1, p = .038), while this association was not significant in females. In follow-up analyses of the male participants, severity of posttraumatic stress disorder (PTSD), depression symptoms, and alcohol misuse were also associated with advanced brain age. CONCLUSION: History of deployment-related mTBI, severity of PTSD and depression symptoms, and alcohol misuse are associated with advanced brain aging in male US military Service Members and Veterans.

Recent Advances in Blood-Based Biomarkers of Remote Combat-Related Traumatic Brain Injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is highly prevalent among service members and Veterans (SMVs) and associated with changes in blood-based biomarkers. This manuscript reviews candidate biomarkers months/years following military-associated TBI. RECENT FINDINGS: Several blood-based biomarkers have been investigated for diagnostic or prognostic use to inform care years after military-associated TBI. The most promising include increased levels of plasma/serum and exosomal proteins reflecting neuronal, axonal and/or vascular injury, and inflammation, as well as altered microRNA expression and auto-antibodies of central nervous system markers. Diagnostic and prognostic biomarkers of remote TBI outcomes remain in the discovery phase. Current evidence does not yet support single or combination biomarkers for clinical diagnostic use remotely after injury, but there are promising candidates that require validation in larger, longitudinal studies. The use of prognostic biomarkers of future neurodegeneration, however, holds much promise and could improve treatments and/or preventive measures for serious TBI outcomes.

Traumatic brain injury: recent advances in plasticity and regeneration.

PURPOSE OF REVIEW: There is an urgent need for effective therapies to restore neurologic function and decrease disability following traumatic brain injury (TBI). Here, emerging findings on the mechanisms of post-TBI neural repair and regeneration, as well as therapeutic implications, are selectively reviewed. RECENT FINDINGS: Recent discoveries include the characterization of the inhibitory signaling systems within the injury site, postinjury stem cell niche activation, the role of serotonin signaling in repair, and environment enrichment. A potentially transformative finding has been the identification of exosomes, nano-sized extracellular vesicles which have key roles in cell signaling, and might serve as novel biomarkers and as vehicles for targeted delivery of repair-inducing molecules. SUMMARY: In the experimental setting, post-TBI repair can be promoted by modulation of inhibitory signaling, neurotrophic factor administration, and amplified serotonin signaling; additional strategies include mobilization of endogenous stem cell populations, exogenous cell-based therapies, and environmental enhancement. Feasibility, safety, and efficacy of these approaches need further investigation in humans. Studies are also needed to evaluate biomarkers based on molecular traces of neural repair and regeneration, which could transform prognostic and predictive modeling of post-TBI recovery trajectories.

A rare case of hyponatremia from a hypothalamic lesion in a patient with multiple sclerosis.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur from a variety of neurologic and systemic processes; however, it has rarely been seen in multiple sclerosis (MS). We report a case of SIADH in a patient with MS and compare it with previously reported English-only cases. A 32-year-old woman experienced generalized fatigue followed by confusion and was found to have profound hyponatremia. Her work-up demonstrated SIADH secondary to a discrete enhancing hypothalamic lesion. Despite the seldom occurrence of SIADH in MS, hypothalamic lesions are more common than appreciated and should be considered in patients presenting with hyponatremia or endocrinopathy symptoms.

Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.

The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.

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.

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.

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.

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.

Chronic headaches after traumatic brain injury: Diagnostic complexity associated with increased cost.

BACKGROUND: Chronic headache after traumatic brain injury (TBI) is a common, yet disabling, disorder whose diverse clinical characteristics and treatment needs remain poorly defined. OBJECTIVE: To examine diagnostic coding patterns and cost among military Veterans with comorbid chronic headache and TBI. METHODS: We identified 141,125 post-9/11 era Veterans who served between 2001 and 2019 with a headache disorder diagnosed after TBI. We first identified patterns of Complex Headache Combinations (CHC) and then compared the patterns of healthcare costs in 2022-dollar values in the three years following the TBI diagnosis. RESULTS: Veterans had diverse individual headache and CHC diagnoses with uniformly high cost of care. Post-whiplash and post-TBI CHCs were common and consistently associated with higher costs after TBI than those with other types of headache and CHCs. Post-TBI migraine had the highest unadjusted mean inpatient ($27,698), outpatient ($61,417), and pharmacy ($4,231) costs, which persisted even after adjustment for confounders including demographic, military, and clinical characteristics. CONCLUSION: Headache diagnoses after TBI, particularly those diagnosed with post-traumatic headache, are complex, and associated with dual high cost and care burdens. More research is needed to examine whether this higher expenditure reflects more intensive treatment and better outcomes or refractory headache with worse outcomes.

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.

p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.

Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.

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.

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.

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 ).