Publications by authors named "Susan S Margulies"

110 Publications

Comparison of Video-Identified Head Contacts and Sensor-Recorded Events in High School Soccer.

J Appl Biomech 2021 Nov 15:1-5. Epub 2021 Nov 15.

Children's Hospital of Philadelphia.

Field studies have evaluated the accuracy of sensors to measure head impact exposure using video analysis, but few have studied false negatives. Therefore, the aim of the current study was to investigate the proportion of potential false negatives in high school soccer head impact data. High school athletes (23 females and 31 males) wore headband-mounted Smart Impact Monitor-G impact sensors during competitive soccer games. Video footage from 41 varsity games was analyzed by 2 independent reviewers to identify head contact events, which were defined as visually observed contact to the head. Of the 1991 video-identified head contact events for which sensors were functioning and worn by the players, 1094 (55%) were recorded by the sensors. For female players, 45% of video-identified head contact events were recorded by the sensor compared with 59% for male players. For both females and males, sensitivity varied by impact mechanism. By quantifying the proportion of potential false negatives, the sensitivity of a sensor can be characterized, which can inform the interpretation of previous studies and the design of future studies using head impact sensors. Owing to the difficulty in obtaining ground truth labels of head impacts, video review should be considered a complementary tool to head impact sensors.
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http://dx.doi.org/10.1123/jab.2021-0191DOI Listing
November 2021

Pre- and post-season visio-vestibular function in healthy adolescent athletes.

Phys Sportsmed 2021 Sep 21:1-9. Epub 2021 Sep 21.

Center for Injury Research and Prevention, the Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Objective: To evaluate pre - to post-season differences in individual subtests of the Visio-Vestibular Examination (VVE) in healthy middle and high school athletes.

Methods: This prospective cohort study recruited participants from a private suburban United States secondary school. Participants completed a demographic questionnaire prior to the start of their season. A proxy for head impact exposure was estimated by incorporating previously published head impact frequencies by team and sport. The VVE was completed pre - and post-season and consisted of 9 subtests: smooth pursuit, horizontal/vertical saccades and gaze stability, binocular convergence, left/right monocular accommodation, and complex tandem gait. Generalized estimating equations were employed to assess the relative risk of an abnormal VVE outcome based on testing session (pre - vs. post-season).

Results: Participants included middle and high school athletes (n = 115; female = 59 (51.3%); median age at first assessment = 14.9 years, [IQR = 13.6, 16.0]) during 2017/18 - 2019/20 school years. During pre-season testing, accommodation (10.0%) and complex tandem gait (9.2%) had the largest proportion of abnormal outcomes, while smooth pursuits (10.6%) and convergence (9.5%) had the largest proportion of abnormal outcomes post-season. When assessing the effect of testing session on the relative risk of any abnormal VVE subtest, there were no significant findings (P ≥ 0.25). Additionally, there were no significant effects of testing session when adjusting for estimated head impact exposure for any VVE subtest (P ≥ 0.25).

Conclusions: Visio-vestibular function as measured by the VVE does not change from pre - to post-season in otherwise healthy adolescent athletes. Our findings suggest that the VVE may be stable and robust to typical neurodevelopment occurring in this dynamic age group and help inform post-injury interpretation of visio-vestibular impairments.
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http://dx.doi.org/10.1080/00913847.2021.1980744DOI Listing
September 2021

Variations in Head Impact Rates in Male and Female High School Soccer.

Med Sci Sports Exerc 2021 06;53(6):1245-1251

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA.

Introduction: Repetitive head impacts in soccer have been linked to short-term neurophysiological deficits, and female soccer players have higher concussion rates than males. These findings have inspired investigation into gender differences in head impact exposure and how head impact rate contributes to the cumulative effect of head impact exposure on neurological outcomes. Various periods of exposure have been used to calculate head impact rates, including head impacts per season, game, and player-hour.

Purpose: The aim of this study was to apply different methodological approaches to quantify and compare head impact rates by gender for two seasons of high school varsity soccer.

Methods: Video review was used to confirm all events recorded by a headband-mounted impact sensor and calculate playing time for all players. Impact rates were calculated per athlete exposure (presence and participation) and per player-hour (scheduled game time, individual play time, and absolute time).

Results: Impact rates per athlete exposure ranged from 2.5 to 3.2 for males and from 1.4 to 1.6 for females, and impact rates per player-hour ranged from 2.7 to 3.8 for males and from 1.0 to 1.6 for females. The exposure calculation method significantly affected head impact rates; however, regardless of approach, the head impact rate for males was higher, up to threefold, than for females. Individual head impact exposure varied substantially within a team with one in five players experiencing no impacts.

Conclusions: Overall, the gender differences found in this study indicate that males experience higher head impact exposure compared with females. Future studies are needed to understand potential clinical implications of variability in head impact exposure and reconcile higher female concussion rates with the reduced head impact rates presented herein.
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http://dx.doi.org/10.1249/MSS.0000000000002567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122001PMC
June 2021

Sport- and Gender-Based Differences in Head Impact Exposure and Mechanism in High School Sports.

Orthop J Sports Med 2021 Mar 2;9(3):2325967120984423. Epub 2021 Mar 2.

Center for Injury Research and Prevention, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Repeated head impacts sustained by athletes have been linked to short-term neurophysiologic deficits; thus, there is growing concern about the number of head impacts sustained in sports. Accurate head impact exposure data obtained via head impact sensors may help identify appropriate strategies across sports and between genders to mitigate repetitive head impacts.

Purpose: To quantify sport- and gender-based differences in head impact rate and mechanism for adolescents.

Study Design: Cohort study; Level of evidence, 2.

Methods: High school female and male varsity soccer, basketball, lacrosse, and field hockey (female only) teams were instrumented with headband-mounted impact sensors during games over 2 seasons of soccer and 1 season of basketball, lacrosse, and field hockey. Video review was used to remove false-positive sensor-recorded events, and the head impact rate per athlete-exposure (AE) was calculated. Impact mechanism was categorized as equipment to head, fall, player to head, or head to ball (soccer only).

Results: Male players had significantly higher head impact rates as compared with female players in soccer (3.08 vs 1.41 impacts/AE; rate ratio, 2.2 [95% CI, 1.8-2.6]), basketball (0.90 vs 0.25; 3.6 [2.6-4.6]), and lacrosse (0.83 vs 0.06; 12.9 [10.1-15.8]). Impact mechanism distributions were similar within sports between boys and girls. In soccer, head to ball represented 78% of impacts, whereas at least 88% in basketball were player-to-player contact.

Conclusion: Across sports for boys and girls, soccer had the highest impact rate. Male high school soccer, basketball, and lacrosse teams had significantly higher head impact rates than did female teams of the same sport. For girls, basketball had a higher head impact rate than did lacrosse and field hockey, and for boys, basketball had a similar impact rate to lacrosse, a collision sport. Sport differences in the distribution of impact mechanisms create sport-specific targets for reducing head impact exposure.
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http://dx.doi.org/10.1177/2325967120984423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933779PMC
March 2021

Evaluation of Tissue-Level Brain Injury Metrics Using Species-Specific Simulations.

J Neurotrauma 2021 06 22;38(13):1879-1888. Epub 2021 Feb 22.

Center for Applied Biomechanics, University of Virginia, Charlottesville, Virginia, USA.

Traumatic brain injury (TBI) is a significant public health burden, and the development of advanced countermeasures to mitigate and prevent these injuries during automotive, sports, and military impact events requires an understanding of the intracranial mechanisms related to TBI. In this study, the efficacy of tissue-level injury metrics for predicting TBI was evaluated using finite element reconstructions from a comprehensive, multi-species TBI database. The database consisted of human volunteer tests, laboratory-reconstructed head impacts from sports, non-human primate (NHP) tests, and pig tests. Eight tissue-level metrics related to brain tissue strain, axonal strain, and strain-rate were evaluated using survival analysis for predicting mild and severe TBI risk. The correlation between TBI risk and most of the assessed metrics were statistically significant, but when injury data was analyzed by species, the best metric was often inconclusive and limited by the small datasets. When the human and animal datasets were combined, the injury analysis was able to delineate maximum axonal strain as the best predictor of injury for all species and TBI severities, with maximum principal strain as a suitable alternative metric. The current study is the first to provide evidence to support the assumption that brain strain response between human, pig, and NHP result in similar injury outcomes through a multi-species analysis. This assumption is the biomechanical foundation for translating animal brain injury findings to humans. The findings in the study provide fundamental guidelines for developing injury criteria that would contribute towards the innovation of more effective safety countermeasures.
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http://dx.doi.org/10.1089/neu.2020.7445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219195PMC
June 2021

Target detection in healthy 4-week old piglets from a passive two-tone auditory oddball paradigm.

BMC Neurosci 2020 12 7;21(1):52. Epub 2020 Dec 7.

Wallace H. Coulter Department of Biomedical Engineering, Emory University, 615 Michael St. Suite 655, Atlanta, GA, USA.

Background: Passive auditory oddball tests are effort independent assessments that evaluate auditory processing and are suitable for paediatric patient groups. Our goal was to develop a two-tone auditory oddball test protocol and use this clinical assessment in an immature large animal model. Event-related potentials captured middle latency P1, N1, and P2 responses in 4-week old (N = 16, female) piglets using a custom piglet 32- electrode array on 3 non-consecutive days. The effect of target tone frequency (250 Hz and 4000 Hz) on middle latency responses were tested in a subset of animals.

Results: Results show that infrequent target tone pulses elicit greater N1 amplitudes than frequent standard tone pulses. There was no effect of day. Electrodes covering the front of the head tend to elicit greater waveform responses. P2 amplitudes increased for higher frequency target tones (4000 Hz) than the regular 1000 Hz target tones (p < 0.05).

Conclusions: Two-tone auditory oddball tests produced consistent responses day-to-day. This clinical assessment was successful in the immature large animal model.
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http://dx.doi.org/10.1186/s12868-020-00601-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720395PMC
December 2020

Evaluation of Diffusion Tensor Imaging and Fluid Based Biomarkers in a Large Animal Trial of Cyclosporine in Focal Traumatic Brain Injury.

J Neurotrauma 2021 06 25;38(13):1870-1878. Epub 2021 Jan 25.

Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, USA.

All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in a novel Cremophor/Kolliphor EL-free lipid emulsion, NeuroSTAT, was administered by continuous intravenous infusion for 5 days. The animals underwent DTI on day 5. Glial fibrillary acidic protein (GFAP), as a measure of astroglia injury, and neurofilament light (NF-L), as a measure of axonal injury, were measured in blood on days 1, 2, and 5, and in cerebrospinal fluid (CSF) on day 5 post-injury. Normalized fractional anisotropy (FA) was significantly ( = 0.027) higher in in the treatment group, indicating preserved tissue integrity with treatment. For the biomarkers, we observed a statistical trend of a decreased level of NF-L in CSF ( = 0.051), in the treatment group relative to placebo, indicating less axonal injury. Our findings suggest that DTI, and possibly CSF NF-L, may be feasible as translational end-points assessing neuroprotective drugs in TBI.
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http://dx.doi.org/10.1089/neu.2020.7317DOI Listing
June 2021

Head Impact Sensor Studies In Sports: A Systematic Review Of Exposure Confirmation Methods.

Ann Biomed Eng 2020 Nov 13;48(11):2497-2507. Epub 2020 Oct 13.

Center for Injury Research and Prevention, Children's Hospital of Philadelphia, Philadelphia, PA, 19146, USA.

To further the understanding of long-term sequelae as a result of repetitive head impacts in sports, in vivo head impact exposure data are critical to expand on existing evidence from animal model and laboratory studies. Recent technological advances have enabled the development of head impact sensors to estimate the head impact exposure of human subjects in vivo. Previous research has identified the limitations of filtering algorithms to process sensor data. In addition, observer and/or video confirmation of sensor-recorded events is crucial to remove false positives. The purpose of the current study was to conduct a systematic review to determine the proportion of published head impact sensor data studies that used filtering algorithms, observer confirmation and/or video confirmation of sensor-recorded events to remove false positives. Articles were eligible for inclusion if collection of head impact sensor data during live sport was reported in the methods section. Descriptive data, confirmation methods and algorithm use for included articles were coded. The primary objective of each study was reviewed to identify the primary measure of exposure, primary outcome and any additional covariates. A total of 168 articles met the inclusion criteria, the publication of which has increased in recent years. The majority used filtering algorithms (74%). The majority did not use observer and/or video confirmation for all sensor-recorded events (64%), which suggests estimates of head impact exposure from these studies may be imprecise.
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http://dx.doi.org/10.1007/s10439-020-02642-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674240PMC
November 2020

Laboratory Assessment of a Headband-Mounted Sensor for Measurement of Head Impact Rotational Kinematics.

J Biomech Eng 2021 02;143(2)

Children's Hospital of Philadelphia, Center for Injury Research and Prevention (CIRP), 2716 South Street, Philadelphia, PA 19146; Department of Pediatrics, University of Pennsylvania, 2716 South Street, Philadelphia, PA 19146.

Head impact sensors measure head kinematics in sports, and sensor accuracy is crucial for investigating the potential link between repetitive head loading and clinical outcomes. Many validation studies mount sensors to human head surrogates and compare kinematic measures during loading from a linear impactor. These studies are often unable to distinguish intrinsic instrumentation limitations from variability caused by sensor coupling. The aim of the current study was to evaluate intrinsic sensor error in angular velocity in the absence of coupling error for a common head impact sensor. Two Triax SIM-G sensors were rigidly attached to a preclinical rotational injury device and subjected to rotational events to assess sensor reproducibility and accuracy. Peak angular velocities between the SIM-G sensors paired for each test were correlated (R2 > 0.99, y = 1.00x, p < 0.001). SIM-G peak angular velocity correlated with the reference (R2 = 0.96, y = 0.82x, p < 0.001); however, SIM-G underestimated the magnitude by 15.0% ± 1.7% (p < 0.001). SIM-G angular velocity rise time (5% to 100% of peak) correlated with the reference (R2 = 0.97, y = 1.06x, p < 0.001) but exhibited a slower fall time (100% to 5% of peak) by 9.0 ± 3.7 ms (p < 0.001). Assessing sensor performance when rigidly coupled is a crucial first step to interpret on-field SIM-G rotational kinematic data. Further testing in increasing biofidelic conditions is needed to fully characterize error from other sources, such as coupling.
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http://dx.doi.org/10.1115/1.4048574DOI Listing
February 2021

Utility of Pupillary Light Reflex Metrics as a Physiologic Biomarker for Adolescent Sport-Related Concussion.

JAMA Ophthalmol 2020 11;138(11):1135-1141

Center for Injury Research and Prevention, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Importance: Concussion diagnosis remains clinical, without objective diagnostic tests available for adolescents. Known deficits in visual accommodation and autonomic function after concussion make the pupillary light reflex (PLR) a promising target as an objective physiological biomarker for concussion.

Objective: To determine the potential utility of PLR metrics as physiological biomarkers for concussion.

Design, Setting, And Participants: Prospective cohort of adolescent athletes between ages 12 and 18 years recruited between August 1, 2017, and December 31, 2018. The study took place at a specialty concussion program and private suburban high school and included healthy control individuals (n = 134) and athletes with a diagnosis of sport-related concussion (SRC) (n = 98). Analysis was completed June 30, 2020.

Exposures: Sports-related concussion and pupillometry assessments.

Main Outcomes And Measures: Pupillary light reflex metrics (maximum and minimum pupillary diameter, peak and average constriction/dilation velocity, percentage constriction, and time to 75% pupillary redilation [T75]).

Results: Pupillary light reflex metrics of 134 healthy control individuals and 98 athletes with concussion were obtained a median of 12.0 days following injury (interquartile range [IQR], 5.0-18.0 days). Eight of 9 metrics were significantly greater among athletes with concussion after Bonferroni correction (maximum pupil diameter: 4.83 mm vs 4.01 mm; difference, 0.82; 99.44% CI, 0.53-1.11; minimum pupil diameter: 2.96 mm vs 2.63 mm; difference, 0.33; 99.4% CI, 0.18-0.48; percentage constriction: 38.23% vs 33.66%; difference, 4.57; 99.4% CI, 2.60-6.55; average constriction velocity: 3.08 mm/s vs 2.50 mm/s; difference, 0.58; 99.4% CI, 0.36-0.81; peak constriction velocity: 4.88 mm/s vs 3.91 mm/s; difference, 0.97; 99.4% CI, 0.63-1.31; average dilation velocity, 1.32 mm/s vs 1.22 mm/s; difference, 0.10; 99.4% CI, 0.00-0.20; peak dilation velocity: 1.83 mm/s vs 1.64 mm/s; difference, 0.19; 99.4% CI, 0.07-0.32; and T75: 1.81 seconds vs 1.51 seconds; difference, 0.30; 0.10-0.51). In exploratory analyses, sex-based differences were observed, with girls with concussion exhibiting longer T75 (1.96 seconds vs 1.63 seconds; difference, 0.33; 99.4% CI, 0.02-0.65). Among healthy control individuals, diminished PLR metrics (eg, smaller maximum pupil size 3.81 mm vs 4.22 mm; difference, -0.41; 99.4% CI, -0.77 to 0.05) were observed after exercise.

Conclusions And Relevance: These findings suggest that enhancement of PLR metrics characterize acute adolescent concussion, while exercise produced smaller pupil sizes and overall slowing of PLR metrics, presumably associated with fatigue. Quantifiable measures of the PLR may serve in the future as objective physiologic biomarkers for concussion in the adolescent athlete.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.3466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516812PMC
November 2020

Nordihydroguaiaretic acid reduces secondary organ injury in septic rats after cecal ligation and puncture.

PLoS One 2020 13;15(8):e0237613. Epub 2020 Aug 13.

Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, United States of America.

Background: Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis.

Methods: Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague-Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival.

Results: NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not.

Conclusions: NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237613PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425931PMC
October 2020

Multi-Scale White Matter Tract Embedded Brain Finite Element Model Predicts the Location of Traumatic Diffuse Axonal Injury.

J Neurotrauma 2021 01 25;38(1):144-157. Epub 2020 Sep 25.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.

Finite element models (FEMs) are used increasingly in the traumatic brain injury (TBI) field to provide an estimation of tissue responses and predict the probability of sustaining TBI after a biomechanical event. However, FEM studies have mainly focused on predicting the absence/presence of TBI rather than estimating the location of injury. In this study, we created a multi-scale FEM of the pig brain with embedded axonal tracts to estimate the sites of acute (≤6 h) traumatic axonal injury (TAI) after rapid head rotation. We examined three finite element (FE)-derived metrics related to the axonal bundle deformation and three FE-derived metrics based on brain tissue deformation for prediction of acute TAI location. Rapid head rotations were performed in pigs, and TAI neuropathological maps were generated and colocalized to the FEM. The distributions of the FEM-derived brain/axonal deformations spatially correlate with the locations of acute TAI. For each of the six metric candidates, we examined a matrix of different injury thresholds (th) and distance to actual TAI sites (d) to maximize the average of two optimization criteria. Three axonal deformation-related TAI candidates predicted the sites of acute TAI within 2.5 mm, but no brain tissue metric succeeded. The optimal range of thresholds for maximum axonal strain, maximum axonal strain rate, and maximum product of axonal strain and strain rate were 0.08-0.14, 40-90, and 2.0-7.5 s, respectively. The upper bounds of these thresholds resulted in higher true-positive prediction rate. In summary, this study confirmed the hypothesis that the large axonal-bundle deformations occur on/close to the areas that sustained TAI.
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http://dx.doi.org/10.1089/neu.2019.6791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757550PMC
January 2021

Management of Coronavirus Disease 2019 Intubation Teams.

A A Pract 2020 Jun;14(8):e01263

From the Emory University, Atlanta, Georgia.

Some patients infected with the Coronavirus Disease 2019 (COVID-19) require endotracheal intubation, an aerosol-generating procedure that is believed to result in viral transmission to personnel performing the procedure. Additionally, donning and doffing personal protective equipment can be time consuming. In particular, doffing requires strict protocol adherence to avoid exposure. We describe the Emory Healthcare intubation team approach during the COVID-19 pandemic. This structure resulted in only 1 team member testing positive for COVID-19 despite 253 patient intubations over a 6-week period with 153 anesthesia providers on service.
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http://dx.doi.org/10.1213/XAA.0000000000001263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323820PMC
June 2020

Predictions of neonatal porcine bridging vein rupture and extra-axial hemorrhage during rapid head rotations.

J Mech Behav Biomed Mater 2020 06 23;106:103740. Epub 2020 Mar 23.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, USA. Electronic address:

When the head is rotated rapidly, the movement of the brain lags that of the skull. Intracranial contents between the brain and skull include meninges, cerebrospinal fluid (CSF), and cerebral vasculature. Among the cerebral vasculature in this space are the parasagittal bridging veins (BVs), which drain blood from the brain into the superior sagittal sinus (SSS), which is housed within the falx cerebri, adhered to the inner surface of the skull. Differential motion between the brain and skull that may occur during a traumatic event is thought to stretch BVs, causing damage and producing extra-axial hemorrhage (EAH). Finite element (FE) modeling is a technique often used to aid in the understanding and prediction of traumatic brain injury (TBI), and estimation of tissue deformation during traumatic events provides insight into kinematic injury thresholds. Using a FE model of the newborn porcine head with neonatal porcine brain and BV properties, single and cyclic rapid head rotations without impact were simulated. Measured BV failure properties were used to predict BV rupture. By comparing simulation outputs to observations of EAH in a development group of in vivo studies of rapid non-impact head rotations in the piglet, it was determined that failure of 16.7% of BV elements was associated with a 50% risk of EAH, and showed in a separate validation group that this threshold predicted the occurrence of EAH with 100% sensitivity and 100% specificity for single rapid non-impact rotations. This threshold for failed BV elements performed with 90% overall correct prediction in simulations of cyclic rotational head injuries. A 50% risk of EAH was associated with head angular velocities of 94.74 rad/s and angular accelerations of 29.60 krad/s in the newborn piglet. Future studies may build on these findings for BV failure in the piglet to develop predictive models for BV failure in human infants.
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http://dx.doi.org/10.1016/j.jmbbm.2020.103740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228785PMC
June 2020

Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers.

Int J Mol Sci 2020 Mar 5;21(5). Epub 2020 Mar 5.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse ( = 13) or focal ( = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.
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http://dx.doi.org/10.3390/ijms21051786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084695PMC
March 2020

Video Confirmation of Head Impact Sensor Data From High School Soccer Players.

Am J Sports Med 2020 04 4;48(5):1246-1253. Epub 2020 Mar 4.

Center for Injury Research and Prevention, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Recent advances in technology have enabled the development of head impact sensors, which provide a unique opportunity for sports medicine researchers to study head kinematics in contact sports. Studies have suggested that video or observer confirmation of head impact sensor data is required to remove false positives. In addition, manufacturer filtering algorithms may be ineffective in identifying true positives and removing true negatives.

Purpose: To (1) identify the percentage of video-confirmed events recorded by headband-mounted sensors in high school soccer through video analysis, overall and by sex; (2) compare video-confirmed events with the classification by the manufacturer filtering algorithms; and (3) quantify and compare the kinematics of true- and false-positive events.

Study Design: Cohort study; Level of evidence, 2.

Methods: Adolescent female and male soccer teams were instrumented with headband-mounted impact sensors (SIM-G; Triax Technologies) during games over 2 seasons of suburban high school competition. Sensor data were sequentially reduced to remove events recorded outside of game times, associated with players not on the pitch (ie, field) and players outside the field of view of the camera. With video analysis, the remaining sensor-recorded events were identified as an impact event, trivial event, or nonevent. The mechanisms of impact events were identified. The classifications of sensor-recorded events by the SIM-G algorithm were analyzed.

Results: A total of 6796 sensor events were recorded during scheduled varsity game times, of which 1893 (20%) were sensor-recorded events associated with players on the pitch in the field of view of the camera during verified game times. Most video-confirmed events were impact events (n = 1316, 70%), followed by trivial events (n = 396, 21%) and nonevents (n = 181, 10%). Female athletes had a significantly higher percentage of trivial events and nonevents with a significantly lower percentage of impact events. Most impact events were head-to-ball impacts (n = 1032, 78%), followed by player contact (n = 144, 11%) and falls (n = 129, 10%) with no significant differences between male and female teams. The SIM-G algorithm correctly identified 70%, 52%, and 66% of video-confirmed impact events, trivial events, and nonevents, respectively.

Conclusion: Video confirmation is critical to the processing of head impact sensor data. Percentages of video-confirmed impact events, trivial events, and nonevents vary by sex in high school soccer. Current manufacturer filtering algorithms and magnitude thresholds are ineffective at correctly classifying sensor-recorded events and should be used with caution.
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http://dx.doi.org/10.1177/0363546520906406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405551PMC
April 2020

Head Rotational Kinematics, Tissue Deformations, and Their Relationships to the Acute Traumatic Axonal Injury.

J Biomech Eng 2020 03;142(3)

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332.

Head rotational kinematics and tissue deformation metrics obtained from finite element models (FEM) have the potential to be used as traumatic axonal injury (TAI) assessment criteria and headgear evaluation standards. These metrics have been used to predict the likelihood of TAI occurrence; however, their ability in the assessment of the extent of TAI has not been explored. In this study, a pig model of TAI was used to examine a wide range of head loading conditions in two directions. The extent of TAI was quantified through histopathology and correlated to the FEM-derived tissue deformations and the head rotational kinematics. Peak angular acceleration and maximum strain rate of axonal fiber and brain tissue showed relatively good correlation to the volume of axonal injury, with similar correlation trends for both directions separately or combined. These rotational kinematics and tissue deformations can estimate the extent of acute TAI. The relationships between the head kinematics and the tissue strain, strain rate, and strain times strain rate were determined over the experimental range examined herein, and beyond that through parametric simulations. These relationships demonstrate that peak angular velocity and acceleration affect the underlying tissue deformations and the knowledge of both help to predict TAI risk. These relationships were combined with the injury thresholds, extracted from the TAI risk curves, and the kinematic-based risk curves representing overall axonal and brain tissue strain and strain rate were determined for predicting TAI. After scaling to humans, these curves can be used for real-time TAI assessment.
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http://dx.doi.org/10.1115/1.4046393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104750PMC
March 2020

Embedded axonal fiber tracts improve finite element model predictions of traumatic brain injury.

Biomech Model Mechanobiol 2020 Jun 6;19(3):1109-1130. Epub 2019 Dec 6.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, U.A. Whitaker Building, 313 Ferst Drive, Atlanta, GA, 30332, USA.

With the growing rate of traumatic brain injury (TBI), there is an increasing interest in validated tools to predict and prevent brain injuries. Finite element models (FEM) are valuable tools to estimate tissue responses, predict probability of TBI, and guide the development of safety equipment. In this study, we developed and validated an anisotropic pig brain multi-scale FEM by explicitly embedding the axonal tract structures and utilized the model to simulate experimental TBI in piglets undergoing dynamic head rotations. Binary logistic regression, survival analysis with Weibull distribution, and receiver operating characteristic curve analysis, coupled with repeated k-fold cross-validation technique, were used to examine 12 FEM-derived metrics related to axonal/brain tissue strain and strain rate for predicting the presence or absence of traumatic axonal injury (TAI). All 12 metrics performed well in predicting of TAI with prediction accuracy rate of 73-90%. The axonal-based metrics outperformed their rival brain tissue-based metrics in predicting TAI. The best predictors of TAI were maximum axonal strain times strain rate (MASxSR) and its corresponding optimal fraction-based metric (AF-MASxSR) that represents the fraction of axonal fibers exceeding MASxSR of 7.5 s. The thresholds compare favorably with tissue tolerances found in in-vitro/in-vivo measurements in the literature. In addition, the damaged volume fractions (DVF) predicted using the axonal-based metrics, especially MASxSR (DVF = 0.05-4.5%), were closer to the actual DVF obtained from histopathology (AIV = 0.02-1.65%) in comparison with the DVF predicted using the brain-related metrics (DVF = 0.11-41.2%). The methods and the results from this study can be used to improve model prediction of TBI in humans.
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http://dx.doi.org/10.1007/s10237-019-01273-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203590PMC
June 2020

Clinical and Device-based Metrics of Gait and Balance in Diagnosing Youth Concussion.

Med Sci Sports Exerc 2020 03;52(3):542-548

Center for Injury Research and Prevention, The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Evaluate the discriminatory ability of two clinical measures and one device-based measure of gait and balance for concussed youth.

Methods: We enrolled 81 cases and 90 controls age 14-18 yr old from August 2017 to June 2018. Controls were recruited from a suburban high school, and cases were recruited from the concussion program of an academic pediatric tertiary care center. Tests included two clinical measures: 1) complex tandem gait, scored as sway/errors walking forward and backward eyes open and closed; 2) Modified Balance Error Scoring System (mBESS), scored as total number of errors on three standing tasks; and one device-based measure; 3) Modified Clinical Test of Sensory Interaction and Balance (mCTSIB) using the Biodex Biosway Balance System, scored as a sway index. Sensitivity, specificity, ideal cutpoint, and area under the receiver operating characteristic curve (AUC) were calculated for all test components.

Results: Ideal cutpoint for total number of sway/errors for tandem gait = 5, sensitivity 41%, specificity 90%. Ideal cutpoint for total mBESS errors = 4, sensitivity 55%, specificity 75%. Ideal cutpoint for mCTSIB = 1.37, sensitivity 37%, specificity 88%. Among each test, some individual components outperformed overall composites, in particular tandem gait (specificity forward eyes open = 99%, sensitivity backward eyes closed = 81%). Among the 40 cases and 65 controls with all three assessments, AUC (95% CI) for tandem gait = 0.63 (0.52,0.75), mBESS = 0.70 (0.60,0.81), and mCTSIB = 0.54 (0.42,0.66).

Conclusions: A device-based measure of balance did not produce better discriminatory ability than two clinical assessments. Complex tandem gait has the additional benefit of being an easy-to-perform and graded test with highly sensitive and specific individual components.
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http://dx.doi.org/10.1249/MSS.0000000000002163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024041PMC
March 2020

Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward.

Exp Neurol 2019 08 2;318:101-123. Epub 2019 May 2.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.

Traumatic brain injury is a leading cause of cognitive and behavioral deficits in children in the US each year. There is an increasing interest in both clinical and pre-clinical studies to discover biomarkers to accurately diagnose traumatic brain injury (TBI), predict its outcomes, and monitor its progression especially in the developing brain. In humans, the heterogeneity of TBI in terms of clinical presentation, injury causation, and mechanism has contributed to the many challenges associated with finding unifying diagnosis, treatment, and management practices. In addition, findings from adult human research may have little application to pediatric TBI, as age and maturation levels affect the injury biomechanics and neurophysiological consequences of injury. Animal models of TBI are vital to address the variability and heterogeneity of TBI seen in human by isolating the causation and mechanism of injury in reproducible manner. However, a gap between the pre-clinical findings and clinical applications remains in TBI research today. To take a step toward bridging this gap, we reviewed several potential TBI tools such as biofluid biomarkers, electroencephalography (EEG), actigraphy, eye responses, and balance that have been explored in both clinical and pre-clinical studies and have shown potential diagnostic, prognostic, or monitoring utility for TBI. Each of these tools measures specific deficits following TBI, is easily accessible, non/minimally invasive, and is potentially highly translatable between animals and human outcomes because they involve effort-independent and non-verbal tasks. Especially conspicuous is the fact that these biomarkers and techniques can be tailored for infants and toddlers. However, translation of preclinical outcomes to clinical applications of these tools necessitates addressing several challenges. Among the challenges are the heterogeneity of clinical TBI, age dependency of some of the biomarkers, different brain structure, life span, and possible variation between temporal profiles of biomarkers in human and animals. Conducting parallel clinical and pre-clinical research, in addition to the integration of findings across species from several pre-clinical models to generate a spectrum of TBI mechanisms and severities is a path toward overcoming some of these challenges. This effort is possible through large scale collaborative research and data sharing across multiple centers. In addition, TBI causes dynamic deficits in multiple domains, and thus, a panel of biomarkers combining these measures to consider different deficits is more promising than a single biomarker for TBI. In this review, each of these tools are presented along with the clinical and pre-clinical findings, advantages, challenges and prospects of translating the pre-clinical knowledge into the human clinical setting.
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http://dx.doi.org/10.1016/j.expneurol.2019.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612432PMC
August 2019

Frequency-Dependent Changes in Resting State Electroencephalogram Functional Networks after Traumatic Brain Injury in Piglets.

J Neurotrauma 2019 09 23;36(17):2558-2578. Epub 2019 May 23.

Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.

Traumatic brain injury (TBI) is a major health concern in children, as it can cause chronic cognitive and behavioral deficits. The lack of objective involuntary metrics for the diagnosis of TBI makes prognosis more challenging, especially in the pediatric context, in which children are often unable to articulate their symptoms. Resting state electroencephalograms (EEG), which are inexpensive and non-invasive, and do not require subjects to perform cognitive tasks, have not yet been used to create functional brain networks in relation to TBI in children or non-human animals; here we report the first such study. We recorded resting state EEG in awake piglets before and after TBI, from which we generated EEG functional networks from the alpha (8-12 Hz), beta (16.5-25 Hz), broad (1-35 Hz), delta (1-3.5 Hz), gamma (30-35 Hz), sigma (13-16 Hz), and theta (4-7.5 Hz) frequency bands. We hypothesize that mild TBI will induce persistent frequency-dependent changes in the 4-week-old piglet at acute and chronic time points. Hyperconnectivity was found in several frequency band networks after TBI. This study serves as proof of concept that the study of EEG functional networks in awake piglets may be useful for the development of diagnostic metrics for TBI in children.
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http://dx.doi.org/10.1089/neu.2017.5574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709726PMC
September 2019

HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch.

Int J Mol Sci 2019 Feb 22;20(4). Epub 2019 Feb 22.

Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA.

Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to VILI. We analyzed a database of differentially expressed genes between cyclically stretched and unstretched rat alveolar epithelial cells (RAEC) for HER ligands and validated the differential expression. The effect of the ligand and HER2 inhibition on RAEC permeability was tested, and in vivo relevance was assessed in a rat model of VILI. Analysis of our expression array revealed the upregulation of NRG1 and amphiregulin (AREG) with stretch. NRG1 protein, but not AREG, increased after stretch in culture media. Treatment with an NRG1-cleavage inhibitor (TAPI2) or an inhibitor of NRG1-binding (anti-HER3 antibody) reduced HER2 phosphorylation and partially mitigated stretch-induced permeability, with the upregulation of claudin-7. The results were reproduced by treatment with a direct inhibitor of HER2 phosphorylation (AG825). The transfection of microRNA miR-15b, predicted to negatively regulate NRG1, also attenuated stretch-induced permeability, and was associated with lower NRG1 mRNA levels. In rats ventilated at damaging tidal volumes, AG825 partly attenuated VILI. We concluded that cyclic stretch activates HER2 via the HER3 ligand NRG1, leading to increased permeability. Outcomes were mitigated by the downregulation of NRG1, prevention of NRG1 binding, and most strongly by the direct inhibition of HER2. In vivo HER2 inhibition also attenuated VILI. Ligand-dependent HER2 activation is a potential target for reducing VILI.
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http://dx.doi.org/10.3390/ijms20040948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412492PMC
February 2019

Infant skull fracture risk for low height falls.

Int J Legal Med 2019 May 7;133(3):847-862. Epub 2018 Sep 7.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, U.A. Whitaker Building, 313 Ferst Drive, Suite 2116, Atlanta, GA, 30332-0535, USA.

Skull fractures are common injuries in young children, typically caused by accidental falls and child abuse. The paucity of detailed biomechanical data from real-world trauma in children has hampered development of biomechanical thresholds for skull fracture in infants. The objectives of this study were to identify biomechanical metrics to predict skull fracture, determine threshold values associated with fracture, and develop skull fracture risk curves for low-height falls in infants. To achieve these objectives, we utilized an integrated approach consisting of case evaluation, anthropomorphic reconstruction, and finite element simulation. Four biomechanical candidates for predicting skull fracture were identified (first principal stress, first principal strain, shear stress, and von Mises stress) and evaluated against well-witnessed falls in infants (0-6 months). Among the predictor candidates, first principal stress and strain correlated best with the occurrence of parietal skull fracture. The principal stress and strain thresholds associated with 50 and 95% probability of parietal skull fracture were 25.229 and 36.015 MPa and 0.0464 and 0.0699, respectively. Risk curves using these predictors determined that infant falls from 0.3 m had a low probability (0-54%) to result in parietal skull fracture, particularly with carpet impact (0-1%). Head-first falls from 0.9 m had a high probability of fracture (86-100%) for concrete impact and a moderate probability (34-81%) for carpet impact. Probabilities of fracture in 0.6 m falls were dependent on impact surface. Occipital impacts from 0.9 m onto the concrete also had the potential (27-90% probability) to generate parietal skull fracture. These data represent a multi-faceted biomechanical assessment of infant skull fracture risk and can assist in the differential diagnosis for head trauma in children.
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http://dx.doi.org/10.1007/s00414-018-1918-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469693PMC
May 2019

Protein kinase R-like endoplasmatic reticulum kinase is a mediator of stretch in ventilator-induced lung injury.

Respir Res 2018 Aug 22;19(1):157. Epub 2018 Aug 22.

Department of Bioengineering, University of Pennsylvania, 210 South 33rd St, Suite 240 Skirkanich Hall Philadelphia, Philadelphia, PA, 19104, USA.

Background: Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential causes of ARDS; however, alveolar injury associated with mechanical ventilation, termed ventilator-induced lung injury (VILI), remains a well-recognized contributor. It is thus critical to understand the mechanism of VILI. Based on our published preliminary data, we hypothesized that the endoplasmic reticulum (ER) stress response molecule Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) plays a role in transmitting mechanosensory signals the alveolar epithelium.

Methods: ER stress signal responses to mechanical stretch were studied in ex-vivo ventilated pig lungs. To explore the effect of PERK inhibition on VILI, we ventilated live rats and compared lung injury parameters to non-ventilated controls. The effect of stretch-induced epithelial ER Ca signaling on PERK was studied in stretched alveolar epithelial monolayers. To confirm the activation of PERK in human disease, ER stress signaling was compared between ARDS and non-ARDS lungs.

Results: Our studies revealed increased PERK-specific ER stress signaling in response to overstretch. PERK inhibition resulted in dose-dependent improvement of alveolar inflammation and permeability. Our data indicate that stretch-induced epithelial ER Ca release is an activator of PERK. Experiments with human lung tissue confirmed PERK activation by ARDS.

Conclusion: Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.
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http://dx.doi.org/10.1186/s12931-018-0856-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106739PMC
August 2018

Changes in event-related potential functional networks predict traumatic brain injury in piglets.

Clin Biomech (Bristol, Avon) 2019 04 1;64:14-21. Epub 2018 Jun 1.

Department of Bioengineering, University of Pennsylvania, 210 S. 33rd St., 240 Skirkanich Hall, Philadelphia, PA 19104-6321, USA. Electronic address:

Background: Traumatic brain injury is a leading cause of cognitive and behavioral deficits in children in the US each year. None of the current diagnostic tools, such as quantitative cognitive and balance tests, have been validated to identify mild traumatic brain injury in infants, adults and animals. In this preliminary study, we report a novel, quantitative tool that has the potential to quickly and reliably diagnose traumatic brain injury and which can track the state of the brain during recovery across multiple ages and species.

Methods: Using 32 scalp electrodes, we recorded involuntary auditory event-related potentials from 22 awake four-week-old piglets one day before and one, four, and seven days after two different injury types (diffuse and focal) or sham. From these recordings, we generated event-related potential functional networks and assessed whether the patterns of the observed changes in these networks could distinguish brain-injured piglets from non-injured.

Findings: Piglet brains exhibited significant changes after injury, as evaluated by five network metrics. The injury prediction algorithm developed from our analysis of the changes in the event-related potentials functional networks ultimately produced a tool with 82% predictive accuracy.

Interpretation: This novel approach is the first application of auditory event-related potential functional networks to the prediction of traumatic brain injury. The resulting tool is a robust, objective and predictive method that offers promise for detecting mild traumatic brain injury, in particular because collecting event-related potentials data is noninvasive and inexpensive.
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http://dx.doi.org/10.1016/j.clinbiomech.2018.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274597PMC
April 2019

Measurement and Finite Element Model Validation of Immature Porcine Brain-Skull Displacement during Rapid Sagittal Head Rotations.

Front Bioeng Biotechnol 2018 21;6:16. Epub 2018 Feb 21.

Injury Biomechanics Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States.

Computational models are valuable tools for studying tissue-level mechanisms of traumatic brain injury, but to produce more accurate estimates of tissue deformation, these models must be validated against experimental data. In this study, we present measurements of brain-skull displacement in the neonatal piglet head ( = 3) at the sagittal midline during six rapid non-impact rotations (two rotations per specimen) with peak angular velocities averaging 51.7 ± 1.4 rad/s. Marks on the sagittally cut brain and skull/rigid potting surfaces were tracked, and peak values of relative brain-skull displacement were extracted and found to be significantly less than values extracted from a previous axial plane model. In a finite element model of the sagittally transected neonatal porcine head, the brain-skull boundary condition was matched to the measured physical experiment data. Despite smaller sagittal plane displacements at the brain-skull boundary, the corresponding finite element boundary condition optimized for sagittal plane rotations is far less stiff than its axial counterpart, likely due to the prominent role of the boundary geometry in restricting interface movement. Finally, bridging veins were included in the finite element model. Varying the bridging vein mechanical behavior over a previously reported range had no influence on the brain-skull boundary displacements. This direction-specific sagittal plane boundary condition can be employed in finite element models of rapid sagittal head rotations.
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http://dx.doi.org/10.3389/fbioe.2018.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826385PMC
February 2018

Improved prediction of direction-dependent, acute axonal injury in piglets.

J Neurosci Res 2018 04 21;96(4):536-544. Epub 2017 Aug 21.

Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.

To guide development of safety equipment that reduces sports-related head injuries, we sought to enhance predictive relationships between head movement and acute axonal injury severity. The severity of traumatic brain injury (TBI) is influenced by the magnitude and direction of head kinematics. Previous studies have demonstrated correlation between rotational head kinematics and symptom severity in the adult. More recent studies have demonstrated brain injury age- and direction-dependence, relating head kinematics to white matter tract-oriented strains. We have recently developed and assessed novel rotational head kinematic parameters as predictors of white matter damage in the female immature piglet. We show that many previously published rotational kinematic injury predictor metrics poorly predict acute axonal pathology induced by rapid, non-impact head rotations and that inclusion of cerebral moments of inertia (MOI) in rotational head injury metrics refines prediction of diffuse axonal injury following rapid head rotations for two immature age groups. Rotational Work (RotWork) was the best significant predictor of traumatic axonal injury in both newborn and pre-adolescent piglets following head rotations in the axial, coronal, and sagittal planes. An improvement over current metrics, we find that RotWork, which incorporates head rotation rate, direction, and brain shape, significantly enhanced acute traumatic axonal injury prediction. For similar injury extent, the RotWork threshold is lower for the newborn piglet than the pre-adolescent.
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http://dx.doi.org/10.1002/jnr.24108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803402PMC
April 2018

Failure and Fatigue Properties of Immature Human and Porcine Parasagittal Bridging Veins.

Ann Biomed Eng 2017 08 12;45(8):1877-1889. Epub 2017 Apr 12.

Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA, 19104-6321, USA.

Tearing of the parasagittal bridging veins (BVs) is thought to be a source of extra-axial hemorrhage (EAH) associated with abusive traumatic brain injuries (TBIs) in children. However, the pediatric BV mechanical properties are unknown. We subjected porcine adult, porcine newborn, and human infant BVs to either a low rate pull to failure, a high rate pull to failure, or 30 s of cyclic loading followed by a pull to failure. An additional subset of human infant BVs was examined for viscoelastic recovery between two cycling episodes. We found that human infant BVs are stronger than porcine BVs, and BV mechanical properties are rate dependent, but not age dependent. Successive cyclic loading to a uniform level of stretch softened BVs with decaying peak stresses, and shifted their stress-stretch relationship. These data are critical in understanding BV tissue behavior in accidental and abusive trauma scenarios, which in turn may clarify circumstances that may be injurious to young children.
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http://dx.doi.org/10.1007/s10439-017-1833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529232PMC
August 2017

Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation.

Am J Respir Cell Mol Biol 2017 08;57(2):193-203

3 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.

Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI.
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http://dx.doi.org/10.1165/rcmb.2016-0404OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576586PMC
August 2017

Repeated Loading Behavior of Pediatric Porcine Common Carotid Arteries.

J Biomech Eng 2016 12;138(12)

Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104-6321 e-mail:

Rapid flexion and extension of the neck may occur during scenarios associated with traumatic brain injury (TBI), and understanding the mechanical response of the common carotid artery (CCA) to longitudinal stretch may enhance understanding of contributing factors that may influence CCA vasospasm and exacerbate ischemic injury associated with TBI. Immature (4-week-old) porcine CCAs were tested under subcatastrophic (1.5 peak stretch ratio) cyclic loading at 3 Hz for 30 s. Under subcatastrophic cyclic longitudinal extension, the immature porcine CCA displays softening behavior. This softening can be represented by decreasing peak stress and increasing corner stretch values with an increasing number of loading cycles. This investigation is an important first step in the exploration of fatiguelike behavior in arterial tissue that may be subjected to repeated longitudinal loads.
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http://dx.doi.org/10.1115/1.4033883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125306PMC
December 2016
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