Distinct Serum Glial Fibrillary Acidic Protein and Neurofilament Light Time-Courses After Rapid Head Rotations.

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.

Head Impact Kinematics and Brain Tissue Strains in High School Lacrosse.

Male lacrosse and female lacrosse have differences in history, rules, and equipment. There is current debate regarding the need for enhanced protective headwear in female lacrosse like that worn by male lacrosse players. To inform this discussion, 17 high school lacrosse players (6 female and 11 male) wore the Stanford Instrumented Mouthguard during 26 competitive games over the 2021 season. Time-windowing and video review were used to remove false-positive recordings and verify head acceleration events (HAEs). The HAE rate in high school female lacrosse (0.21 per athlete exposure and 0.24 per player hour) was approximately 35% lower than the HAE rate in high school male lacrosse (0.33 per athlete exposure and 0.36 per player hour). Previously collected kinematics data from the 2019 high school male and female lacrosse season were combined with the newly collected 2021 kinematics data, which were used to drive a finite element head model and simulate 42 HAEs. Peak linear acceleration (PLA), peak angular velocity (PAV), and 95th percentile maximum principal strain (MPS95) of brain tissue were compared between HAEs in high school female and male lacrosse. Median values for peak kinematics and MPS95 of HAEs in high school female lacrosse (PLA, 22.3 g; PAV, 10.4 rad/s; MPS95, 0.05) were lower than for high school male lacrosse (PLA, 24.2 g; PAV, 15.4 rad/s; MPS95, 0.07), but the differences were not statistically significant. Quantifying a lower HAE rate in high school female lacrosse compared to high school male lacrosse, but similar HAE magnitudes, provides insight into the debate regarding helmets in female lacrosse. However, due to the small sample size, additional video-verified data from instrumented mouthguards are required.

Finite element brain deformation in adolescent soccer heading.

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.

Use of functional near-infrared spectroscopy to quantify neurophysiological deficits after repetitive head impacts in adolescent athletes.

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.

Neurophysiological Effects of Repeated Soccer Heading in Youth.

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.

Quantifying head impact exposure, mechanisms and kinematics using instrumented mouthguards in female high school lacrosse.

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.

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

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

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.

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

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.

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

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.

NON-HEADER IMPACT EXPOSURE AND KINEMATICS OF MALE YOUTH SOCCER PLAYERS.

Previous studies have investigated the head impact kinematics of purposeful heading in youth soccer; however, less than a third of all head injuries in youth soccer have been found to involve ball contact. The aim of the current study was to identity the head impact kinematics and exposure not associated with purposeful heading of the ball in male youth soccer. Headband-mounted sensors were used to monitor the head kinematics of male junior varsity and middle school teams during games. Video analysis of sensor-recorded events was used to code impact mechanism, surface and site. Junior varsity players had non-header impact rates of 0.28 per athlete-exposure (AE) and 0.37 per player-hour (PH), whereas middle school players had relatively lower non-header impact rates of 0.16 per AE and 0.25 per PH. Such impact rates fell within the large range of values reported by previous studies, which is likely affected by sensor type and recording trigger threshold. The most common non-header impact mechanism in junior varsity soccer was player contact, whereas ball-to-head was the most common non-header impact mechanism in middle school soccer. Non-header impacts for junior varsity players had median peak kinematics of 31.0 g and 17.4 rad/s. Non-header impacts for middle school players had median peak kinematics of 40.6 g and 16.2 rad/s. For non-header impacts, ball impacts to the rear of the head the highest peak kinematics recorded by the sensor. Such data provide targets for future efforts in injury prevention, such as officiating efforts to control player-to-player contact.

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

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.

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

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.

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

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.

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

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.

Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy.

 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-ß (Aß), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aß (Aß40, Aß42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aß or directly measured Aß meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aß. Despite pTau's lower physical concentration than Aß, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aß levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3ß, GSK3ß, CDK5), identified phosphorylated ser9 GSK3ß as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aß. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aß and pTau, possibly through the GSK3 pathway.