Colin M. Huber

Background/Objectives: Traumatic brain injury (TBI) in the pediatric patient results in acute neurophysiological deficits and can have potential long-term sequelae, impacting neurodevelopment. Serum biomarkers are an active area of study for TBI prognosis and diagnosis. Cyclosporin A (CsA), an immunosuppressant drug with neuroprotective qualities, targets mitochondria to stabilize the neurometabolic energy crisis following TBI. The objective of this study was to determine the acute effect of CsA treatment following focal and diffuse TBI on piglet serum biomarkers associated with glial neurofilaments, axonal dysfunction, and neuronal injury. Methods: Biomarker concentrations of GFAP, Nf-L, and UCH-L1 were quantified retrospectively from porcine serum samples (n = 488) at multiple timepoints from three experimental groups: anesthetized sham (n = 10), controlled cortical impact (CCI, n = 49), or rapid, non-impact rotations (RNR, n = 151) of the head. Injured animals received 24 h post-injury intravenous administration of saline or one of four CsA treatment doses (10, 20, 40, or 60 mg/kg/day), and then, were sacrificed. Results: After RNR, GFAP levels significantly increased from baseline at 1 h and recovered by 1 day to healthy reference ranges, while Nf-L increased at 1 day. Multiple CsA treatment doses (10, 40 mg/kg/day) significantly reduced Nf-L levels at 1 day compared to the untreated group. After CCI, GFAP and Nf-L increased at 1 day; there were no significant treatment effects. Conclusions: Focal and diffuse brain injury mechanisms resulted in distinct biomarker timelines. CsA reduced Nf-L levels at 1 day after diffuse TBI, showing promise of acute therapeutic benefit and warranting further investigation in extended timelines.

Traumatic brain injury (TBI) causes significant neurophysiological deficits and is typically associated with rapid head accelerations common in sports-related incidents and automobile accidents. There are over 1.5 million TBIs in the United States each year, with children aged 0–4 being particularly vulnerable. TBI diagnosis is currently achieved through interpretation of clinical signs and symptoms and neuroimaging; however, there is increasing interest in minimally invasive fluid biomarkers to detect TBI objectively across all ages. Pre-clinical porcine models offer controlled conditions to evaluate TBI with known biomechanical conditions and without comorbidities. The objective of the current study was to establish pediatric porcine healthy reference ranges (RRs) of common human serum TBI biomarkers and to report their acute time-course after nonimpact rotational head injury. A retrospective analysis was completed to quantify biomarker concentrations in porcine serum samples collected from 4-week-old female ( n = 215) and uncastrated male ( n = 6) Yorkshire piglets. Subjects were assigned to one of three experimental groups (sham, sagittal-single, sagittal-multiple) or to a baseline only group. A rapid nonimpact rotational head injury model was used to produce mild-to-moderate TBI in piglets following a single rotation and moderate-to-severe TBI following multiple rotations. The Quanterix Simoa Human Neurology 4-Plex A assay was used to quantify glial fibrillary acidic protein (GFAP), neurofilament light (Nf-L), tau, and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). The 95% healthy RRs for females were calculated and validated for GFAP (6.3–69.4 pg/mL), Nf-L (9.5–67.2 pg/mL), and UCH-L1 (3.8–533.7 pg/mL). Rising early, GFAP increased significantly above the healthy RRs for sagittal-single (to 164 and 243 pg/mL) and increased significantly higher in sagittal-multiple (to 494 and 413 pg/mL) groups at 30 min and 1 h postinjury, respectively, returning to healthy RRs by 1-week postinjury. Rising later, Nf-L increased significantly above the healthy RRs by 1 day in sagittal-single (to 69 pg/mL) and sagittal-multiple groups (to 140 pg/mL) and rising further at 1 week (single = 231 pg/mL, multiple = 481 pg/mL). Sagittal-single and sagittal-multiple UCH-L1 serum samples did not differ from shams or the healthy RRs. Sex differences were observed but inconsistent. Serum GFAP and Nf-L levels had distinct time-courses following head rotations in piglets, and both corresponded to load exposure. We conclude that serum GFAP and Nf-L offer promise for early TBI diagnosis and intervention decisions for TBI and other neurological trauma.

Finite element (FE) modeling provides a means to examine how global kinematics of repetitive head loading in sports influences tissue level injury metrics. FE simulations of controlled soccer headers in two directions were completed using a human head FE model to estimate biomechanical loading on the brain by direction. Overall, headers were associated with 95th percentile peak maximum principal strains up to 0.07 and von Mises stresses up to 1450 Pa, and oblique headers trended toward higher values than frontal headers but below typical injury levels. These quantitative data provide insight into repetitive loading effects on the brain.

There is concern that repetitive head impact exposure (RHIE) may lead to neurophysiological deficits in adolescents. Twelve high school varsity soccer players (5 female) completed the King-Devick (K-D) and complex tandem gait (CTG) assessments pre- and post-season while wearing a functional near-infrared spectroscopy (fNIRS) sensor. The average head impact load (AHIL) for each athlete-season was determined via a standardised protocol of video-verification of headband-based head impact sensor data. Linear mixed effect models were used to determine the effects of AHIL and task condition (3 K-D cards or 4 CTG conditions) on the change in mean prefrontal cortical activation measured by fNIRS, and performance on K-D and CTG, from pre- to post-season. Although there was no difference in the pre- to post-season change in K-D or CTG performance, greater AHIL was associated with greater cortical activation at post-season in comparison to pre-season during the most challenging conditions of K-D (p = 0.003) and CTG (p = 0.02), suggesting that greater RHIE necessitates increased cortical activation to complete the more challenging aspects of these assessments at the same level of performance. These results describe the effect of RHIE on neurofunction and suggest the need for further study of the time course of these effects.

Repeated head loading in sports is associated with negative long-term brain health, and there is growing evidence of short-term neurophysiological changes after repeated soccer heading. The objective of this study was to quantify the head kinematics and effects of repetitive soccer headers in adolescents using an instrumented mouthguard. Adolescent soccer players aged 13–18 years were randomly assigned to a kicking control, frontal heading, or oblique heading group. Participants completed neurophysiological assessments at three-time points: immediately prior to, immediately after, and approximately 24 h after completing 10 headers or kicks. The suite of assessments included the Post-Concussion Symptom Inventory, visio-vestibular exam, King-Devick test, modified Clinical Test of Sensory Interaction and Balance with force plate sway measurement, pupillary light reflex, and visual evoked potential. Data were collected for 19 participants (17 male). Frontal headers resulted in significantly higher peak resultant linear acceleration (17.4 ± 0.5 g) compared to oblique headers (12.1 ± 0.4 g, p < 0.001), and oblique headers resulted in significantly higher peak resultant angular acceleration (frontal: 1147 ± 45 rad/s², oblique: 1410 ± 65 rad/s², p < 0.001). There were no neurophysiological deficits for either heading group or significant differences from controls at either post-heading timepoint, and therefore, a bout of repeated headers did not result in changes in the neurophysiological measures evaluated in this study. The current study provided data regarding the direction of headers with the goal to reduce the risk of repetitive head loading for adolescent athletes.

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.

Current debate exists regarding the need for protective headwear in female lacrosse. To inform this issue, the current study quantified head impact exposure, mechanisms and kinematics in female lacrosse using instrumented mouthguards. A female high school varsity lacrosse team of 17 players wore the Stanford Instrumented Mouthguard (MiG) during 14 competitive games. Video footage was reviewed to remove false-positive recordings and verify head impacts, which resulted in a rate of 0.32 head impacts per athlete-exposure. Of the 31 video-confirmed head impacts, 54.8% were identified as stick contacts, 38.7% were player contacts and 6.5% were falls. Stick contacts had the greatest peak head kinematics. The most common impact site was the side of the head (35.5%), followed by the face/jaw (25.8%), forehead (6.5%), and crown (6.5%). Impacts to the face/jaw region of the head had significantly (p < 0.05) greater peak kinematics compared to other regions of the head, which may have resulted from the interaction of the impacting surface, or the lower jaw, and the sensor. The current study provides initial data regarding the frequency, magnitude and site of impacts sustained in female high school lacrosse. A larger sample size of high quality head impact data in female lacrosse is required to confirm these findings.

Objective To quantify the head impact biomechanics, by impact mechanism, of female high school lacrosse players during games using an instrumented mouthguard. Background There is growing concern for the neurologic effects of repetitive head impacts in sports, which have been linked with several short-term neurophysiologic deficits. Girls' lacrosse represents a popular but understudied sport with regard to head impact exposure and current debate exists as to the need for enhanced protective equipment. Design/Methods A female high school varsity lacrosse team wore the Stanford Instrumented Mouthguard during competitive games for the 2019 season. Video footage was reviewed to confirm head impact events and remove false-positive recordings. For each impact event, the mechanism was coded as stick contact, player contact, fall, or ball contact. Head impact rates were calculated per athlete exposure (AE, defined as a single player participating in a single game). Results Sensor data were recorded for 15 female varsity lacrosse players for 14 games and 97 AEs. During games, 31 sensor-recorded head impacts were video-confirmed resulting in a pooled average head impact rate of 0.32 impacts/AE. The video-confirmed impacts were distributed between stick contact (17, 54.8%), player contact (12, 38.7%), and falls (2, 6.5%). There were no ball impacts. Overall peak kinematics were 34.0 ± 26.6 g, 12.0 ± 9.1 rad/s, and 3,666.5 ± 2,987.6 rad/s2. Stick contacts had the highest peak linear acceleration (42.7 ± 32.2 g), angular velocity (14.5 ± 11.1 rad/s), and angular acceleration (4,242.4 ± 3,634.9 rad/s2). Conclusions Stick impacts were the most common impact mechanism and resulted in the highest peak linear and angular kinematics, which may help explain why they are the most common cause of head injury in female lacrosse. By quantifying the head impact exposure, kinematics and mechanisms in female high school lacrosse, targeted injury preventions can be developed, such as rule changes and protective equipment.

We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer’s disease (AD) quantitative clinical outcome measures, including amyloid-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive perf