Traumatic Brain Injury Subjects Research Articles

Cerebral and Peripheral Immune Cell Changes following Rodent Juvenile Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of death and disability. TBI is associated with neuroinflammation, but temporal changes in immune and inflammatory signaling following TBI have not been fully elucidated. Furthermore, there have been no previous studies on changes in immune cell populations following TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). The current study aimed to determine the time course changes to inflammatory marker mRNA expression in the acute period following TBI in juvenile rats and to determine acute changes to brain and circulating immune cell populations. For this study, post-natal day (PND)-30 male Long Evans rats sustained a TBI or Sham TBI and were euthanized at 0, 3, 6, 12, 24, or 96 h post-injury. Prefrontal cortex and hippocampus samples were used to determine mRNA expression changes of inflammatory factors. The mRNA expression of the pro-inflammatory cytokine TNF-α was significantly elevated at 6 h post-injury in both regions evaluated. To evaluate immune cell populations, male Long Evans rats were euthanized at 48 h post-injury, and brain and blood samples were used for cell sorting by marker-specific antibodies. In the peripheral blood, there was an elevation in CD3+ total T cells, CD45R+ total B cells, and CD3+CD4+ helper T cells in the TBI subjects. However, there were no changes to natural killer cells or CD3+CD8+ cytotoxic T cell populations. In the brain, there was a reduction in CD11b/c+ monocytes/macrophages, but no changes in other immune cell populations. At 48 h post-injury, the TBI subjects also demonstrated expansion of the thymic medulla. These changes in the cerebral and blood immune cell populations and thymic medulla expansion may implicate the subacute recovery timeframe as a vulnerable window for the immune system in the pediatric population.

Brain Fluid Clearance After Traumatic Brain Injury Measured Using Dynamic Positron Emission Tomography.

Brain fluid clearance by pathways including the recently described paravascular glymphatic system is a critical homeostatic mechanism by which metabolic products, toxins, and other wastes are removed from the brain. Brain fluid clearance may be especially important after traumatic brain injury (TBI), when blood, neuronal debris, inflammatory cells, and other substances can be released and/or deposited. Using a non-invasive dynamic positron emission tomography (PET) method that models the rate at which an intravenously injected radiolabeled molecule (in this case 11C-flumazenil) is cleared from ventricular cerebrospinal fluid (CSF), we estimated the overall efficiency of brain fluid clearance in humans who had experienced complicated-mild or moderate TBI 3-6 months before neuroimaging (n = 7) as compared to healthy controls (n = 9). While there was no significant difference in ventricular clearance between TBI subjects and controls, there was a significant group difference in dependence of ventricular clearance upon tracer delivery/blood flow to the ventricles. Specifically, in controls, ventricular clearance was highly, linearly dependent upon blood flow to the ventricle, but this relation was disrupted in TBI subjects. When accounting for blood flow and group-specific alterations in blood flow, ventricular clearance was slightly (non-significantly) increased in TBI subjects as compared to controls. Current results contrast with past studies showing reduced glymphatic function after TBI and are consistent with possible differential effects of TBI on glymphatic versus non-glymphatic clearance mechanisms. Further study using multi-modal methods capable of assessing and disentangling blood flow and different aspects of fluid clearance is needed to clarify clearance alterations after TBI.

Multi-modal MRI of hippocampal morphometry and connectivity after pediatric severe TBI

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1–2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies.

Outcomes and physiologic responses associated with ketamine administration after traumatic brain injury in the United States and Canada: a retrospective analysis

Purpose: Ketamine has historically been contraindicated in traumatic brain injury (TBI) due to concern for raising intracranial pressure. However, it is increasingly being used in TBI due to the favorable respiratory and hemodynamic properties. To date, no studies have evaluated whether ketamine administered in subjects with TBI is associated with patient survival or disability. Methods: We performed a retrospective analysis of data from the multicenter Prehospital Tranexamic Acid Use for Traumatic Brain Injury trial, comparing ketamine-exposed and ketamine-unexposed TBI subjects to determine whether an association exists between ketamine administration and mortality, as well as secondary outcome measures.Results: We analyzed 841 eligible subjects from the original study, of which 131 (15.5%) received ketamine. Ketamine-exposed subjects were younger (37.3±16.9 years vs. 42.0±18.6 years, P=0.037), had a worse initial Glasgow Coma Scale score (7±3 vs. 8±4, P=0.003), and were more likely to be intubated than ketamine-unexposed subjects (88.5% vs. 44.2%, P<0.001). Overall, there was no difference in mortality (12.2% vs. 15.5%, P=0.391) or disability measures between groups. Ketamine-exposed subjects had significantly fewer instances of elevated intracranial pressure (ICP) compared to ketamine-unexposed subjects (56.3% vs. 82.3%, P=0.048). In the very rare outcomes of cardiac events and seizure activity, seizure activity was statistically more likely in ketamine-exposed subjects (3.1% vs. 1.0%, P=0.010). In the intracranial hemorrhage subgroup, cardiac events were more likely in ketamine-exposed subjects (2.3% vs. 0.2%, P=0.025). Ketamine exposure was associated with a smaller increase in TBI protein biomarker concentrations.Conclusions: Ketamine administration was not associated with worse survival or disability despite being administered to more severely injured subjects. Ketamine exposure was associated with reduced elevations of ICP, more instances of seizure activity, and lower concentrations of TBI protein biomarkers.

A-093 Clinical Performance of Biomarkers for Traumatic Brain Injury

Abstract Background An estimated 5 million people are evaluated in emergency departments (ED) for Traumatic Brain Injury (TBI) in the United States each year. The vast majority (80%) of patients evaluated for TBI in the ED will receive head CT scans, however less than 10% of those will have any findings of acute traumatic abnormalities. This highlights the need for objective, rapid, accurate tools to help clinicians evaluate and triage TBI patients and reduce unnecessary radiation exposure. The Alinity i TBI test is a panel of in vitro diagnostic chemiluminescent microparticle immunoassays used to measure glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in human plasma and serum. TBI performance was evaluated in a multi-center study by performing reproducibility and a pivotal study. Methods A pivotal study using prospectively collected archived (frozen) plasma specimens was conducted to establish the clinical performance of the TBI test on the Alinity i system. The testing of the archived specimens was performed at three clinical sites in the United States. The specimens tested were originally collected in a prospective, multi-center clinical study and were from individuals 18 years of age or older who presented to a health care facility or emergency department with suspected traumatic brain injury. These subjects had an initial Glasgow Coma Scale (GCS) score of 13–15 and had a computed tomography (CT) scan of the head performed per the clinical site’s standard of care. Reproducibility was assessed using multiple panel/control members for 5 days based on guidance from Clinical and Laboratory Standards Institute EP05-A3. Testing was conducted using 3 lots of GFAP and UCH-L1 reagents, and 1 Alinity i system at each of 3 testing sites. Results Of the 1899 mild TBI subjects, 120 had positive head CT scan results; 116 of the 120 specimens had a positive TBI interpretation (Sensitivity 96.7%;95%CI:91.7%,98.7%). Of the 1779 subjects with negative CT scan results, 713 had a negative TBI interpretation (Specificity 40.1%;95%CI:37.8%,42.4%). The negative predictive value (NPV) of the test was 99.4% (713/717, 95%CI:98.6%,99.8%). Within-Laboratory imprecision (includes repeatability, between-run, and between-day variance components) results ranged from 2.2% to 3.5% CV for GFAP and 1.8 to 3.2 %CV for UCH-L1. The Overall Reproducibility (includes repeatability, between-run, between-day, between-lot, between-site, and site-lot interaction variance components) results ranged from 2.5% to 4.7% CV for GFAP and 2.6 to 6.6 %CV for UCH-L1. Conclusion The Alinity i TBI clinical performance results demonstrated that the TBI test is characterized by high sensitivity and high NPV, which supports the clinical utility to assist in determining the need for a CT scan of the head in subjects presenting with suspected mild TBI. The GFAP and UCH-L1 assays demonstrated acceptable reproducibility across a wide dynamic range. These assays can report results within 18 min and be conveniently loaded into the Electronic Health Records to aid clinicians in their triage (or imaging) decisions. Funding The study was funded by Abbott Laboratories and in collaboration with the US Army Medical Materiel Development Activity, US Army Medical Research and Development Command CRADA 20-1266-CRA.

Covert Tracking to Immersive Stimuli in Traumatic Brain Injury Subjects With Disorders of Consciousness.

Eye tracking assessments are clinician dependent and can contribute to misclassification of coma. We investigated responsiveness to videos with and without audio in traumatic brain injury (TBI) subjects using video eye-tracking (VET). We recruited 20 healthy volunteers and 10 unresponsive TBI subjects. Clinicians were surveyed whether the subject was tracking on their bedside assessment. The Coma Recovery Scale-Revised (CRS-R) was also performed. Eye movements in response to three different 30-second videos with and without sound were recorded using VET. The videos consisted of moving characters (a dancer, a person skateboarding, and Spiderman). Tracking on VET was defined as visual fixation on the character and gaze movement in the same direction of the character on two separate occasions. Subjects were classified as "covert tracking" (tracking using VET only), "overt tracking" (VET and clinical exam by clinicians), and "no tracking". A k-nearest-neighbors model was also used to identify tracking computationally. Thalamocortical connectivity and structural integrity were evaluated with EEG and MRI. The ability to obey commands was evaluated at 6- and 12-month follow-up. The average age was 29 (± 17) years old. Three subjects demonstrated "covert tracking" (CRS-R of 6, 8, 7), two "overt tracking" (CRS-R 22, 11), and five subjects "no tracking" (CRS-R 8, 6, 5, 6, 7). Among the 84 tested trials in all subjects, 11 trials (13%) met the criteria for "covert tracking". Using the k-nearest approach, 14 trials (17%) were classified as "covert tracking". Subjects with "tracking" had higher thalamocortical connectivity, and had fewer structures injured in the eye-tracking network than those without tracking. At follow-up, 2 out of 3 "covert" and all "overt" subjects recovered consciousness versus only 2 subjects in the "no tracking" group. Immersive stimuli may serve as important objective tools to differentiate subtle tracking using VET.

Prevalence of comorbidities post mild traumatic brain injuries: a traumatic brain injury model systems study.

Traumatic brain injury (TBI) is associated with an increased risk of long-lasting health-related complications. Survivors of brain trauma often experience comorbidities which could further dampen functional recovery and severely interfere with their day-to-day functioning after injury. Of the three TBI severity types, mild TBI constitutes a significant proportion of total TBI cases, yet a comprehensive study on medical and psychiatric complications experienced by mild TBI subjects at a particular time point is missing in the field. In this study, we aim to quantify the prevalence of psychiatric and medical comorbidities post mild TBI and understand how these comorbidities are influenced by demographic factors (age, and sex) through secondary analysis of patient data from the TBI Model Systems (TBIMS) national database. Utilizing self-reported information from National Health and Nutrition Examination Survey (NHANES), we have performed this analysis on subjects who received inpatient rehabilitation at 5 years post mild TBI. Our analysis revealed that psychiatric comorbidities (anxiety, depression, and post-traumatic stress disorder (PTSD)), chronic pain, and cardiovascular comorbidities were common among survivors with mild TBI. Furthermore, depression exhibits an increased prevalence in the younger compared to an older cohort of subjects whereas the prevalence of rheumatologic, ophthalmological, and cardiovascular comorbidities was higher in the older cohort. Lastly, female survivors of mild TBI demonstrated increased odds of developing PTSD compared to male subjects. The findings of this study would motivate additional analysis and research in the field and could have broader implications for the management of comorbidities after mild TBI.

Role of Remifentanil on MAC, Bcl-2, and Bax Levels in Traumatic Brain Injury Rat Models

Abstract: Introduction: Traumatic Brain Injury (TBI) conditions require immediate treatment such as the administration of analgesics and sedation, including remifentanil. TBI will affect the levels of several inflammatory and apoptotic proteins such as MAC, Bax, and Bcl-2. Remifentanil with its high affinity to μ-receptors is thought to affect the levels of these proteins and has neuroprotective properties to prevent secondary brain injury. Objectives: This research aims to determine the effect of giving remifentanil on MAC, Bcl-2, and Bax levels in rats with traumatic brain injury. Materials and Methods: Experimental research was conducted on 24 male Wistar rats, which were randomly divided into four groups. The Group-1 (G1) received an intravenous injection of NaCl, the Group-2 (G2) was given normal saline after TBI induction using the modified Feeney method. Furthermore, the Group-3 and Group-4 (G3 and G4) received fentanyl or remifentanil after TBI induction. The rat brain tissue was analyzed for MAC, Bcl-2, and Bax levels using the ELISA method. The data were analyzed statistically by ANOVA test, followed by Post-Hoc Multiple Comparison Test (p<0.05). Results: The MAC and Bax levels were reduced by the administration of fentanyl and remifentanil to TBI subjects, but increased Bcl-2 levels. The Post Hoc Multiple comparisons showed a significant difference between all group pairs (p<0.05). Meanwhile, the group given remifentanil showed more optimal results than those with fentanyl. Conclusion: The administration of remifentanil injection can act as a neuroprotector in TBI model Wistar rats by decreasing MAC and Bax levels and increasing Bcl-2 levels. Keywords: Bax, Bcl-2, MAC, Remifentanil, Traumatic brain injury.

Effects of apolipoprotein E polymorphism on cerebral oxygen saturation, cerebral perfusion, and early prognosis after traumatic brain injury.

To investigate the effects of the apolipoprotein E (APOE) gene on oxygen saturation and cerebral perfusion in the early stages of traumatic brain injury (TBI). This study included 136 consecutive TBI patients and 51 healthy individuals. The APOE genotypes of all subjects were determined using quantitative fluorescence polymerase chain reaction (QF-PCR). Regional cerebral oxygen saturation (rScO2) of patients with TBI and normal subjects was monitored using near-infrared spectroscopy (NIRS). Computed tomography (CT) perfusion was used to obtain cerebral perfusion in patientswith TBI and normal subjects. In the TBI group, the rScO2 of APOEε4 carriers (53.06 ± 6.87%) was significantly lower than that of non-carriers (58.19 ± 5.83%, p < 0.05). Meanwhile, the MTT of APOEε4 carriers (6.75 ± 1.30 s) was significantly longer than that of non-carriers (5.87 ± 1.00 s, p < 0.05). Furthermore, correlation analysis showed a negative correlation between rSCO2 and MTT in patients with TBI. Both the univariate and multifactorial logistic regression analyses revealed that APOE ε4, hypoxia, MTT >5.75 s, Marshall CT Class, and GCS were independent risk factors for early poor prognosis in patients with TBI. Both cerebral perfusion and cerebral oxygen were significantly impaired after TBI, and low cerebral perfusion and hypoxia were related to poor prognosis of patients with TBI. Compared with APOE ε4 non-carriers, APOE ε4 carriers not only had poorer cerebral perfusion and cerebral oxygen metabolism but also worse prognosis in the early stages of TBI. Furthermore, a negative correlation was observed between the rSCO2 and MTT levels. In addition, both CT perfusion scanning (CTP) and NIRS are reliable for monitoring the condition of patients with TBI in the neurological intensive care unit (NICU).

High-Fat Diet Exacerbates Stress Responsivity in Juvenile Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of death for children in the United States. Juveniles are more likely to sustain TBIs than most other age groups, and TBI has been shown to result in increased anxiety and stress behaviors. In addition, the hypothalamic-pituitary-adrenal (HPA) axis has previously been shown to become dysregulated after a TBI. Further, many children consume diets high in saturated fats and refined sugars, which are also connected to alterations in HPA axis function and behavior disorders. The goal of the current study was to identify a potential relationship between high-fat diet (HFD) consumption and TBI on HPA axis function in juvenile rats. In the present study, male juvenile Long-Evans rats were fed either a combination of an HFD with a high-fructose corn syrup solution or a standard chow diet. On post-natal Day 30, subjects sustained either a sham TBI or a TBI via the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Subjects participated in a trial of the open field test (OFT) following injury. In addition, some rats performed in an acute restraint stress test. All subjects were euthanized 7 days post-injury. Brain and blood plasma samples were collected for use in real-time polymerase chain reaction (RT-PCR), immunohistochemistry, and corticosterone or adrenocorticotropic hormone (ACTH) assays. Immediately following TBI, injured juveniles had increased time to righting and walking, with HFD-fed TBI rats having increased time to walking over Chow-fed TBI rats. HFD-fed TBI rats had a reduced number of entries to the center of the OFT, in addition to reduced time spent in the center compared with HFD Sham controls and Chow TBI rats. During the acute restraint stress test, HFD-fed TBI rats had elevated pre-stress ACTH and corticosterone and post-stress ACTH levels. Pre-stress ACTH levels were significantly elevated in HFD TBI compared with Chow TBI. Further, pre-stress ACTH:corticosterone ratios were elevated in HFD TBI compared with Chow TBI. cFos immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus following the acute restraint stress test was elevated in HFD-fed TBI rats. HFD TBI rats had greater activation of cFos in the PVN compared with Chow TBI. In addition, RT-PCR showed significantly reduced expression of relevant HPA axis genes, NR3C1, NR3C2, and CRHR2, in the hypothalamus of TBI subjects compared with Sham subjects. Further, AVP and CRHR2 in the hypothalamus were significantly reduced in HFD TBI compared with Chow TBI. These results offer evidence that TBI paired with high-fat diet consumption can cause HPA axis dysfunction, resulting in more anxiety-like behaviors.

Functional connectivity alterations in traumatic brain injury patients with late seizures

PTE is a neurological disorder characterized by recurrent and spontaneous epileptic seizures. PTE is a major public health problem occurring in 2–50% of TBI patients. Identifying PTE biomarkers is crucial for the development of effective treatments. Functional neuroimaging studies in patients with epilepsy and in epileptic rodents have observed that abnormal functional brain activity plays a role in the development of epilepsy. Network representations of complex systems ease quantitative analysis of heterogeneous interactions within a unified mathematical framework. In this work, graph theory was used to study resting state functional magnetic resonance imaging (rs-fMRI) and reveal functional connectivity abnormalities that are associated with seizure development in traumatic brain injury (TBI) patients. We examined rs-fMRI of 75 TBI patients from Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) which aims to identify validated Post-traumatic epilepsy (PTE) biomarkers and antiepileptogenic therapies using multimodal and longitudinal data acquired from 14 international sites. The dataset includes 28 subjects who had at least one late seizure after TBI and 47 subjects who had no seizures within 2 years post-injury. Each subject’s neural functional network was investigated by computing the correlation between the low frequency time series of 116 regions of interest (ROIs). Each subject’s functional organization was represented as a network consisting of nodes, brain regions, and edges that show the relationship between the nodes. Then, several graph measures concerning the integration and the segregation of the functional brain networks were extracted in order to highlight changes in functional connectivity between the two TBI groups. Results showed that the late seizure-affected group had a compromised balance between integration and segregation and presents functional networks that are hyperconnected, hyperintegrated but at the same time hyposegregated compared with seizure-free patients. Moreover, TBI subjects who developed late seizures had more low betweenness hubs.

Neuroworsening in the Emergency Department Is a Predictor of Traumatic Brain Injury Intervention and Outcome: A TRACK-TBI Pilot Study.

Neuroworsening may be a sign of progressive brain injury and is a factor for treatment of traumatic brain injury (TBI) in intensive care settings. The implications of neuroworsening for clinical management and long-term sequelae of TBI in the emergency department (ED) require characterization. Adult TBI subjects from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study with ED admission and disposition Glasgow Coma Scale (GCS) scores were extracted. All patients received head computed tomography (CT) scan <24 h post-injury. Neuroworsening was defined as a decline in motor GCS at ED disposition (vs. ED admission). Clinical and CT characteristics, neurosurgical intervention, in-hospital mortality, and 3- and 6-month Glasgow Outcome Scale-Extended (GOS-E) scores were compared by neuroworsening status. Multivariable regressions were performed for neurosurgical intervention and unfavorable outcome (GOS-E ≤ 3). Multivariable odds ratios (mOR) with [95% confidence intervals] were reported. In 481 subjects, 91.1% had ED admission GCS 13-15 and 3.3% had neuroworsening. All neuroworsening subjects were admitted to intensive care unit (vs. non-neuroworsening: 26.2%) and were CT-positive for structural injury (vs. 45.4%). Neuroworsening was associated with subdural (75.0%/22.2%), subarachnoid (81.3%/31.2%), and intraventricular hemorrhage (18.8%/2.2%), contusion (68.8%/20.4%), midline shift (50.0%/2.6%), cisternal compression (56.3%/5.6%), and cerebral edema (68.8%/12.3%; all p < 0.001). Neuroworsening subjects had higher likelihoods of cranial surgery (56.3%/3.5%), intracranial pressure (ICP) monitoring (62.5%/2.6%), in-hospital mortality (37.5%/0.6%), and unfavorable 3- and 6-month outcome (58.3%/4.9%; 53.8%/6.2%; all p < 0.001). On multivariable analysis, neuroworsening predicted surgery (mOR = 4.65 [1.02-21.19]), ICP monitoring (mOR = 15.48 [2.92-81.85], and unfavorable 3- and 6-month outcome (mOR = 5.36 [1.13-25.36]; mOR = 5.68 [1.18-27.35]). Neuroworsening in the ED is an early indicator of TBI severity, and a predictor of neurosurgical intervention and unfavorable outcome. Clinicians must be vigilant in detecting neuroworsening, as affected patients are at increased risk for poor outcomes and may benefit from immediate therapeutic interventions.

Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study.

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Influence of Sex and Muscarinic Activity on Memory Retrieval in Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious global risk factor leading to the onset of cognitive impairment and neurodegenerative diseases. Cognitive and memory impairment following a TBI is associated with the dysregulation of cholinergic neurotransmission in the brains of subjects. The extent of memory impairment following a TBI is linked with the sex of the subject. This study aimed to identify the sex-dimorphic role of muscarinic cholinergic modulation in neurological functioning and episodic memory retrieval in a mouse model of TBI. Balb/c mice were divided into four groups of males and four groups of females (i.e., Sham, TBI, TBI + Scopolamine 1 mg/kg, and TBI + Donepezil 1 mg/kg). After training with the Morris water maze test and fear conditioning, all groups were subjected to brain injury (7.84 × 10-5 J impact force) except for the Sham mice. Following brain injury, scopolamine or donepezil was administered to the respective groups for 5 days. Acute scopolamine immediately after brain trauma showed a neuroprotective effect in the males only, while subchronic donepezil significantly impaired neurological functioning in both sexes. Subchronic scopolamine and donepezil treatment reversed the TBI-induced retrograde amnesia for spatial memory in male mice. Contextual fear memory retrieval was not affected by the TBI and treatments in both sexes. Thus, we concluded that the sex-dimorphic response of the muscarinic receptors in TBI-induced memory impairment depends on the type of memory. This study highlights the potential for therapeutic modalities in TBI subjects.

The Effect of Remifentanil, MgSO4, or Remifentanil-MgSO4 as Neuroprotectors on BDNF, MAC, and Caspase-3 Levels in Wistar Rats with Traumatic Brain Injury

BACKGROUND: Traumatic brain injury (TBI) can lead to cell death and neurologic dysfunction. Meanwhile, Remifentanyl is an opioid with potent analgesia, while magnesium sulfate (MgSO4) has antinociceptive properties that can prevent hemodynamic instability during laryngoscopy. AIM: This study aims to examine the effect of remifentanil, MgSO4 and their combination on BDNF, MAC, and Caspase-3 levels in Wistar rat models with TBI. METHODOLOGY: An experimental study was conducted on 30 male Wistar rats which were randomly divided into five groups. The control group (G1) received normal saline, the induced group (G2) received normal saline after TBI induction using the modified Feeney method, and the treated group (G3, G4, and G5) received remifentanil, MgSO4, and their combination after TBI induction. The rats’ brain tissues were analyzed for BDNF, MAC, and Caspase-3 levels using ELISA. The data were analyzed statistically with ANOVA followed by post hoc Multiple Comparison Test (p &lt; 0.05). RESULTS: Treatment with remifentanil, MgSO4 or the combination of both in TBI subjects reduced MAC and Caspase-3 but increased the BDNF level. The post hoc multiple comparisons showed significant differences in all groups except groups 3 and 5 in terms of MAC (p = 0.190) and Caspase-3 (p = 0.999). The combination of remifentanil-MgSO4 increased BDNF levels significantly. CONCLUSION: The administration of remifentanil, MgSO4 , or their combination can serve as a neuroprotector in Wistar rat models with TBI by lowering MAC and Caspase-3 as well as increasing BDNF levels.

Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury.

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). Methods: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject’s medical history was unknown to the experimenters until after individual subject memory retention results were scored. Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

TNF-α, VEGF, and Procalcitonin Levels Dynamic Changes During Severe Traumatic Brain Injury

BACKGROUND: The variety of traumatic brain injury (TBI) creates difficulty in evaluating its level and the clinical outcome correctly. This study aimed to analyze the level variations and dynamic of serum biomarkers, such as tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and procalcitonin (PCT) in response to severe TBI.METHODS: Intravenous blood samples were collected from 20 TBI subjects at different time points: 0, 12, 24, and 48 hours. The serum levels of TNF-α, VEGF, and PCT were measured using specific monoclonal antibodies by quantitative sandwich enzyme-linked immunosorbent assay (ELISA).RESULTS: In 0, 12, 24, and 48 hours, the serum levels were significantly higher for TNF-α (p&lt;0.0001), VEGF (p&lt;0.0001) and PCT (p&lt;0.0001) compared to the healthy control. In comparison to admission time point, TNF-α had elevated significantly (p&lt;0.001) at 24 hours. PCT showed a significant increase after 48 hours (p&lt;0.02) and VEGF showed no significant differences. Comparing the 3 biomarkers dynamic changes at 0, 12 and 24 hours, PCT level showed to be lower than VEGF and TNF-α levels, while VEGF level showed to be higher than PCT and TNF-α levels. However after 48 hours, PCT level (0.25 ng/mL) had elevated more than VEGF (0.21 ng/mL) and TNF- α (0.18 ng/mL) levels.CONCLUSION: Monitoring PCT in comparison to VEGF and TNF-α can be used to assist the progress of severe TBI, since PCT level progressive changes were associated with time increase.KEYWORDS: trauma, TNF-α, VEGF, PCT, Glasgow Coma Scale

Deficits in Acoustic Startle Reactivity and Auditory Temporal Processing after Traumatic Brain Injury.

Traumatic brain injury (TBI) exacts significant neurological and financial costs on patients and their families. In adult patients with moderate-to-severe TBI, central auditory impairments have been reported. These auditory impairments may interfere with language receptivity, as observed in children with developmental brain injury. Although rodent models of TBI have been widely used to examine behavioral outcomes, few studies have evaluated how TBI affects higher-order central auditory processing across a range of cue complexities. Here, auditory processing was assessed using a modified acoustic startle paradigm. We used a battery of progressively complex stimuli (single-tone, silent gaps in white noise, and frequency-modulated [FM] sweeps) in adult rats that received unilateral controlled cortical impact injury. TBI subjects showed significant reductions in acoustic startle absolute responses across nearly all stimuli, regardless of cue, duration of stimuli, or cue complexity. Despite this overall reduction of startle magnitudes in injured animals, the detection of single-tone stimuli was comparable between TBI and sham-injured subjects, indicating intact hearing after TBI. TBI subjects showed deficits in rapid gap (5 ms) and FM sweep (175 ms) detection, and, in contrast to shams, they did not improve on detecting silent gaps and FM sweeps across days of testing. Our findings provide evidence for both low-level (brainstem-mediated) and higher-order central auditory processing deficits in a rodent model of TBI, which parallel sensory impairments observed in TBI patients. The present findings support the use of modified pre-pule auditory detection paradigms to investigate clinically relevant processes in TBI.

Automated Classification of Resting-State fMRI ICA Components Using a Deep Siamese Network.

Manual classification of functional resting state networks (RSNs) derived from Independent Component Analysis (ICA) decomposition can be labor intensive and requires expertise, particularly in large multi-subject analyses. Hence, a fully automatic algorithm that can reliably classify these RSNs is desirable. In this paper, we present a deep learning approach based on a Siamese Network to learn a discriminative feature representation for single-subject ICA component classification. Advantages of this supervised framework are that it requires relatively few training data examples and it does not require the number of ICA components to be specified. In addition, our approach permits one-shot learning, which allows generalization to new classes not seen in the training set with only one example of each new class. The proposed method is shown to out-perform traditional convolutional neural network (CNN) and template matching methods in identifying eleven subject-specific RSNs, achieving 100% accuracy on a holdout data set and over 99% accuracy on an outside data set. We also demonstrate that the method is robust to scan-rescan variation. Finally, we show that the functional connectivity of default mode and salience networks identified by the proposed technique is altered in a group analysis of mild traumatic brain injury (TBI), severe TBI, and healthy subjects.

322 Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: Results From the TRACK-TBI Pilot Study

INTRODUCTION: The relationship between systemic inflammation and traumatic brain injury (TBI) is complex. Primary injury triggers release of pro- and anti-inflammatory cytokines, chemokines, and alarmins/alarmin response proteins. METHODS: The prospective, multicenter TRACK-TBI Pilot study was used. Subjects received head CT and blood draw within 24h of TBI. Biomarkers were extracted from plasma and included: cytokines (IL-6, IL-10, IL-15, IL-16), chemokines (monocyte chemoattractant protein 4 (MCP-4), thymus activation-regulated chemokine (TARC)), alarmin/alarmin response proteins (high mobility group box 1 (HMGB-1), serum amyloid A (SAA), c-reactive protein (CRP)), and others. Area Under the Curve (AUC) was used to evaluate marker discriminability for clinical diagnosis (TBI vs. orthopedic control (OC)/healthy control (HC)), TBI severity (GCS 3-12 vs. 13-15), radiographic injury on CT, and unfavorable vs. favorable 3- and 6-month outcome (Glasgow Outcome Scale Extended (GOSE) 1-4 vs. 5-8). Statistical significance was assessed at p&lt;0.05. RESULTS: One-hundred sixty-eight TBI subjects, 28 OC, and 18 HCs were included. Markers associated with TBI clinical diagnosis were: IL-6, IL-10, IL-16, MCP-4, TARC, HMGB-1, SAA, CRP. Markers for TBI severity: IL-6, IL-10, IL-15, IL-16, TARC, HMGB-1, SAA, CRP. Markers for radiographic TBI: IL-6, IL-10, IL-15, IL-16, HMGB-1, SAA, CRP. Predictors (AUC &gt; 0.70) for TBI vs. OC: HMGB-1 (AUC = 0.84), IL-16 (AUC = 0.78), TARC (AUC = 0.73). Predictors for TBI vs. HC: IL-6 (AUC = 0.92), IL-10 (AUC = 0.87), HMGB-1 (AUC = 0.87), IL-16 (AUC = 0.72). Predictors for radiographic TBI: SAA (AUC = 0.77), IL-6 (AUC = 0.76), CRP (AUC = 0.73). IL-15 predicted 3- and 6-month GOSE (AUC = 0.74/0.70, respectively). SAA predicted 6-month GOSE (AUC = 0.70). CONCLUSION: We identified a distinct profile of cytokines, chemokines and alarmin/alarmin response proteins detectable systemically within 24h of TBI. These markers may have unique importance in TBI detection, severity differentiation, and prognosis. Future research on neuroinflammatory pathways will elucidate the evolution of injury and yield potential targets for therapeutic intervention.