Post-injury Time Points Research Articles

Factors affecting the direct red cell effect on thrombosis: Hematocrit dilution and injury patterns.

Red blood cell (RBC) aggregation can be initiated by calcium and tissue factor, which may independently contribute to microvascular and macrovascular thrombosis after injury and transfusion. Previous studies have demonstrated that increased blood storage duration may contribute to thrombotic events. The aims of this study were to first determine the effect of blood product components, age, and hematocrit (HCT) on the aggregability of RBCs, followed by measurement of RBC aggregability in two specific injury models including traumatic brain injury (TBI) and hemorrhagic shock. Human whole blood (WB) units were obtained following the standard 21-day storage period. Whole blood was separated into components including RBCs, platelet-rich plasma (PRP), and platelet-poor plasma (PPP) via serial centrifugation and diluted to a standardized HCT on Days 2 and 23 following isolation. Finally, WB was collected from murine models of TBI and hemorrhagic shock at sequential, postinjury timepoints. Whole blood and component groups were analyzed for RBC aggregability with calcium and tissue factor initiated electrical impedance aggregometry. At both timepoints, nondiluted HCT RBCs demonstrated similar aggregability to standardized-HCT RBCs when diluted with phosphate buffered saline (PBS). Red blood cells diluted with PRP and PPP demonstrated significantly higher aggregation than RBCs diluted with PBS at both timepoints. Reconstitution with PRP and PPP demonstrated similar aggregability. Murine RBCs demonstrated increased aggregation at the 4-hour postinjury timepoint following TBI and decreased aggregation at the 1-hour postinjury following hemorrhagic shock. Neither hemoconcentration or age of donated blood products affect the calcium and tissue-factor dependent aggregability of RBCs. Further, RBC aggregation is increased in the presence of plasma, not platelets-indicating a potential role for plasma in regulating RBC aggregation. Finally, injury patterns including TBI and hemorrhagic shock may influence hypercoagulability or coagulopathy via change in RBC aggregability. Human sample and animal model-based study; Basic science paper.

Supra-Prophylactic Doses of Enoxaparin Reduces Fibrin Deposition Without Exacerbation of Intracerebral Hemorrhage in a Rat Model of Penetrating Traumatic Brain Injury.

Deep vein thrombosis and pulmonary embolism prophylaxis is an important part of trauma care. Despite an increased risk of thrombotic complications, the use of venous thrombosis chemoprophylaxis in penetrating traumatic brain injury (pTBI) patients is met with reluctance from neurosurgeons because of concern for the exacerbation of intracerebral hemorrhage. The objective of this study was to provide initial pre-clinical evidence of the effects of Lovenox (LVX) administration following pTBI with significant intracerebral hemorrhage. Sprague-Dawley rats received a penetrating ballistic-like brain injury. Animals were randomly divided into two groups following injury: LVX (25 mg/kg) or vehicle (VEH, saline). LVX or vehicle was administered subcutaneously beginning 24 h after the injury and continued daily for 7 days post-injury. A neurological assessment was performed daily and magnetic resonance imaging (MRI) was performed at baseline, 1, 2, 3, and 7 days post-injury. Following the final MRI, brains were isolated and prepared for histological analysis. Thromboelastography demonstrated dramatic anticoagulation effects which were confirmed by significant increases in partial thromboplastin time (p < 0.001). Daily neurological assessment revealed no worsening of functional deficits following LVX treatment. MRI analysis demonstrated no differences in cerebral edema or intracranial hemorrhage volumes between treatment groups at any tested post-injury time points. However, LVX elicited a significant reduction in fibrin deposition in the ipsilateral striatum and lesion site at 7 days post-injury (p < 0.05). Serum levels of beta-amyloid were decreased at 7 days following LVX treatment (p < 0.05) which may indicate neuroprotective effects but was not correlated to brain levels. The results presented indicate that administration of LVX at a dose capable of inducing anticoagulation is safe in a rodent model of pTBI without exacerbation of intracerebral hemorrhage within the first 7 days of injury.

The neurocognitive correlates of DTI indicators of white matter disorganization in pediatric moderate-to-severe traumatic brain injury.

Neuroimaging has expanded our understanding of pediatric brain disorders in which white matter organization and connectivity are crucial to functioning. Paralleling the known pathobiology of many neurodevelopmental disorders, traumatic brain injury (TBI) in childhood can alter trajectories of brain development. Specifically, diffusion tensor imaging (DTI) studies in TBI have demonstrated white matter (WM) abnormalities that suggest microstructural disruptions that may underlie atypical neurodevelopment. The neurocognitive correlates of these previous findings will be explored in this study. Indicators of WM organization were collected in 44 pediatric patients with moderate/severe TBI and 76 controls over two post-injury time points: T1 (8-20 weeks) and T2 (54-96 weeks). Our previous work identified two TBI subgroups based on information processing differences: one with slower interhemispheric transfer times (IHTT) of visual information than controls and another with comparable IHTT. We extend this prior work by evaluating neurocognitive trajectories associated with divergent WM structure post-injury in slow and normal IHTT TBI subgroups. At T1, both TBI subgroups performed significantly worse than controls on a norm-referenced working memory index (WMI), but only the Normal IHTT TBI subgroup significantly improved over the 12-month follow-up period (p = 0.014) to match controls (p = 0.119). In contrast, the Slow IHTT TBI subgroup did not show any recovery in working memory performance over time and performed more poorly than the control group (p < 0.001) at T2. Improvement in one of the two WMI subtests was associated with DTI indicators of WM disorganization in CC tracts to the precentral, postcentral, frontal, and parietal cortices. IHTT and WM mean diffusivity predicted 79% of the variance in cognitive recovery from T1 to T2 when also accounting for other known predictors of TBI recovery. In the year following TBI, some pediatric patients experienced persisting working memory disturbance while others exhibited recovery; stratification was based on an event-related potential marker. More or less improvement in neurocognition was also associated with the degree of WM disorganization. IHTT, measured post-acutely after TBI, and progression of WM disorganization over time predicted neurocognitive trajectories at the chronic timeframe - potentially representing a prognostic biomarker.

Predictors of Psychiatric Hospitalization After Discharge From Inpatient Neurorehabilitation for Traumatic Brain Injury.

To examine, among persons discharged from inpatient rehabilitation for traumatic brain injury (TBI), the degree to which pre-TBI factors were associated with post-TBI hospitalization for psychiatric reasons. The authors hypothesized that pre-TBI psychiatric hospitalization and other pre-TBI mental health treatment would predict post-TBI psychiatric hospitalization following rehabilitation discharge, up to 5years post-TBI. Five Veterans Affairs Polytrauma Rehabilitation Centers. Participants with nonmissing rehospitalization status and reason, who were followed at 1 year (N=1006), 2years (N =985), and 5years (N =772) post-TBI. A secondary analysis of the Veterans Affairs TBI Model Systems, a multicenter, longitudinal study of veterans and active-duty service members with a history of mild, moderate, or severe TBI previously admitted to comprehensive inpatient medical rehabilitation. This study examined participants cross-sectionally at 3 follow-up timepoints. Psychiatric Rehospitalization was classified according to Healthcare Cost and Utilization Project multilevel Clinical Classifications diagnosis terminology (Category 5). Rates of post-TBI psychiatric hospitalization at years 1, 2, and 5 were 4.3%, 4.7%, and 4.1%, respectively. While bivariate comparisons identified pre-TBI psychiatric hospitalization and pre-TBI mental health treatment as factors associated with psychiatric rehospitalization after TBI across all postinjury timepoints, these factors were statistically nonsignificant when examined in a multivariate model across all timepoints. In the multivariable analysis, pre-TBI psychiatric hospitalization was significantly associated with increased odds of post-TBI psychiatric hospitalization only at 1-year post-TBI (adjusted odds ratio=2.65; 95% confidence interval, 1.07-6.55, P =.04). Posttraumatic amnesia duration was unrelated to psychiatric rehospitalization. Study findings suggest the limited utility of age, education, and pre-TBI substance use and mental health utilization in predicting post-TBI psychiatric hospitalization. Temporally closer social and behavior factors, particularly those that are potentially modifiable, should be considered in future research.

Enhancement of Heme-Oxygenase 1 in the Injured Peripheral Nerve Following Sulforaphane Administration Fosters Regeneration via Proliferation and Maintenance of Repair Schwann Cells.

Nuclear erythroid 2-related factor 2 (Nrf2) and its downstream effector heme oxygenase 1 (HO-1) are commonly activated in response to cellular stresses. The elevated expression of HO-1 has been associated with markedly accelerated peripheral nerve regeneration. This study aimed to evaluate the impact of a naturally occurring dietary Nrf2/HO-1 activator-sulforaphane (SFN)-on regeneration in a murine sciatic nerve crush model. The beneficial safety profile of SFN has been thoroughly investigated and confirmed several times. Here, SFN was administered daily, starting immediately after C57BL/6 mice were subjected to sciatic nerve crush injury. Injured sciatic nerves were excised at various time points post injury for molecular, immunohistochemical and morphometric analyses. Moreover, functional assessment was performed by grip strength analysis and electrophysiology. Following SFN treatment, the early response to injury includes a modulation of autophagic pathways and marked upregulation of Nrf2/HO-1 expression. This enhancement of HO-1 expression was maintained throughout the regeneration phase and accompanied by a significant increase in repair Schwann cells. In these cells, elevated proliferation rates were observed. Significant improvements in grip strength test performance, nerve conduction velocity and remyelination were also noted following SFN treatment. Collectively, SFN modulates cytoprotective and autophagic pathways in the injured nerve, increasing the number of repair Schwann cells and contributing to effective nerve regeneration. Given the availability of SFN as a nutritional supplement, this compound might constitute a novel regenerative approach with broad patient accessibility and further studies on this topic are warranted.

Longitudinal assessment of glymphatic changes following mild traumatic brain injury: Insights from perivascular space burden and DTI-ALPS imaging.

Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Our key findings include: (1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. (2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. (3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information. ePVS burden and ALPS index offers distinct values in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Repeated birth injuries lead to long-term pelvic floor muscle dysfunction in the preclinical rat model

ObjectivesVaginal childbirth is a key risk factor for pelvic floor muscle injury and dysfunction, and subsequent pelvic floor disorders. Multiparity further exacerbates these risks. Using the rat model, validated for the studies of the human pelvic floor muscles, we have previously identified that a single simulated birth injury results in pelvic floor muscle atrophy and fibrosis. We hypothesized that multiple birth injuries would further overwhelm the muscle regenerative capacity, leading to functionally relevant pathological alterations long-term. Study DesignSprague-Dawley rats underwent simulated birth injury and were allowed to recover for 8 weeks before undergoing additional birth injury. Animals were sacrificed at acute (3- and 7-days post injury), subacute (21-, 28-, and 35-days post-injury), and long-term (8- and 12-weeks post-injury) time points post-second injury (N=3-8/time point), and the pubocaudalis portion of the rat levator ani complex was harvested to assess the impact of repeated birth injuries on muscle mechanical and histomorphological properties. The accompanying transcriptional changes were assessed by a customized NanoString panel. Uninjured animals were used as controls. Data with a parametric distribution were analyzed by a two-way analysis of variance followed by post hoc pairwise comparisons using Tukey’s or Sidak’s tests; non-parametrically distributed data were compared with Kruskal-Wallis test followed by pairwise comparisons with Dunn’s test. Data, analyzed using GraphPad Prism v8.0, San Diego, CA, are presented as mean ± SEM or median (range). ResultsFollowing the 1st simulated birth injury, active muscle force decreased acutely relative to uninjured controls (12.9±0.9 vs 25.98±2.1 g/mm2, P<0.01). At 4 weeks, muscle active force production recovered to baseline and remained unchanged at 8 weeks after birth injury (P>0.99). Similarly, precipitous decrease in active force was observed immediately after repeated birth injury (18.07±1.2 vs 25.98±2.1 g/mm2, P<0.05). In contrast to the functional recovery after a single birth injury, a long-term decrease in muscle contractile function was observed up to 12 weeks after repeated birth injuries (18.3±1.6 vs 25.98±2.1 g/mm2, P<0.05). Fiber size was smaller at the long-term time points after 2nd injury compared to the uninjured group (12 weeks vs uninjured control: 1485 (60.7-5000) vs 1989 (65.6-4702) μm2, P<0.0001). The proportion of fibers with centralized nuclei, indicating active myofiber regeneration, returned to baseline at 8 weeks post-1st birth injury, (P=0.95), but remained elevated as far as 12 weeks post-2nd injury (12 weeks vs uninjured control: 7.1±1.5 vs 0.84±0.13%, P<0.0001). In contrast to the plateauing intramuscular collagen content after 4 weeks post-1st injury, fibrotic degeneration increased progressively over 12 weeks after repeated injury (12 weeks vs uninjured control: 6. 7±1.1 vs 2.03±0.2%, P<0.001). Prolonged expression of pro-inflammatory genes accompanied by a greater immune infiltrate was observed after repeated compared to a single birth injury. ConclusionsOverall, repeated birth injuries led to a greater magnitude of pathological alterations compared to a single injury, resulting in more pronounced pelvic floor muscle degeneration and muscle dysfunction in the rat model. The above provides a putative mechanistic link between multiparity and the increased risk of pelvic floor dysfunction in women.

Working Memory Recovery in Adolescents with Concussion: Longitudinal fMRI Study.

Background: Understanding the behavioral and neural underpinnings of the post-concussion recovery of working memory function is critically important for improving clinical outcomes and adequately planning return-to-activity decisions. Previous studies provided inconsistent results due to small sample sizes and the use of a mixed population of participants who were at different post-injury time points. We aimed to examine working memory recovery during the first 6 months post-concussion in adolescents. Methods: We used functional magnetic resonance imaging (fMRI) to scan 45 concussed adolescents [CONCs] at baseline (<10 days post-concussion) and at 6 months post-concussion. Healthy control adolescents [HCs; n = 32] without a history of concussion were scanned once. During the scans, participants performed one-back and two-back working memory tasks with letters as the stimuli and angry, happy, neutral, and sad faces as distractors. Results: All affected adolescents were asymptomatic and cleared to return to activity 6 months after concussion. Working memory recovery was associated with faster and more accurate responses at 6 months vs. baseline (p-values < 0.05). It was also characterized by significant difficulty-related activation increases in the left inferior frontal gyrus (LIFG) and the left orbitofrontal cortex (LOFC) at 6 months vs. baseline. Although the activation differences between one-back and two-back were comparable between HCs and CONCs at 6 months, HCs had more pronounced activation in the LIFG than concussed adolescents. Conclusions: Post-concussion recovery is associated with significant performance improvements in speed and accuracy, as well as the normalization of brain responses in the LIFG and LOFC during the n-back task. The observed patterns of LOFC activation might reflect compensatory strategies to distribute neural processing and reduce neural fatigue post-concussion.

Longitudinal Assessment of Glymphatic Changes Following Mild Traumatic Brain Injury: Insights from PVS burden and DTI-ALPS Imaging.

Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Our key findings include: 1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. 2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. 3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information, highlighting their distinct roles in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Septin4 Promotes Fibrosis In The Heart After Pressure Overload

Background: In response to cardiac injury, the heart undergoes a remodeling process, which may be defined by a complex set of genomic, expression, molecular, cellular and interstitial changes, which can become maladaptive and contribute to the development of heart failure (HF). One of the most important components in cardiac remodeling is the development of fibrosis, which is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts, which disrupts the myocardial architecture and function, thus predisposing the progression of cardiac diseases to HF. The small GTPase Septin4 (Sept4) has been described to regulate regeneration and apoptosis in several organs. However, the role of Sept4 in regulating the cardiac stress response is unknown. The present study was designed to investigate if Sept4 would be mediating the alterations associated with cardiac remodeling induced by cardiac pressure overload. Hypothesis: We hypothesized that Sept4 deletion prevents the fibrotic response associated with cardiac remodeling, and the development and progression of HF triggered by transverse aortic constriction (TAC). Methods: 10-week-old wild type (WT) and Sept4 knockout (KO) mice were subjected to TAC to induce cardiac pressure overload. Functional and molecular analyses on WT and KO hearts were performed either at baseline, 1- or 4-weeks post-injury timepoints. Results: After TAC injury, WT mice showed a significant reduction of cardiac function and the development of heart failure, while KO mice were able to maintain normal cardiac function. KO hearts exhibited decreased levels of cardiac ECM deposition and fibrosis compared with WT hearts. Furthermore, KO hearts were more compliant and demonstrated improved end diastolic pressure compared with their WT counterparts. The differentiation of fibroblasts into myofibroblasts was impaired in KO hearts compared with WT controls, which appeared to be associated with attenuated TGF-β-triggered signaling pathway in KO hearts after TAC injury. In line with these findings, we verified in cultured cardiac fibroblasts (CFBs) that Sept4 deletion resulted in reduced myofibroblasts differentiation and a blunted ability of CFBs to contract. Conclusion: Our results demonstrate that Sept4 is an important regulator of ECM remodeling in the heart. Sept4 deletion leads to reduced levels of cardiac fibrosis and attenuation of pressure overload-induced cardiac dysfunction. These findings highlight Sept4 as a potential target to prevent fibrosis in cardiac stress response. This study was supported by grants from the National Institutes of Health (HL155993 and HL160665). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rehabilitation with intensive attention training early after acquired brain injury promotes better long-term status on health-related quality of life, daily activities, work ability and return to work.

To describe long-term effects on activity, participation, and quality of life (i) at different post-injury starting time points of attention training and (ii) of two different types of rehabilitation with attention training in patients after stroke or traumatic brain injury; and to describe their functioning level. 2 years after rehabilitation intervention, comparisons were made in one cohort receiving attention training subacute (< 4 months) or post-acute (4-12 months) and in one cohort with two different training methods, a process-based and an activity-based method respectively. 100 patients were recruited from our earlier RCT study. They had mild to moderate stroke or traumatic brain injury with relatively limited symptomatology, and all had moderate to severe attention impairment. A questionnaire-based interview: EuroQol 5 dimensions, Occupational Gaps Questionnaire, Work Ability Index, self-assessed work status, self-reported employment conditions, sick leave, and experienced cognitive limitations in work performance. An advantage for patients receiving subacute attention training regarding daily activities, work ability and returning to work. The results indicate that subacute rehabilitation with attention training (< 4 months) is preferable compared to post-acute intervention (4-12 months). There were only minor differences between the training methods.

Reduced Concussion Symptom Burden in Early Adolescent Athletes Using a Head-Neck Cooling Device.

To determine whether an investigational head-neck cooling device, Pro2cool, can better reduce symptom severity compared with standard postconcussion care in early adolescent athletes after a sports-related concussion. Prospective, longitudinal, randomized trial design conducted over a 28-day period. Six pediatric medical centers in Ohio and Michigan. The study enrolled 167 male and female 12- to 19-year-old athletes who experienced a sports-related concussion within 8 days of study enrollment and registering a Sports Concussion Assessment Tool 5 (SCAT5) composite score >7. Pro2cool, an investigational head-neck cooling therapy device, was applied at 2 postinjury time points compared with postconcussion standard of care only. Baseline SCAT5 composite symptom severity scores were determined for all subjects. Sports Concussion Assessment Tool 5 scores for concussed athletes receiving cooling treatment were analyzed across 6 independent postenrollment time points compared with subjects who did not receive cooling therapy and only standard care. Adverse reactions and participate demographics were also compared. Athletes who received Pro2cool cooling therapy (n = 79) experienced a 14.4% greater reduction in SCAT5 symptom severity scores at the initial visit posttreatment, a 25.5% greater reduction at the 72-hour visit posttreatment, and a 3.4% greater reduction at the 10-day visit compared with subjects receiving only standard care (n = 88). Overall, 36 adverse events (increased blood pressure, decreased pulse, and dizziness) were reported, with 13 events associated with the device, of which 3 were classified as moderate in severity. This study demonstrates the efficacy and safety of head and neck cooling for the management of concussion symptoms in adolescent athletes of an age group for which little to no prior data are available.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury.

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

47 Predicting Impulsivity Across Multiple Stages of Time-Since-Injury in mild TBI using Resting State Functional Connectivity

Objective:Mild traumatic brain injury (mTBI) remains one of the most silent recurrent head injuries reported in the United States. mTBI accounts for nearly 75 percent of all traumatic brain injuries in the American population. Brain injury is often associated with impulsivity, but the association between resting state functional connectivity (rsFC) and impulsivity at multiple stages since time-since-injury (TSI) is unclear. We hypothesized that rsFC within the default mode network (DMN) would predict impulsivity across multiples stages of recovery in mild TBI.Participants and Methods:Participants healthy controls (HC: n=35 total [15 male, 20 female], age M=24.40, SD=5.95; mTBI: n=121 total [43 male; 78 female], age M=24.76, SD=7.48). Participants completed a cross-sectional study design at various post-injury time points ranging from (2W, 1M,3M,6M,12M). Participants a neuroimaging session and behavioral tasks including a psychomotor vigilance task. Impulsivity was assessed as a combination of false starts and impulsive responses on behavioral tasks. The neuroimaging session included a rsFC scan. To predict impulsivity from brain connectivity, we conducted a series of stepwise linear regression analyses with the 11 functional brain connections (extracted as Fisher’s z-transformed correlations between regions) as predictors and each of the 13 neurocognitive factor scores separately. We focus here on the outcomes for the impulsivity factor.Results:Results showed greater positive connectivity between the and Right Frontal Pole and the anterior cingulate cortex (ACC; seed) (ß = .158, t = 1.98, p = .049) which was associated with greater impulsivity. Individuals in the 2W group demonstrated one significant predictor (R = .632, R2 = .399, F = 5.32, p = .050). Largely, there was greater positive connectivity between the Right Frontal Pole and the ACC (seed) and (ß = .632, t = 2.31, p = .050) which was associated with higher impulsivity at the 2W time-since-injury. No predictors emerged for the 1M, 3M, or 6M conditions. However, individuals in the 12M group demonstrated two significant predictor connections (R = .497, R2 = .247, F = 5.73, p = .007). Overall, a linear combination of greater negative (anticorrelated) connectivity between the Right Frontal Pole and the mPFC (seed) (/? = -.576, t = -3.53, p = .002) and greater positive connectivity between the Paracingulate Cortex (seed) and the Left Lateral Prefrontal Cortex (ß = .368, t = 2.14, p = .039) was also associated with greater impulsivity in individuals with mTBI at 12M.Conclusions:These findings suggest functional connectivity between the anterior node of the DMN and prefrontal cortex regions involved in behavioral control was predictive of higher impulsivity in individuals with mTBI at 2W and 12M post injury, but not at other time frames. Interestingly, these connections differed at the two time points. Acutely, greater impulsivity was associated with greater connectivity among regions involved in error detection, exploration, and emotion. At one year, the connections involve regions associated with error monitoring and inhibitory processes. This may reflect compensatory strategy development during recovery.

46 Resting State FC in the Default Mode Networks: A Prediction Model for Elevated Aggression from Connectivity Metrics and Neurocognitive Performance Across Multiple Stages of Recovery in mild TBI

Objective:Mild traumatic brain injury (mTBI) remains one of the most prevalent brain injuries, affecting approximately one-in-sixty Americans. Previous studies have shown an association between white matter integrity and aggression at chronic stages (either 6-months or 12 months post-mTBI) however, the association between white matter axonal damage, neuropsychological outcomes, and elevated aggression in multiple stages since time-since-injury (TSI) is unclear. We hypothesized that functional connectivity between the default mode network (DMN), a key brain network involved in cognitive, self-reflective, and emotional processes, and other cortical regions would predict elevated aggression and emotional disturbances across multiples stages of recovery in mild TBI.Participants and Methods:Participants healthy controls (HC: n=35 total [15 male, 20 female], age M=24.40, SD=5.95; mTBI: n=121 total [43 male; 78 female], age M = 24.76, SD=7.48). Participants completed a cross-sectional study design at specific post-injury time points ranging from (2W, 1M,3M,6M,12M). Participants completed a comprehensive neuropsychological battery and a neuroimaging session, including resting state functional connectivity (FC). Here, we focus on the FC outcomes for the DMN. During the neuropsychological assessment, participants completed tests that measured learning and memory, speed of information processing, executive function, and attention. To predict neuropsychological performance from brain connectivity, we conducted a series of stepwise linear regression analyses with the 11 functional brain connections (extracted as Fisher’s z-transformed correlations between regions) as predictors and each of the 13 neurocognitive factor scores separately.Results:Consistent with our hypothesis, one predictor materialized as significant (R = .187, R2 = .035, F = 5.55, p = .020) for the Total Sample. Largely, positive connectivity between Right Inferior Frontal Gyrus and the PCC (seed) was associated with increased aggression in the Total Sample of all participants (ß = .187, t = 2.36, p = .020). One predictor materialized as significant in Individuals the 2W group, (R = .719, R2 = .518, F = 8.58, p = .019). In general, greater negative (anticorrelated) connectivity between the Left Lateral Occipital Cortex (ß = -.719, t = -2.93, p = .019) and the PCC (seed) and was associated with greater aggression at 2W, but no predictors emerged at 1M or 3M. Individuals in the 6M group showed one significant predictor (R = .675, R2 = .455, F = 16.71, p = .001). Specifically, greater positive connectivity between the Right Lateral Occipital Cortex (/? = .675, t = 4.09, p = .001) and PCC (seed) was associated with greater aggression at 6M. No associations were evident at 12M.Conclusions:Overall, these findings suggest functional connectivity between the posterior hub of the DMN and cortical regions within the occipital cortex was predictive of higher aggression in individuals with mTBI. However, the direction of this connectivity differed at 2W versus 6M, suggesting a complex process of recovery that may contribute differentially to aggression in patients with mTBI. As these regions are involved in self-consciousness and visual perception, this may point toward future avenues for aiding in functional recovery of emotional dysregulation in patients with persistent post-concussion syndrome.

4 Extending the 5P Clinical Decision Rule Predicting Concussion Recovery Using an Evidence-Based Assessment Model

Objective:Construction of predictive algorithms of concussion symptom recovery at 4 and 12 weeks post-injury using an evidence-based assessment (EBA) model to guide clinical decision-making, extending the 2016 5P decision rule.Participants and Methods:Children and adolescents, ages 8-18 (n=1,551; mean age=12.78; 62% male), followed over 12 weeks in the prospective multicenter cohort study (Predicting Persistent Post-Concussive Problems in Pediatrics, 5P; Zemek et al., 2016). The age-specific PostConcussion Symptom Inventory (PCSI) (8-12, 17 items; 1318 years, 20 items) was completed at six timepoints from the ED and at 1, 2, 4, 8, and 12-weeks post-injury. Logistic regression analysis was applied to the set of key variables including the PCSI Total Retrospective-Adjusted PostInjury Difference (RAPID) scores, patient demographics and pre-injury history, and injury characteristics to predict participant recovery status (Recovered, Not Recovered) at the 4- and 12-week endpoints. The resulting recovery-predictive equations identified the significant sets of variables with symptom scores at four successive post-injury timepoints (ED, 1, 2, 4 weeks). Logistic Regression Threshold values were established at the 90th CI against which individual patient data was applied to determine recovery status. Participants with sub-threshold sums were deemed recovered at the target endpoint (4- or 12-weeks post-injury).Results:A total of 19 predictive equations were generated for the two age groups across the recovery timeline. Four sets of equations were developed to predict symptom recovery status at 4-weeks post-injury for the two age groups (8-12 AUC=0.679-0.884; 13-18 AUC=0.752-0.909). Prediction of symptom recovery status at 12-weeks post-injury yielded six equations for the 8-12 age group (AUC=0.723-0.825), and five equations for the 13-18 age group (AUC=0.724-0.887). Total PCSI RAPID score was identified as a significant variable in each of these 19 equations. Participant sex was identified as significant in 18 of the 19 constructed equations. Other variables that were identified as significant at varying timepoints included age, pre-injury history of learning disability and migraines, and an early post-injury sign in the ED (answering questions more slowly than usual). Examples of the equations include: Week 1 predicting symptom recovery status at 4-weeks: 8-12 yr group-(Sex*.802)+(week 1 Total RAPID Score*.142)+(Age2* .053)+(-3.851) with AUC=0.808; 13-18 yr group-(Sex*.980)+(Week 1 Total RAPID Score*.071)+(-3.261) with AUC=0.861.Conclusions:Clinicians’ management of the concussion recovery of children and adolescents can benefit from EBA guidance. The 5P dataset (Zemek et al., 2016) provides an important window into “typical” and “atypical” recovery trajectories, establishing an initial predictive decision rule for a 4-week recovery endpoint, at the ED timepoint only, reporting AUC=0.69. The current study extends the prediction modeling using successive post-injury timepoints reflecting a typical management timeline. Symptom reports from both 1- and 2-weeks post injury with patient demographics/ history predicted symptom recovery status at 4- and 12-weeks post-injury, significantly improve predictive accuracy over the ED timepoint alone. These predictive equations, when applied to the individual patient, can serve to assist the clinician’s understanding of the patients’ recovery trajectory, i.e., on track for a typical or atypical recovery, further informing the intervention strategy.

Sex- and Age-Related Differences in Post-Concussive Symptom Reporting Among Children and Their Parents.

Pediatric mild traumatic brain injury (pmTBI) has received increased public attention over the past decade, especially for children who experience persistent post-concussive symptoms (PCS). Common methods for obtaining pediatric PCS rely on both self- and parental report, exhibit moderate test-retest reliability, and variable child-parent agreement, and may yield high false positives. The current study investigated the impact of age and biological sex on PCS reporting (Post-Concussion Symptom Inventory) in patients with pmTBI (n = 286) at retrospective, 1 week, 4 months, and 1 year post-injury time points, as well as reported symptoms in healthy controls (HC; n = 218) at equivalent assessment times. HC and their parents reported higher PCS for their retrospective rating relative to the other three other study visits. Child-parent agreement was highest for female adolescents, but only approached acceptable ranges (≥ 0.75) immediately post-injury. Poor-to-fair child/parental agreement was observed for most other study visits for pmTBI and at all visits for HC. Parents rated female adolescents as being more symptomatic than their male counterparts in spite of small (pmTBI) or no (HC) sex-related differences in self-reported ratings, suggestive of a potential cultural bias in parental ratings. Test-retest reliability for self-report was typically below acceptable ranges for both pmTBI and HC groups, with reliability decreasing for HC and increasing for pmTBI as a function of time between visits. Parental test-retest reliability was higher for females. Although continued research is needed, current results support the use of child self-report over parental ratings for estimating PCS burden. Results also highlight the perils of relying on symptom self-report for diagnostic and prognostic purposes.

Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.

Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control = 52, mTBI = 21, PTSD = 34, and TBI + PTSD = 13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.

Cerebrospinal fluid levels of neuroinflammatory biomarkers are increased in athletes with persistent post-concussive symptoms following sports-related concussion

A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < − 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.

A mouse model of repeated traumatic brain injury-induced hearing impairment: Early cochlear neurodegeneration in the absence of hair cell loss

PurposeTraumatic Brain Injury (TBI) is a major cause of death and disability worldwide. Mounting evidence suggests that even mild TBI injuries, which comprise >75% of all TBIs, can cause chronic post-concussive neurological symptoms, especially when experienced repetitively (rTBI). The most common post-concussive symptoms include auditory dysfunction in the form of hearing loss, tinnitus, or impaired auditory processing, which can occur even in the absence of direct damage to the auditory system at the time of injury. The mechanism by which indirect damage causes loss of auditory function is poorly understood, and treatment is currently limited to symptom management rather than preventative care. We reasoned that secondary injury mechanisms, such as inflammation, may lead to damage of the inner ear and parts of the brain used for hearing after rTBI. Herein, we established a model of indirect damage to the auditory system induced by rTBI and characterized the pathology of hearing loss. MethodsWe established a mouse model of rTBI in order to determine a timeline of auditory pathology following multiple mild injuries. Mice were subject to controlled cortical impact at the skull midline once every 48 h, for a total of 5 hits. Auditory function was assessed via the auditory brainstem response (ABR) at various timepoints post injury. Brain and cochleae were collected to establish a timeline of cellular pathology. ResultsWe observed increased ABR thresholds and decreased (ABR) P1 amplitudes in rTBI vs sham animals at 14 days post-impact (dpi). This effect persisted for up to 60 days (dpi). Auditory temporal processing was impaired beginning at 30 dpi. Spiral ganglion degeneration was evident at 14 dpi. No loss of hair cells was detected at this time, suggesting that neuronal loss is one of the earliest notable events in hearing loss caused by this type of rTBI. ConclusionsWe conclude that rTBI results in chronic auditory dysfunction via damage to the spiral ganglion which occurs in the absence of any reduction in hair cell number. This suggests early neuronal damage that may be caused by systemic mechanisms similar to those leading to the spread of neuronal death in the brain following TBI. This TBI-hearing loss model provides an important first step towards identifying therapeutic targets to attenuate damage to the auditory system following head injury.