Posttraumatic Headache.

OBJECTIVE: This article provides an overview of the epidemiology, diagnosis, clinical presentation, pathophysiology, prognosis, and treatment of posttraumatic headache attributed to mild traumatic brain injury (mTBI). LATEST DEVELOPMENTS: The International Classification of Headache Disorders, Third Edition requires that posttraumatic headache begin within 7 days of the inciting trauma. Although posttraumatic headache characteristics and associated symptoms vary, most commonly there is substantial overlap with symptoms of migraine or tension-type headache. New insights into posttraumatic headache pathophysiology suggest roles for neuroinflammation, altered pain processing and modulation, and changes in brain structure and function. Although the majority of posttraumatic headache resolves during the acute phase, about one-third of individuals have posttraumatic headache that persists for at least several months. Additional work is needed to identify predictors and early markers of posttraumatic headache persistence, but several potential predictors have been identified such as having migraine prior to the mTBI, the total number of TBIs ever experienced, and the severity of initial symptoms following the mTBI. Few data are available regarding posttraumatic headache treatment; studies investigating different treatments and the optimal timing for initiating posttraumatic headache treatment are needed. ESSENTIAL POINTS: Posttraumatic headache begins within 7 days of the causative injury. The characteristics of posttraumatic headache most commonly resemble those of migraine or tension-type headache. Posttraumatic headache persists for 3 months or longer in about one-third of individuals. Additional studies investigating posttraumatic headache treatment are needed.

The Postconcussion Syndrome and Posttraumatic Headaches in Civilians, Soldiers, and Athletes.

Posttraumatic headaches are one of the most common and controversial secondary headache types. After a mild traumatic brain, an estimated 11% to 82% of people develop a postconcussion syndrome, which has been controversial for more than 160 years. Headache is estimated as present in 30% to 90% of patients after a mild head injury. Most headaches are tension-type-like or migraine-like. Headaches in civilians, soldiers, athletes, and postcraniotomy are reviewed. The treatments are the same as for the primary headaches. Persistent posttraumatic headaches can continue for many years.

Olfactory function after mild traumatic brain injury in children-a longitudinal case control study.

The prevalence of posttraumatic olfactory dysfunction in children after mild traumatic brain injury ranges from 3 to 58%, with potential factors influencing this variation, including traumatic brain injury severity and assessment methods. This prospective longitudinal study examines the association between mild traumatic brain injury and olfactory dysfunction in children. Seventy-five pediatric patients with mild traumatic brain injury and an age-matched healthy control group were enrolled. Olfactory function was assessed using the Sniffin' Sticks battery, which focuses on olfactory threshold and odor identification. The study found that children with mild traumatic brain injury had impaired olfactory function compared with healthy controls, particularly in olfactory threshold scores. The prevalence of olfactory dysfunction in the patient group was 33% and persisted for 1 yr. No significant association was found between traumatic brain injury symptoms (e.g. amnesia, loss of consciousness) and olfactory dysfunction. The study highlights the importance of assessing olfactory function in children after mild traumatic brain injury, given its potential impact on daily life. Although most olfactory dysfunction appears transient, long-term follow-up is essential to fully understand the recovery process. The findings add valuable insights to the limited literature on this topic and urge the inclusion of olfactory assessments in the management of pediatric mild traumatic brain injury.

A Proposed Mechanism for Visual Vertigo: Post-Concussion Patients Have Higher Gain From Visual Input Into Subcortical Gaze Stabilization.

Purpose: Post-concussion syndrome (PCS) is commonly associated with dizziness and visual motion sensitivity. This case-control study set out to explore altered motion processing in PCS by measuring gaze stabilization as a reflection of the capacity of the brain to integrate motion, and it aimed to uncover mechanisms of injury where invasive subcortical recordings are not feasible. Methods: A total of 554 eye movements were analyzed in 10 PCS patients and nine healthy controls across 171 trials. Optokinetic and vestibulo-ocular reflexes were recorded using a head-mounted eye tracker while participants were exposed to visual, vestibular, and visuo-vestibular motion stimulations in the roll plane. Torsional and vergence eye movements were analyzed in terms of slow-phase velocities, gain, nystagmus frequency, and sensory-specific contributions toward gaze stabilization. Results: Participants expressed eye-movement responses consistent with expected gaze stabilization; slow phases were fastest for visuo-vestibular trials and slowest for visual stimulations (P < 0.001) and increased with stimulus acceleration (P < 0.001). Concussed patients demonstrated increased gain from visual input to gaze stabilization (P = 0.005), faster slow phases (P = 0.013), earlier nystagmus beats (P = 0.003), and higher relative visual influence over the gaze-stabilizing response (P = 0.001), presenting robust effect sizes despite the limited population size. Conclusions: The enhanced neural responsiveness to visual motion in PCS, combined with semi-intact visuo-vestibular integration, presented a subcortical hierarchy for altered gaze stabilization. Drawing on comparable animal trials, findings suggest that concussed patients may suffer from diffuse injuries to inhibiting pathways for optokinetic information, likely early in the visuo-vestibular hierarchy of sensorimotor integration. These findings offer context for common but elusive symptoms, presenting a neurological explanation for motion sensitivity and visual vertigo in PCS.

The effect of repeated concussions on clinical and neurocognitive symptom severity in different contact sports.

INTRODUCTION: The potential consequences of repeated concussions in sport are well documented. However, it remains unclear whether the cumulative impact of sports-related concussions differs between different contact sports. Therefore, the aim of the current study was to investigate the cumulative effects of sports-related concussions on clinical and neurocognitive health in different contact sports. MATERIALS AND METHODS: In a prospective multicenter study, we examined 507 (74 females) active professional athletes between 18 and 40 years of age from five different contact sports (soccer, handball, American football, basketball, and ice hockey). Data collection involved concussion history, clinical symptom evaluation, neurocognitive assessment, and the collection of other sports-related information. Composite scores were built for clinical symptoms (such as neck pain and balance disturbances) and for neurocognitive symptoms (such as memory and attention impairments). RESULTS: Athletes having suffered 3+ concussions in the past showed disproportionally higher clinical symptom severity than athletes with less than three concussions across all sports. The level of clinical symptom burden in athletes with 3+ concussions indicated mild impairment. The number of past concussions did not affect neurocognitive performance. DISCUSSION: Repeated sports-related concussions appear to have a cumulative impact on clinical-but not cognitive-symptom severity. Although clinical symptom burden in athletes with 3+ concussions in the past was not alarmingly high yet in our sample, increased caution should be advised at this point. Despite few exceptions, results are similar for different contact sports, suggesting a similar multidisciplinary concussion management across all types of sport.

Stressful life events are associated with self-reported fatigue and depressive symptoms in patients with mild traumatic brain injury.

OBJECTIVE: To examine the associations between recent stressful life events and self-reported fatigue and depressive symptoms in patients with mild traumatic brain injury. DESIGN: Observational cohort study. PARTICIPANTS: Patients (aged 18-68 years) with mild traumatic brain injury (n = 99) or lower extremity orthopaedic injury (n = 34). METHODS: Data on stressful life events and self-reported symptoms were collected 3 months post-injury. Stressful life events in the last 12 months were assessed as part of a structured interview using a checklist of 11 common life events, self-reported fatigue with Barrow Neurological Institute Fatigue Scale, and depressive symptoms with Beck Depression Inventory - Fast Screen. RESULTS: Median number of stressful life events was 1 (range 0-7) in the mild traumatic brain injury group and 1.5 (range 0-6) in the orthopaedic injury group. The groups did not differ significantly in terms of fatigue or depressive symptoms. In the mild traumatic brain injury group, the total number of recent stressful life events correlated significantly with self-reported fatigue (rs = 0.270, p = 0.007) and depressive symptoms (rs = 0.271, p = 0.007). CONCLUSION: Stressful life events are associated with self-reported fatigue and depressive symptoms in patients with mild traumatic brain injury. Clinicians should consider stressful life events when managing patients who experience these symptoms, as this may help identifying potential targets for intervention.

CSF ß-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Moderate-to-severe traumatic brain injuries (TBI) have been reported to increase the risk of Alzheimer disease (AD). Whether mild TBI (mTBI) in veterans confers a similar increased risk of AD is less known. This study investigated early AD changes using CSF biomarkers in veterans with blast mTBI. METHODS: This was a cross-sectional case-control study of veterans with mTBI and non-mTBI veterans and civilians from 2 study sources. Blast-mTBI veterans had at least 1 war zone blast or combined blast/impact mTBI meeting Veterans Affairs (VA) and Department of Defense (DoD) criteria for mTBI. Non-mTBI participants had no lifetime history of TBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of the CSF. CSF biomarkers were measured using MesoScale Discovery assays for Aß40 and Aß42 and INNOTEST ELISAs for phosphorylated tau181 (p-tau181) and total tau (t-tau). RESULTS: Our sample comprised 51 participants with mTBI and 85 non-mTBI participants with mean (SD) ages 34.0 (10.1) and 33.5 years (8.9), respectively. All participants but 1 (99%) were male. Differences in CSF AD biomarkers between mTBI and non-mTBI groups were age dependent and most pronounced at older ages (omnibus test p ≤ 0.08). At age 50 years, the mTBI group had lower mean [95% CI] CSF Aß42 and Aß40 than the non-mTBI group by 154 [-12 to 319] and 1864 [610-3,118] pg/mL, respectively. By contrast, CSF p-tau181 and t-tau mean levels remained relatively constant with age in participants with mTBI, while tending to be higher at older ages for the non-mTBI group. The mTBI group also demonstrated poorer cognitive performance at older ages (omnibus p < 0.08): at age 50 years, the mean TMT-B time was higher by 34 seconds [10-58] and the mean CVLT-II short-delay recall was lower by 4.2 points [1.9-6.6]. Poorer verbal memory and verbal fluency performance were associated with lower CSF Aß42 (p ≤ 0.05) in older participants. DISCUSSION: CSF Aß levels decreased in middle-aged veterans with blast-related mTBI. These data suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes known to portend AD onset, thus raising concern that veterans with blast-related mTBI may develop a dementing disorder later in life.

Prefrontal Cortex Activity During Gait in People With Persistent Symptoms After Concussion.

BACKGROUND: Concussions result in transient symptoms stemming from a cortical metabolic energy crisis. Though this metabolic energy crisis typically resolves in a month, symptoms can persist for years. The symptomatic period is associated with gait dysfunction, the cortical underpinnings of which are poorly understood. Quantifying prefrontal cortex (PFC) activity during gait may provide insight into post-concussion gait dysfunction. The purpose of this study was to explore the effects of persisting concussion symptoms on PFC activity during gait. We hypothesized that adults with persisting concussion symptoms would have greater PFC activity during gait than controls. Within the concussed group, we hypothesized that worse symptoms would relate to increased PFC activity during gait, and that increased PFC activity would relate to worse gait characteristics. METHODS: The Neurobehavior Symptom Inventory (NSI) characterized concussion symptoms. Functional near-infrared spectroscopy quantified PFC activity (relative concentration changes of oxygenated hemoglobin [HbO2]) in 14 people with a concussion and 25 controls. Gait was assessed using six inertial sensors in the concussion group. RESULTS: Average NSI total score was 26.4 (13.2). HbO2 was significantly higher (P = .007) for the concussed group (0.058 [0.108]) compared to the control group (-0.016 [0.057]). Within the concussion group, HbO2 correlated with NSI total symptom score (ρ = .62; P = .02), sagittal range of motion (r = .79; P = .001), and stride time variability (r = -.54; P = .046). CONCLUSION: These data suggest PFC activity relates to symptom severity and some gait characteristics in people with persistent concussion symptoms. Identifying the neurophysiological underpinnings to gait deficits post-concussion expands our knowledge of motor behavior deficits in people with persistent concussion symptoms.

Cognitive Impairment following Mild Traumatic Brain Injury (mTBI): A Review.

Background: Mild Traumatic Brain Injury (mTBI) has been increasingly recognized as a public health concern due to its prevalence and potential to induce long-term cognitive impairment. We aimed to consolidate this observation by focusing on findings of neuropsychological assessments, neuroimaging, risk factors, and potential strategies for intervention to prevent and treat mTBI-associated cognitive impairments. Methods: A thorough search of PubMed, PsycINFO, and Embase databases was performed for studies published until 2024. Studies focusing on cognitive impairment after mTBI, with neurocognitive assessment as a primary outcome, were included. Results: We found consistent evidence of cognitive deficits, such as memory and attention impairments, and affected executive functions following mTBI. Neuroimaging studies corroborate these findings, highlighting structural and functional changes in the brain. Several risk factors for developing cognitive impairment post-mTBI were identified, including age, gender, genetics, and pre-existing mental health conditions. The efficacy of interventions, including cognitive rehabilitation and pharmaceutical treatment, varied across studies. Conclusions: Mild TBI can lead to significant long-term cognitive impairments, impacting an individual's quality of life. Further research is necessary to validate and standardize cognitive assessment tools post-mTBI, to elucidate the underlying neural mechanisms, and to optimize therapeutic interventions.

Association of Blast Exposure in Military Breaching with Intestinal Permeability Blood Biomarkers Associated with Leaky Gut.

Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from "breachers" exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP.

Postconcussive Symptoms After Early Childhood Concussion.

Importance: Research on postconcussive symptoms (PCS) following early childhood concussion has been hindered by a lack of measures suitable for this age group, resulting in a limited understanding of their evolution in young children. Objective: To document PCS in the first 3 months after early childhood concussion using a developmentally appropriate measure. Design, Setting, and Participants: This cohort study used data collected at 3 Canadian and 1 US urban pediatric emergency departments (EDs) and 8 Canadian daycares from December 2018 to December 2022 as part of the Kids' Outcomes and Long-Term Abilities (KOALA) project, a prospective, multicenter, longitudinal cohort study. Participants included children aged 6 to 72 months with early childhood concussion or orthopedic injury (OI) or uninjured children from the community to serve as controls. Data were analyzed from March 2023 to January 2024. Exposure: Concussion sustained between ages 6 and 72 months. Main Outcomes and Measures: Primary outcomes were cognitive, physical, behavioral and total PCS assessed prior to injury (retrospectively), acutely (within 48 hours), and at 10 days, 1 month, and 3 months after injury or recruitment through caregiver observations using the Report of Early Childhood Traumatic Injury Observations & Symptoms inventory. Group comparisons were analyzed using ordinal regression models. Results: The study included 303 children (mean [SD] age, 35.8 [20.2] months; 152 [50.2%] male). Of these, 174 children had a concussion (mean [SD] age, 33.3 [19.9] months), 60 children had an OI (mean [SD] age, 38.4 [19.8] months) and 69 children were uninjured controls (mean [SD] age, 39.7 [20.8] months). No meaningful differences were found between the concussion and comparison groups in retrospective preinjury PCS. Significant group differences were found for total PCS at the initial ED visit (concussion vs OI: odds ratio [OR], 4.33 [95% CI, 2.44-7.69]; concussion vs control: OR, 7.28 [95% CI, 3.80-13.93]), 10 days (concussion vs OI: OR, 4.44 [95% CI, 2.17-9.06]; concussion vs control: OR, 5.94 [95% CI, 3.22-10.94]), 1 month (concussion vs OI: OR, 2.70 [95% CI, 1.56-4.68]; concussion vs control: OR, 4.32 [95% CI, 2.36-7.92]), and 3 months (concussion vs OI: OR, 2.61 [95% CI, 1.30-5.25]; concussion vs control: OR, 2.40 [95% CI, 1.36-4.24]). Significant group differences were also found for domain-level scores (cognitive, physical, behavioral) at various time points. Conclusions and Relevance: In this early childhood cohort study, concussion was associated with more PCS than OIs or typical development up to 3 months after injury. Given the limited verbal and cognitive abilities typical of early childhood, using developmentally appropriate manifestations and behaviors is a valuable way of tracking PCS and could aid in concussion diagnosis in young children.

Prevalence of fatigue and cognitive impairment after traumatic brain injury.

BACKGROUND: Following traumatic brain injury (TBI) some patients develop lingering comorbid symptoms of fatigue and cognitive impairment. The mild cognitive impairment self-reported by patients is often not detected with neurocognitive tests making it difficult to determine how common and severe these symptoms are in individuals with a history of TBI. This study was conducted to determine the relative prevalence of fatigue and cognitive impairment in individuals with a history of TBI. METHODS: The Fatigue and Altered Cognition Scale (FACs) digital questionnaire was used to assess self-reported fatigue and cognitive impairment. Adults aged 18-70 were digitally recruited for the online anonymous study. Eligible participants provided online consent, demographic data, information about lifetime TBI history, and completed the 20 item FACs questionnaire. RESULTS: A total of 519 qualifying participants completed the online digital study which included 204 participants with a history of TBI of varied cause and severity and 315 with no history of TBI. FACs Total Score was significantly higher in the TBI group (57.7 ± 22.2) compared to non-TBI (39.5 ± 23.9; p<0.0001) indicating more fatigue and cognitive impairment. When stratified by TBI severity, FACs score was significantly higher for all severity including mild (53.9 ± 21.9, p<0.0001), moderate (54.8 ± 24.4, p<0.0001), and severe (59.7 ± 20.9, p<0.0001) TBI. Correlation analysis indicated that more severe TBI was associated with greater symptom severity (p<0.0001, r = 0.3165). Ancillary analysis also suggested that FACs scores may be elevated in participants with prior COVID-19 infection but no history of TBI. CONCLUSIONS: Adults with a history of even mild TBI report significantly greater fatigue and cognitive impairment than those with no history of TBI, and symptoms are more profound with greater TBI severity.

Study protocol: Identifying transcriptional regulatory alterations of chronic effects of blast and disturbed sleep in United States Veterans.

Injury related to blast exposure dramatically rose during post-911 era military conflicts in Iraq and Afghanistan. Mild traumatic brain injury (mTBI) is among the most common injuries following blast, an exposure that may not result in a definitive physiologic marker (e.g., loss of consciousness). Recent research suggests that exposure to low level blasts and, more specifically repetitive blast exposure (RBE), which may be subconcussive in nature, may also impact long term physiologic and psychological outcomes, though findings have been mixed. For military personnel, blast-related injuries often occur in chaotic settings (e.g., combat), which create challenges in the immediate assessment of related-injuries, as well as acute and post-acute sequelae. As such, alternate means of identifying blast-related injuries are needed. Results from previous work suggest that epigenetic markers, such as DNA methylation, may provide a potential stable biomarker of cumulative blast exposure that can persist over time. However, more research regarding blast exposure and associations with short- and long-term sequelae is needed. Here we present the protocol for an observational study that will be completed in two phases: Phase 1 will address blast exposure among Active Duty Personnel and Phase 2 will focus on long term sequelae and biological signatures among Veterans who served in the recent conflicts and were exposed to repeated blast events as part of their military occupation. Phase 2 will be the focus of this paper. We hypothesize that Veterans will exhibit similar differentially methylated regions (DMRs) associated with changes in sleep and other psychological and physical metrics, as observed with Active Duty Personnel. Additional analyses will be conducted to compare DMRs between Phase 1 and 2 cohorts, as well as self-reported psychological and physical symptoms. This comparison between Service Members and Veterans will allow for exploration regarding the natural history of blast exposure in a quasi-longitudinal manner. Findings from this study are expected to provide additional evidence for repetitive blast-related physiologic changes associated with long-term neurobehavioral symptoms. It is expected that findings will provide foundational data for the development of effective interventions following RBE that could lead to improved long-term physical and psychological health.

Dose-Response Effect of Mental Health Diagnoses on Concussion Recovery in Children and Adolescents.

BACKGROUND: Pre-existing mental health diagnoses may contribute to greater emotional symptom burden and prolonged recovery after concussion. HYPOTHESIS: Youth with pre-existing mental health diagnoses will have greater emotional symptom burden, greater risk for delayed return to exercise, and more prolonged recovery from concussion than those without those diagnoses. STUDY DESIGN: Prospective cohort. LEVEL OF EVIDENCE: Level 3. METHODS: A prospective registry of youth concussion was examined for differences in emotional symptom burden after injury to develop a predictive risk model for prolonged recovery. The impact of individual and total number of pre-existing mental health diagnoses (0, 1, 2, and 3+) was assessed, and multivariable logistic regression was performed to identify factors associated with prolonged recovery. RESULTS: Among a cohort of 3105 youth with concussion, those with a history of mental health diagnoses, in a dose-response fashion, had greater postinjury emotional symptom burden (7 emotional symptoms vs 4; P < 0.01), visio-vestibular dysfunction (65% abnormal vs 56% abnormal; P < 0.01), later return to symptom-limited exercise (23 vs 21 days; P < 0.01), and overall longer concussion recovery (38 days, interquartile range [IQR] 18, 80) versus 25 days (IQR 13, 54; P < 0.01). Boys with prolonged recovery after concussion had greater emotional symptom burden than girls (5 emotional symptoms vs 3; P < 0.01). CONCLUSION: Pre-existing mental health diagnoses are associated with greater postinjury emotional symptom burden and longer concussion recovery in a dose-response fashion. Visiovestibular deficits and delayed return to exercise are also associated with pre-existing mental health diagnoses and prolonged recovery. Boys with prolonged recovery from concussion experience greater emotional symptom burden than girls. CLINICAL RELEVANCE: Addressing pre-existing mental health diagnoses is essential to concussion management. Boys with prolonged recovery from concussion may particularly benefit from interventions to address their higher emotional symptom burden. Interventions, including a home visio-vestibular exercise program and symptom-limited exercise, may contribute to improving time to concussion recovery.

Clinical characteristics of benign paroxysmal positional vertigo after traumatic brain injury.

INTRODUCTION: The aim of the present study was to evaluate the characteristics of brain injury and to assess the relationship between them and treatment outcomes in patients with traumatic benign paroxysmal positional vertigo (t-BPPV). MATERIALS AND METHODS: Sixty-three consecutive patients who were diagnosed with BPPV within 2 weeks after head trauma were included. RESULTS: Cerebral concussion, intracranial hemorrhages (ICH), skull fracture without ICH, and hemorrhagic contusion were observed in 68%, 24%, 5%, and 3% of t-BPPV patients, respectively. BPPV with single canal involvement was observed in 52 (83%) patients and that with multiple canal involvement was observed in 11 (17%) patients. The number of treatment sessions was not significantly different according to the cause of head trauma (p = 0.252), type of brain injury (p = 0.308) or location of head trauma (p = 0.287). The number of recurrences was not significantly different according to the cause of head trauma (p = 0.308), type of brain injury (p = 0.536) or location of head trauma (p = 0.138). CONCLUSION: The present study demonstrated that there were no significant differences in treatment sessions until resolution and the mean number of recurrences according to the type of brain injury.

Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans.

More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741; p = 0.0012). The optimal cutoff for VLDLR-AS1 was ≤153.8 ng. A secondary analysis of clinical data from LIMBIC CENC was conducted to evaluate the psychological symptom burden, and the results show that lncRNAs VLDLR-AS1 and MALAT1 are correlated with symptoms of depression. In conclusion, lncRNA VLDLR-AS1 may serve as a blood biomarker for identifying chronic rmTBI and depression in patients.

Association of mild traumatic brain injury, post-traumatic stress disorder, and other comorbidities on photosensitivity.

SIGNIFICANCE: Photosensitivity is common after mild traumatic brain injury. However, this study demonstrates that photosensitivity is also impacted by common comorbidities that often occur with mild traumatic brain injury. Understanding how physical and psychological traumas impact photosensitivity can help improve provider care to trauma survivors and guide novel therapeutic interventions. PURPOSE: This study aimed to characterize the association between mild traumatic brain injury and common comorbidities on photosensitivity in post-9/11 veterans. METHODS: Existing data from the Translational Research Center for TBI and Stress Disorders cohort study were analyzed including traumatic brain injury history and post-traumatic stress disorder clinical diagnostic interviews; sleep quality, anxiety, and depression symptoms self-report questionnaires; and photosensitivity severity self-report from the Neurobehavioral Symptom Inventory. Analysis of covariance and multiple ordinal regression models were used to assess associations between mild traumatic brain injury and common comorbidities with photosensitivity severity. RESULTS: Six hundred forty-one post-9/11 veterans were included in this study. An initial analysis showed that both mild traumatic brain injury and current post-traumatic stress disorder diagnosis were independently associated with higher photosensitivity ratings compared with veterans without either condition, with no interaction observed between these two conditions. Results of the ordinal regression models demonstrated positive associations between degree of photosensitivity and the number of mild traumatic brain injuries during military service and current post-traumatic stress disorder symptom severity, particularly hyperarousal symptoms, even when controlling for other factors. In addition, the degree of sleep disturbances and current anxiety symptoms were both positively associated with photosensitivity ratings, whereas depression symptoms, age, and sex were not. CONCLUSIONS: Repetitive mild traumatic brain injury, post-traumatic stress disorder, anxiety, and sleep disturbances were all found to significantly impact photosensitivity severity and are therefore important clinical factors that eye care providers should consider when managing veterans with a history of deployment-related trauma reporting photosensitivity symptoms.

Co-existence of depression and post-concussion syndrome one month after mild traumatic brain injury.

BACKGROUND: Previous studies suggest an association between Post-concussion syndrome (PCS) and depression, both highly prevalent after mTBI. OBJECTIVE: To assess the prevalence and risk-factors of depression among patients with PCS 1 month after mTBI. METHODS: We prospectively screened 372 mTBI patients admitted in two academic Emergency Departments between 2017 and 2019. One month after mTBI, we administered the Rivermead Post-concussion symptoms Questionnaire (RPQ) and the Patient Health Questionnaire (PHQ-9) questionnaires over the telephone. PCS and depression were defined by RPQ ≥ 12 and PHQ-9 ≥ 10. Multivariate multinomial regression identified baseline factors associated with PCS and depression. RESULTS: Two hundred and eight completed RPQ and PHQ-9. Forty-seven patients (22.5%) met criteria for PCS, among which 22 (46.8%) met criteria for depression (PCS+D+). Patients with PCS but without depression were less likely to present with an associated injury (Coefficient = -1.6, p = 0.047) and to report initial sadness (Coefficient = -2.5, p = 0.03). Initial sadness (Coefficient = -1.3, p = 0.047), associated injury (Coefficient = -1.9, p = 0.008), as well as initial nausea (Coefficient = -1.8, p = 0.002), and male sex (Coefficient = 1.8, p = 0.002), were associated with the absence of depression and PCS in comparison with PCS+D+ patients. CONCLUSION: Among patients with PCS 1 month after mTBI, those with depression are more likely to present with initial sadness and with an associated injury.

Evaluation of Quantitative Pupillometry in Acute Postinjury Pediatric Concussion.

BACKGROUND: Although millions of children sustain concussions each year, a rapid and objective test for concussion has remained elusive. The aim of this study was to investigate quantitative pupillometry in pediatric patients in the acute, postinjury setting. METHODS: This was a prospective case-control study of concussed patients presenting to the emergency department within 72 hours of injury. Pupillary measurements were gathered using NeurOptics' PLR 3000; evaluation included a symptom checklist and neurocognitive assessment. Data were analyzed using descriptive statistics and regression models. RESULTS: A total of 126 participants were enrolled. One significant difference in pupillometry between concussed and control participants was found: left minimum pupil diameter in 12- to 18 year-olds (P = 0.02). Models demonstrating odds of a concussion revealed significant associations for time to 75% recovery (T75) of the left pupil in five- to 11-year-olds and average dilation velocity of the left pupil in 12- to 18-year-olds (P = 0.03 and 0.02 respectively). Models predicting symptom improvement showed one significant association: percent change of the right pupil in five-to-11-year-olds (P = 0.02). Models predicting neurocognitive improvement in 12- to 18-year-olds demonstrated significant association in T75 in the left pupil for visual memory, visual motor processing speed, and reaction time (P = 0.002, P = 0.04, P = 0.04). CONCLUSIONS: The limited statistically significant associations found in this study suggest that pupillometry may not be useful in pediatrics in the acute postinjury setting for either the diagnosis of concussion or to stratify risk for prolonged recovery.

Symptom resolution following a repeat concussion within the same athlete.

INTRODUCTION: Repeat sport-related concussion (SRC) is anecdotally associated with prolonged recovery. Few studies have examined repeat concussion within the same athlete. We sought to explore differences in symptom burden and recovery outcomes in an individual athlete's initial and repeat SRC. METHODS: A retrospective within-subject cohort study of athletes aged 12-23 years diagnosed with two separate SRCs from 11/2017-10/2020 was conducted. Primary outcomes were initial symptom severity and time-to-symptom-resolution. Secondary outcomes included return-to-learn (RTL) and return-to-play (RTP) duration. RESULTS: Of 868 athletes seen, 47 athletes presented with repeat concussions. Median time between concussions was 244 days (IQR 136-395). Comparing initial to repeat concussion, no differences were observed in time-to-clinic (4.3 ± 7.3vs.3.7 ± 4.6 days, p = 0.56) or initial PCSS (26.2 ± 25.3 vs. 30.5 ± 24.1, p = 0.32). While a difference was observed in time-to-symptom resolution between initial/repeat concussion (21.2 ± 16.3 vs. 41.7 ± 86.0 days, p = 0.30), this did not reach statistical significance. No significant differences were observed in time-to-RTL (17.8 ± 60.6 vs. 6.0 ± 8.3 days, p = 0.26) and RTP (33.2 ± 44.1 vs. 29.4 ± 39.1 days, p = 0.75). Repeat concussion was not associated with symptom resolution on univariate (HR 1.64, 95% CI 0.96-2.78, p = 0.07) and multivariable (HR 0.85, 95% CI 0.49-1.46, p = 0.55) Cox regression. CONCLUSION: No significant differences in symptom duration and RTP/RTL were seen between initial/repeat concussion.