Longitudinal changes in resting state fMRI brain self-similarity of asymptomatic high school American football athletes.

American football has become the focus of numerous studies highlighting a growing concern that cumulative exposure to repetitive, sports-related head acceleration events (HAEs) may have negative consequences for brain health, even in the absence of a diagnosed concussion. In this longitudinal study, brain functional connectivity was analyzed in a cohort of high school American football athletes over a single play season and compared against participants in non-collision high school sports. Football athletes underwent four resting-state functional magnetic resonance imaging sessions: once before (pre-season), twice during (in-season), and once 34-80 days after the contact activities play season ended (post-season). For each imaging session, functional connectomes (FCs) were computed for each athlete and compared across sessions using a metric reflecting the (self) similarity between two FCs. HAEs were monitored during all practices and games throughout the season using head-mounted sensors. Relative to the pre-season scan session, football athletes exhibited decreased FC self-similarity at the later in-season session, with apparent recovery of self-similarity by the time of the post-season session. In addition, both within and post-season self-similarity was correlated with cumulative exposure to head acceleration events. These results suggest that repetitive exposure to HAEs produces alterations in functional brain connectivity and highlight the necessity of collision-free recovery periods for football athletes.

Design Considerations for the Attenuation of Translational and Rotational Accelerations in American Football Helmets.

Participants in American football experience repetitive head impacts that induce negative changes in neurocognitive function over the course of a single season. This study aimed to quantify the transfer function connecting the force input to the measured output acceleration of the helmet system to provide a comparison of the impact attenuation of various modern American football helmets. Impact mitigation varied considerably between helmet models and with location for each helmet model. The current data indicate that helmet mass is a key variable driving force attenuation, however flexible helmet shells, helmet shell cutouts, and more compliant padding can improve energy absorption.

American Football Position-Specific Neurometabolic Changes in High School Athletes: A Magnetic Resonance Spectroscopic Study.

Reports estimate between 1.6-3.8 million sports-related concussions occur annually, with 30% occurring in youth male American football athletes. Many studies report neurophysiological changes in these athletes, but the exact reasons for these changes remain elusive. Investigation of injury mechanics highlights a need to address how player position might impact these changes. Here, 55 high school American football athletes (20 linemen; 35 non-linemen) underwent magnetic resonance spectroscopy four times over the course of a football season-once prior to the season (Pre), twice during (In1, In2), and once following (Post) to quantify metabolites (N-acetyl aspartate, choline, creatine, myo-inositol, and glutamate/glutamine) in the dorsolateral prefrontal cortex (DLPFC) and primary motor cortex (M1). Head acceleration events (HAEs) were monitored at each practice and game. Spectroscopic and HAE data were analyzed by imaging session and player position. Linear regression analyses were conducted between metabolite levels and HAEs, and metabolite levels in football athletes were compared with age-and gender-matched non-contact athletes. Across-season (i.e., between Pre and In1, In2, Post), different DLPFC and M1 metabolites decreased (p < 0.05) according to player position (i.e., linemen vs. non-linemen). The majority of regression results involved DLPFC metabolites in linemen, where metabolite levels were higher from Pre to Post, with increasing HAE load. Comparisons with control athletes revealed higher metabolite levels in football athletes both before and after the season. This study highlights the importance of player position when conducting analyses on American football athletes and demonstrates elevated DLPFC and M1 brain metabolites in football athletes compared with control athletes at both Pre and Post, suggesting potential HAE-related neurocompensatory mechanisms.

Metabolomic response to collegiate football participation: Pre- and Post-season analysis.

Contact sports participation has been shown to have both beneficial and detrimental effects on health, however little is known about the metabolic sequelae of these effects. We aimed to identify metabolite alterations across a collegiate American football season. Serum was collected from 23 male collegiate football athletes before the athletic season (Pre) and after the last game (Post). Samples underwent nontargeted metabolomic profiling and 1131 metabolites were included for univariate, pathway enrichment, and multivariate analyses. Significant metabolites were assessed against head acceleration events (HAEs). 200 metabolites changed from Pre to Post (P < 0.05 and Q < 0.05); 160 had known identity and mapped to one of 57 pre-defined biological pathways. There was significant enrichment of metabolites belonging to five pathways (P < 0.05): xanthine, fatty acid (acyl choline), medium chain fatty acid, primary bile acid, and glycolysis, gluconeogenesis, and pyruvate metabolism. A set of 12 metabolites was sufficient to discriminate Pre from Post status, and changes in 64 of the 200 metabolites were also associated with HAEs (P < 0.05). In summary, the identified metabolites, and candidate pathways, argue there are metabolic consequences of both physical training and head impacts with football participation. These findings additionally identify a potential set of objective biomarkers of repetitive head injury.

A preliminary model of football-related neural stress that integrates metabolomics with transcriptomics and virtual reality.

Research suggests contact sports affect neurological health. This study used permutation-based mediation statistics to integrate measures of metabolomics, neuroinflammatory miRNAs, and virtual reality (VR)-based motor control to investigate multi-scale relationships across a season of collegiate American football. Fourteen significant mediations (six pre-season, eight across-season) were observed where metabolites always mediated the statistical relationship between miRNAs and VR-based motor control ( p S o b e l p e r m ≤ 0.05; total effect > 50%), suggesting a hypothesis that metabolites sit in the statistical pathway between transcriptome and behavior. Three results further supported a model of chronic neuroinflammation, consistent with mitochondrial dysfunction: (1) Mediating metabolites were consistently medium-to-long chain fatty acids, (2) tricarboxylic acid cycle metabolites decreased across-season, and (3) accumulated head acceleration events statistically moderated pre-season metabolite levels to directionally model post-season metabolite levels. These preliminary findings implicate potential mitochondrial dysfunction and highlight probable peripheral blood biomarkers underlying repetitive head impacts in otherwise healthy collegiate football athletes.

Normalized Brain Tissue-Level Evaluation of Volumetric Changes of Youth Athletes Participating in Collision Sports.

Observations of short-term changes in the neural health of youth athletes participating in collision sports (e.g., football and soccer) have highlighted a need to explore potential structural alterations in brain tissue volumes for these persons. Studies have shown biochemical, vascular, functional connectivity, and white matter diffusivity changes in the brain physiology of these athletes that are strongly correlated with repetitive head acceleration exposure. Here, research is presented that highlights regional anatomical volumetric measures that change longitudinally with accrued subconcussive trauma. A novel pipeline is introduced that provides simplified data analysis on standard-space template to quantify group-level longitudinal volumetric changes within these populations. For both sports, results highlight incremental relative regional volumetric changes in the subcortical cerebrospinal fluid that are strongly correlated with head exposure events greater than a 50-G threshold at the short-term post-season assessment. Moreover, longitudinal regional gray matter volumes are observed to decrease with time, only returning to baseline/pre-participation levels after sufficient (5-6 months) rest from collision-based exposure. These temporal structural volumetric alterations are significantly different from normal aging observed in sex- and age-matched controls participating in non-collision sports. Future work involves modeling repetitive head exposure thresholds with multi-modal image analysis and understanding the underlying physiological reason. A possible pathophysiological pathway is presented, highlighting the probable metabolic regulatory mechanisms. Continual participation in collision-based activities may represent a risk wherein recovery cannot occur. Even when present, the degree of the eventual recovery remains to be explored, but has strong implications for the well-being of collision-sport participants.

Coupling between cerebrovascular oscillations and CSF flow fluctuations during wakefulness: An fMRI study.

It is commonly believed that cerebrospinal fluid (CSF) movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. This finding raises other fundamental questions: 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. Time delays between CSF movement and global hemodynamics were calculated. The observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by changes in cerebral blood volume mainly in the low frequency range, even when the individual is awake.

Euclidean Distance Approximations From Replacement Product Graphs.

We introduce a new chamfering paradigm, locally connecting pixels to produce path distances that approximate Euclidean space by building a small network (a replacement product) inside each pixel. These " RE -grid graphs" maintain near-Euclidean polygonal distance contours even in noisy data sets, making them useful tools for approximation when exact numerical solutions are unobtainable or impractical. The RE -grid graph creates a modular global architecture with lower pixel-to-pixel valency and simplified topology at the cost of increased computational complexity due to its internal structure. We present an introduction to chamfering replacement products with a number of case study examples to demonstrate the potential of these graphs for path-finding in high frequency and low resolution image spaces which motivate further study. Possible future applications include morphology, watershed segmentation, halftoning, neural network design, anisotropic image processing, image skeletonization, dendritic shaping, and cellular automata.

Evaluation of the Effectiveness of Newer Helmet Designs with Emergent Shell and Padding Technologies Versus Older Helmet Models for Preserving White Matter Following a Season of High School Football.

We aimed to objectively compare the effects of wearing newer, higher-ranked football helmets (HRank) vs. wearing older, lower-ranked helmets (LRank) on pre- to post-season alterations to neuroimaging-derived metrics of athletes' white matter. Fifty-four high-school athletes wore an HRank helmet, and 62 athletes wore an LRank helmet during their competitive football season and completed pre- and post-season diffusion tensor imaging (DTI). Longitudinal within- and between-group DTI metrics [fractional anisotropy (FA) and mean/axial/radial diffusivity (MD, AD, RD)] were analyzed using tract-based spatial statistics. The LRank helmet group exhibited significant pre- to post-season reductions in MD, AD, and RD, the HRank helmet group displayed significant pre- to post-season increases in FA, and both groups showed significant pre- to post-season increases in AD (p's < .05 [corrected]). Between-group analyses revealed the pre- to post-season increase in AD was significantly less for athletes wearing HRank compared to LRank (p < .05 [corrected]). These data provide in vivo evidence that wearing an HRank helmet may be efficacious for preserving white matter from head impact exposure during high school football. Future prospective longitudinal investigations with complimentary imaging and behavioral outcomes are warranted to corroborate these initial in vivo findings.

Using Dynamics of Eye Movements, Speech Articulation and Brain Activity to Predict and Track mTBI Screening Outcomes.

Repeated subconcussive blows to the head during sports or other contact activities may have a cumulative and long lasting effect on cognitive functioning. Unobtrusive measurement and tracking of cognitive functioning is needed to enable preventative interventions for people at elevated risk of concussive injury. The focus of the present study is to investigate the potential for using passive measurements of fine motor movements (smooth pursuit eye tracking and read speech) and resting state brain activity (measured using fMRI) to complement existing diagnostic tools, such as the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT), that are used for this purpose. Thirty-one high school American football and soccer athletes were tracked through the course of a sports season. Hypotheses were that (1) measures of complexity of fine motor coordination and of resting state brain activity are predictive of cognitive functioning measured by the ImPACT test, and (2) within-subject changes in these measures over the course of a sports season are predictive of changes in ImPACT scores. The first principal component of the six ImPACT composite scores was used as a latent factor that represents cognitive functioning. This latent factor was positively correlated with four of the ImPACT composites: verbal memory, visual memory, visual motor speed and reaction speed. Strong correlations, ranging between r = 0.26 and r = 0.49, were found between this latent factor and complexity features derived from each sensor modality. Based on a regression model, the complexity features were combined across sensor modalities and used to predict the latent factor on out-of-sample subjects. The predictions correlated with the true latent factor with r = 0.71. Within-subject changes over time were predicted with r = 0.34. These results indicate the potential to predict cognitive performance from passive monitoring of fine motor movements and brain activity, offering initial support for future application in detection of performance deficits associated with subconcussive events.

Using carpet plots to analyze transit times of low frequency oscillations in resting state fMRI.

A "carpet plot" is a 2-dimensional plot (time vs. voxel) of scaled fMRI voxel intensity values. Low frequency oscillations (LFOs) can be successfully identified from BOLD fMRI and used to study characteristics of neuronal and physiological activity. Here, we evaluate the use of carpet plots paired with a developed slope-detection algorithm as a means to study LFOs in resting state fMRI (rs-fMRI) data with the help of dynamic susceptibility contrast (DSC) MRI data. Carpet plots were constructed by ordering voxels according to signal delay time for each voxel. The slope-detection algorithm was used to identify and calculate propagation times, or "transit times", of tilted vertical edges across which a sudden signal change was observed. We aim to show that this metric has applications in understanding LFOs in fMRI data, possibly reflecting changes in blood flow speed during the scan, and for evaluating alternative blood-tracking contrast agents such as inhaled CO2. We demonstrate that the propagations of LFOs can be visualized and automatically identified in a carpet plot as tilted lines of sudden intensity change. Resting state carpet plots produce edges with transit times similar to those of DSC carpet plots. Additionally, resting state carpet plots indicate that edge transit times vary at different time points during the scan.

Development of brain atlases for early-to-middle adolescent collision-sport athletes.

Human brains develop across the life span and largely vary in morphology. Adolescent collision-sport athletes undergo repetitive head impacts over years of practices and competitions, and therefore may exhibit a neuroanatomical trajectory different from healthy adolescents in general. However, an unbiased brain atlas targeting these individuals does not exist. Although standardized brain atlases facilitate spatial normalization and voxel-wise analysis at the group level, when the underlying neuroanatomy does not represent the study population, greater biases and errors can be introduced during spatial normalization, confounding subsequent voxel-wise analysis and statistical findings. In this work, targeting early-to-middle adolescent (EMA, ages 13-19) collision-sport athletes, we developed population-specific brain atlases that include templates (T1-weighted and diffusion tensor magnetic resonance imaging) and semantic labels (cortical and white matter parcellations). Compared to standardized adult or age-appropriate templates, our templates better characterized the neuroanatomy of the EMA collision-sport athletes, reduced biases introduced during spatial normalization, and exhibited higher sensitivity in diffusion tensor imaging analysis. In summary, these results suggest the population-specific brain atlases are more appropriate towards reproducible and meaningful statistical results, which better clarify mechanisms of traumatic brain injury and monitor brain health for EMA collision-sport athletes.

Using Oculomotor Features to Predict Changes in Optic Nerve Sheath Diameter and ImPACT Scores From Contact-Sport Athletes.

There is mounting evidence linking the cumulative effects of repetitive head impacts to neuro-degenerative conditions. Robust clinical assessment tools to identify mild traumatic brain injuries are needed to assist with timely diagnosis for return-to-field decisions and appropriately guide rehabilitation. The focus of the present study is to investigate the potential for oculomotor features to complement existing diagnostic tools, such as measurements of Optic Nerve Sheath Diameter (ONSD) and Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). Thirty-one high school American football and soccer athletes were tracked through the course of a sports season. Given the high risk of repetitive head impacts associated with both soccer and football, our hypotheses were that (1) ONSD and ImPACT scores would worsen through the season and (2) oculomotor features would effectively capture both neurophysiological changes reflected by ONSD and neuro-functional status assessed via ImPACT. Oculomotor features were used as input to Linear Mixed-Effects Regression models to predict ONSD and ImPACT scores as outcomes. Prediction accuracy was evaluated to identify explicit relationships between eye movements, ONSD, and ImPACT scores. Significant Pearson correlations were observed between predicted and actual outcomes for ONSD (Raw = 0.70; Normalized = 0.45) and for ImPACT (Raw = 0.86; Normalized = 0.71), demonstrating the capability of oculomotor features to capture neurological changes detected by both ONSD and ImPACT. The most predictive features were found to relate to motor control and visual-motor processing. In future work, oculomotor models, linking neural structures to oculomotor function, can be built to gain extended mechanistic insights into neurophysiological changes observed through seasons of participation in contact sports.

A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

Elevated carbon dioxide (CO2) in breathing air is widely used as a vasoactive stimulus to assess cerebrovascular functions under hypercapnia (i.e., "stress test" for the brain). Blood-oxygen-level-dependent (BOLD) is a contrast mechanism used in functional magnetic resonance imaging (fMRI). BOLD is used to study CO2-induced cerebrovascular reactivity (CVR), which is defined as the voxel-wise percentage BOLD signal change per mmHg change in the arterial partial pressure of CO2 (PaCO2). Besides the CVR, two additional important parameters reflecting the cerebrovascular functions are the arrival time of arterial CO2 at each voxel, and the waveform of the local BOLD signal. In this study, we developed a novel analytical method to accurately calculate the arrival time of elevated CO2 at each voxel using the systemic low frequency oscillations (sLFO: 0.01-0.1 Hz) extracted from the CO2 challenge data. In addition, 26 candidate hemodynamic response functions (HRF) were used to quantitatively describe the temporal brain reactions to a CO2 stimulus. We demonstrated that our approach improved the traditional method by allowing us to accurately map three perfusion-related parameters: the relative arrival time of blood, the hemodynamic response function, and CVR during a CO2 challenge.

Brain Perfusion Bridges Virtual-Reality Spatial Behavior to TPH2 Genotype for Head Acceleration Events.

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 (TPH2), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.

Distribution of Head Acceleration Events Varies by Position and Play Type in North American Football.

OBJECTIVE: The goal of this pilot study was to evaluate the number of head acceleration events (HAEs) based on position, play type, and starting stance. DESIGN: Prospective cohort study. SETTING: Postcollegiate skill development camp during practice sessions and 1 exhibition game. PARTICIPANTS: Seventy-eight male adult North American football athletes. INDEPENDENT VARIABLES: A position was assigned to each participant, and plays in the exhibition game were separated by play type for analysis. During the exhibition game, video data were used to determine the effects of the starting position ("up" in a 2-point stance or "down" in a 3- or 4-point stance) on the HAEs experienced by players on the offensive line. MAIN OUTCOME MEASURES: Peak linear acceleration and number of HAEs greater than 20 g (g = 9.81 m/s2) were measured using an xPatch (X2 Biosystems, Seattle, WA). RESULTS: Four hundred thirty-seven HAEs were recorded during practices and 272 recorded during the exhibition game; 98 and 52 HAEs, the greatest number of HAEs by position in the game, were experienced by the offensive and defensive linemen, respectively. Linebackers and tight ends experienced high percentages of HAEs above 60 g. Offensive line players in a down stance had a higher likelihood of sustaining a HAE than players in an up stance regardless of the type of play (run vs pass). CONCLUSIONS: Changing the stance of players on the offensive line and reducing the number of full-contact practices will lower HAEs.

Head acceleration event metrics in youth contact sports more dependent on sport than level of play.

The goal of the study was to evaluate how repetitive head traumas sustained by athletes in contact sports depend on sport and level of play. A total of 16 middle school football players, 107 high school football players, and 65 high school female soccer players participated. Players were separated into levels of play: middle school (MS), freshman (FR), junior varsity (JV), junior varsity-varsity (JV-V), and varsity (V). xPatch sensors were used to measure peak translational and angular accelerations (PTA and PAA, respectively) for each head acceleration event (HAE) during practice and game sessions. Data were analyzed using a custom MATLAB program to compare metrics that have been correlated with functional neurological changes: session metrics (median HAEs per contact session), season metrics (total HAEs, cumulative PTA/PAA), and regressions (cumulative PTA/PAA versus total HAEs, total HAEs versus median HAEs per contact session). Football players had greater session (p<.001) and season (p<.001) metrics than soccer players, but soccer players had a significantly greater player average PAA per HAE than football players (p<.001). Middle school football players had similar session and season metrics to high school level athletes. In conclusion, sport has a greater influence on HAE characteristics than level of play.

Short-wave Infrared Neural Stimulation Drives Graded Sciatic Nerve Activation Across A Continuum of Wavelengths.

Infrared neural stimulation (INS) is an optical stimulation technique which uses coherent light to stimulate nerves and neurons and which shows increased spatial selectivity compared to electrical stimulation. This could improve deep brain, high channel count, or vagus nerve stimulation. In this study, we seek to understand the wavelength dependence of INS in the near-infrared optical window. Rat sciatic nerves were excised ex vivo and stimulated with wavelengths between 700 and 900 nm. Recorded compound nerve action potentials (CNAPs) showed that stimulation was maximized in the 700 nm window despite comparable laser power levels across wavelengths. Computational models demonstrated that wavelength-based activation dependencies were not a result of passive optical properties. This data demonstrates that INS is both wavelength and power level dependent, which inform stimulation systems to actively target neural microcircuits in humans.

Factors affecting peak impact force during soccer headers and implications for the mitigation of head injuries.

It has been documented that up to 22% of all soccer injuries are concussions. This is in part due to players purposely using their head to direct the ball during play. To provide a more complete understanding of head trauma in soccer athletes, this study characterized the effects of four soccer ball characteristics (size, inflation pressure, mass, velocity) on the resulting peak impact force as it relates to the potential for incurring neurophysiological changes. A total of six hundred trials were performed on size 4 and 5 soccer balls as well as a novel lightweight soccer ball. Impact force was measured with a force plate and ball velocity was determined using motion capture. These data were used, in conjunction with dimensional analysis to relate impact force to ball size, mass, velocity, and pressure. Reasonable reductions in allowable ball parameters resulted in a 19.7% decrease in peak impact force. Adjustments to ball parameters could reduce a high cumulative peak translational acceleration soccer athlete down into a previously defined safer low loading range. In addition, it was noted that water absorption by soccer balls can result in masses that substantially increase impact force and quickly surpass the NCAA weight limit for game play. Additional research is required to determine whether varying soccer ball characteristics will enable soccer players to avoid persistent neurophysiological deficits or what additional interventions may be necessary and the legal implications of these data are discussed.

Characterizing near-infrared spectroscopy signal under hypercapnia.

Vasoactive stress tests (i.e. hypercapnia, elevated partial pressure of arterial CO2 [PaCO2 ]) are commonly used in functional MRI (fMRI), to induce cerebral blood flow changes and expose hidden perfusion deficits in the brain. Compared with fMRI, near-infrared spectroscopy (NIRS) is an alternative low-cost, real-time, and non-invasive tool, which can be applied in out-of-hospital settings. To develop and optimize vasoactive stress tests for NIRS, several hypercapnia-induced tasks were tested using concurrent-NIRS/fMRI on healthy subjects. The results indicated that the cerebral and extracerebral reactivity to elevated PaCO2 depended on the rate of the CO2 increase. A steep increase resulted in different cerebral and extracerebral reactivities, leading to unpredictable NIRS measurements compared with fMRI. However, a ramped increase, induced by ramped-CO2 inhalation or breath-holding tasks, induced synchronized cerebral, and extracerebral reactivities, resulting in consistent NIRS and fMRI measurements. These results demonstrate that only tasks that increase PaCO2 gradually can produce reliable NIRS results.