Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Mild Traumatic Brain Injury and Career Stage Associate with Visible Perivascular Spaces in Special Operations Forces Soldiers.

Mild traumatic brain injury (mTBI) and occupational blast exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk. Perivascular spaces (PVS) are a key part of the glymphatic system which supports brain waste clearance, preferentially during sleep. Visible PVS on clinical magnetic resonance imaging have been previously observed in patients with neurodegenerative diseases and animal neurotrauma models. The purpose of this study was to determine associations between PVS morphological characteristics, military career stage, and mTBI history in Special Operations Forces (SOF) Soldiers. Participants underwent T2-weighed neuroimaging to capture three-dimensional whole brain volumes. Segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. Only PVS clusters within the white matter mask were quantified for analyses. Due to non-normal PVS metric distribution, non-parametric Mann-Whitney U tests were used to determine group differences in PVS outcomes. In total, 223 healthy SOF combat Soldiers (age = 33.1 ± 4.3yrs) were included, 217 reported career stage. Soldiers with mTBI history had greater PVS number (z = 2.51, P = 0.013) and PVS volume (z = 2.42, P = 0.016). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02) compared to a baseline cohort. Mild TBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk and if clinical interventions such as improving sleep can reduce PVS burden.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Cumulative Blast Exposure Estimate Model for Special Operations Forces Combat Soldiers.

Special Operations Forces (SOF) Service members endure frequent exposures to blast and overpressure mechanisms given their high training tempo. The link between cumulative subconcussive blasts on short- and long-term neurological impairment is largely understudied. Neurodegenerative diseases such as brain dysfunction, cognitive decline, mild cognitive impairment, and dementia may develop with chronic exposures. This hypothesis remains unproven because of lack of ecologically valid occupational blast exposure surveillance among SOF Service members. The purpose of the study was to measure occupational blast exposures in a close quarter battle (CQB) training environment and to use those outcomes to develop a pragmatic cumulative blast exposure (CBE) estimate model. Four blast silhouettes equipped with a field-deployable wireless blast gauge system were positioned in breaching positions during CQB training scenarios. Silhouettes were exposed to flashbangs and three interior breaching charges (single strand roll-up interior charge, 300 grain (gr) explosive cutting tape (ECT), and Jelly charge). Mean blast measures were calculated for each silhouette for flashbangs (n = 93), single strand roll-up interior charge (n = 80), 300 gr ECT (n = 28), and Jelly charge (n = 71). Mean peak blast pressures per detonation are reported as follows: (1) flashbangs (1.97 pounds per square inch [psi]); (2) single strand roll-up interior charge (3.88 psi); (3) 300 gr ECT (2.78 psi); and (4) Jelly charge (1.89 psi). Pragmatic CBE estimates for SOF Service members suggest 36.8 psi, 184 psi, and 2760 psi may represent daily, weekly, and training cycle cumulative pressure exposures. Estimating blast exposures during routine CQB training can be determined from empirical measures taken in CQB environments. Factoring in daily, weekly, training cycle, or even career length may reasonably estimate cumulative occupational training blast exposures for SOF Service members. Future work may permit more granular exposure estimates based on operational blast exposures and those experienced by other military occupational specialties.

Associations of lifetime concussion history and repetitive head impact exposure with resting-state functional connectivity in former collegiate American football players: An NCAA 15-year follow-up study.

The objective of this study was to examine associations of lifetime concussion history (CHx) and an advanced metric of lifetime repetitive head impact exposure with resting-state functional connectivity (rsFC) across the whole-brain and among large-scale functional networks (Default Mode; Dorsal Attention; and Frontoparietal Control) in former collegiate football players. Individuals who completed at least one year of varsity collegiate football were eligible to participate in this observational cohort study (n = 48; aged 36-41 years; 79.2% white/Caucasian; 12.5±4.4 years of football played; all men). Individuals were excluded if they reported history/suspicion of psychotic disorder with active symptoms, contraindications to participation in study procedures (e.g., MRI safety concern), or inability to travel. Each participant provided concussion and football playing histories. Self-reported concussion history was analyzed in two different ways based on prior research: dichotomous "High" (≥3 concussions; n = 28) versus "Low" (<3 concussions; n = 20); and four ordinal categories (0-1 concussion [n = 19]; 2-4 concussions [n = 8]; 5-7 concussions [n = 9]; and ≥8 concussions [n = 12]). The Head Impact Exposure Estimate (HIEE) was calculated from football playing history captured via structured interview. Resting-state fMRI and T1-weighted MRI were acquired and preprocessed using established pipelines. Next, rsFC was calculated using the Seitzman et al., (2020) 300-ROI functional atlas. Whole-brain, within-network, and between-network rsFC were calculated using all ROIs and network-specific ROIs, respectively. Effects of CHx and HIEE on rsFC values were examined using separate multivariable linear regression models, with a-priori α set to 0.05. We observed no statistically significant associations between rsFC outcomes and either CHx or HIEE (ps ≥ .12). Neither CHx nor HIEE were associated with neural signatures that have been observed in studies of typical and pathological aging. While CHx and repetitive head impacts have been associated with changes in brain health in older former athletes, our preliminary results suggest that associations with rsFC may not be present in early midlife former football players.

Association Between Head Impact Biomechanics and Physical Load in College Football.

Head impacts and physical exertion are ubiquitous in American football, but the relationship between these factors is poorly understood across a competitive season or even within an individual session. Gameplay characteristics, including player position and session type, may contribute to these relationships but have not been prospectively examined. The current study aimed to determine if an association exists between head impact biomechanics and physical load metrics. We prospectively studied college football players during the 2017-2021 football seasons across representative playing positions (15 offensive and defensive linemen, 11 linebackers and tight ends, and 15 defensive backs, running backs, and receivers). Participants wore halters embedded with Catapult Vector GPS monitoring systems to quantify player load and participant helmets were equipped with the Head Impact Telemetry System to quantify head impact biomechanics and repetitive head impact exposure (RHIE). Generalized linear models and linear regression models were employed to analyze in-session and season-long outcomes, while addressing factors such as player position and session type on our data. Player load was associated with RHIE (p < 0.001). Season-long player load predicted season-long RHIE (R2 = 0.31; p < 0.001). Position group affected in-session player load (p = 0.025). Both player load and RHIE were greater in games than in practices (p < 0.001), and position group did not affect RHIE (p = 0.343). Physical load burden was associated with RHIE within sessions and across an entire season. Session type affected both RHIE and player load, while position group only affected player load. Our data point to tracking physical load burden as a potential proxy for monitoring anticipated RHIE during the season.

Relationship between Anterior Pituitary Volume and IGF-1 Serum Levels in Soldiers with Mild Traumatic Brain Injury History.

PURPOSE: A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is an mTBI sequela; however, few studies have examined this phenomenon in those with an mTBI history. This cross-sectional study of Special Operations Forces combat soldiers aimed 1) to relate anterior pituitary gland volumes (actual and normalized) to insulin-like growth factor 1 (IGF-1) concentrations, 2) to examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and 3) to measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history. METHODS: Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRI sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n = 74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n = 54). RESULTS: A significant linear relationship between the subjects' anterior pituitary gland volumes and IGF-1 concentrations (r72 = 0.35, P = 0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (P < 0.001) and lower anterior pituitary gland volumes (P = 0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (odds ratio = 5.73; 95% confidence interval = 1.77-18.55). CONCLUSIONS: Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.

Head Impact Exposure, Gray Matter Volume, and Moderating Effects of Estimated Intelligence Quotient and Educational Attainment in Former Athletes at Midlife.

Repetitive head impact (RHI) exposure has been associated with differences in brain structure among younger active athletes, most often within the hippocampus. Studies of former athletes at early-midlife are limited. We investigated the association between RHI exposure and gray matter (GM) structure, as well as moderating factors, among former athletes in early-midlife. Former collegiate football players (n = 55; age = 37.9 + 1.5 years) completed magnetic resonance imaging to quantify GM morphometry and extensive structured interviews of RHI history (Head Impact Exposure Estimate). Linear regression models tested the association between RHI exposure and GM structures of interest. Interactions were tested for moderators: two estimates of intelligence quotient (IQ) (single word reading and picture vocabulary) and education history. Greater RHI exposure was associated with smaller hippocampal volume, ß = -0.36, p = 0.004. Conversely, RHI exposure was not significantly associated with other GM outcomes ps > 0.05. Education history significantly moderated the association between RHI exposure and hippocampal volume, ß = 0.31, p = 0.047. Among those with a bachelor's degree, greater RHI exposure was significantly associated with smaller hippocampal volumes, ß = -0.58, p < 0.001. For those with graduate/professional degrees, the association between RHI and hippocampal volume was not significant, ß = -0.33, p = 0.134. Consistent with studies involving younger, active athletes, smaller hippocampal volumes were selectively associated with greater RHI exposure among former collegiate football players at midlife. This relationship was moderated by higher levels of education. Future longitudinal studies are needed to investigate the course of possible changes that can occur between early-midlife and older ages, as well as the continued protective effect of education and other potential influential factors.

Epidemiology of Injuries in National Collegiate Athletic Association Men's Baseball: 2014-2015 Through 2018-2019.

CONTEXT: The National Collegiate Athletic Association has supported men's baseball championships since 1947. Since its inception, the number of participating teams and athletes has considerably expanded. BACKGROUND: Frequently conducting injury surveillance of collegiate baseball athletes is essential for identifying developing temporal patterns. METHODS: Exposure and injury data collected in the National Collegiate Athletic Association Injury Surveillance Program during 2014-2015 through 2018-2019 were analyzed. Injury counts, rates, and proportions were used to describe injury characteristics; injury rate ratios were used to examine differential injury rates. RESULTS: The overall injury rate was 3.16 per 1000 athlete-exposures. The preseason injury rate was significantly higher than the regular season injury rate. The most commonly injured body parts were shoulder (16.1%), arm or elbow (16%), and hand or wrist (13.9%). The most reported specific injury was hamstring tear (7.9%). CONCLUSIONS: The findings of this study aligned with previous studies-most injuries were due to noncontact and overuse mechanisms, less than one-half of injuries were related to upper extremity body parts, and one-third of all injuries were reported among pitchers.

Epidemiology of Injuries in National Collegiate Athletic Association Men's Football: 2014-2015 Through 2018-2019.

CONTEXT: Football is among the most popular collegiate sports in the United States, and participation in National Collegiate Athletic Association (NCAA) football has risen in recent years. BACKGROUND: Continued monitoring of football injuries is important for capturing the evolving burden of injuries in NCAA football. The purpose of this study was to describe the epidemiology of football-related injuries among men's NCAA football players during the 2014-2015 through 2018-2019 academic years. METHODS: Exposure and injury data collected in the NCAA Injury Surveillance Program were analyzed. Injury counts, rates, and proportions were used to describe injury characteristics, and injury rate ratios were used to examine differential injury rates. RESULTS: The overall injury rate was 9.31 per 1000 athlete-exposures. Most injuries occurred during general play (17.5%), blocking (15.8%), and tackling (14.0%). Concussions (7.5%), lateral ligament complex tears (6.9%), and hamstring tears (4.7%) were the most commonly reported injuries. CONCLUSIONS: Results of this study were generally consistent with previous findings, though changes over time in rates of commonly reported injuries warrant attention. Continued monitoring of injury incidence is needed to appraise the effectiveness of recently implemented rules changes.

Epidemiology of Injuries in National Collegiate Athletic Association Men's Wrestling: 2014-2015 Through 2018-2019.

CONTEXT: The first men's wrestling National Collegiate Athletic Association (NCAA) Championship was sponsored in 1928; since then, participation has increased. BACKGROUND: Continued study of wrestling injury data is essential to identify areas for intervention based on emerging trends. METHODS: Exposure and injury data collected in the NCAA Injury Surveillance Program during 2014-2015 through 2018-2019 were analyzed. Injury counts, rates, and proportions were used to describe injury characteristics, and injury rate ratios (IRRs) were used to examine differential injury rates. RESULTS: The overall injury rate was 8.82 per 1000 athlete exposures. The competition injury rate was significantly higher than practice injury rate (IRR = 4.11; 95% CI = 3.72, 4.55). The most commonly injured body parts were the knee (21.4%), shoulder (13.4%), and head/face (13.3%), and the most prevalently reported specific injury was concussion. SUMMARY: These findings provide the most current update to injury incidence and outcomes in NCAA men's wrestling. We identify notable trends that warrant consideration in future research.

Do Head Injury Biomechanics Predict Concussion Clinical Recovery in College American Football Players?

Identifying the associations between head impact biomechanics and clinical recovery may inform better head impact monitoring procedures and identify athletes who may benefit from early treatments aimed to enhance recovery. The purpose of this study was to test whether head injury biomechanics are associated with clinical recovery of symptom severity, balance, and mental status, as well as symptom resolution time (SRT) and return-to-participation (RTP) time. We studied 45 college American football players (n = 51 concussions) who sustained an incident concussion while participating in a multi-site study. Player race/ethnicity, prior concussion, medical history, position, body mass index, event type, and impact location were covariates in our multivariable analyses. Multivariable negative binomial regression models analyzed associations between our study outcomes and (1) injury-causing linear and rotational head impact severity, (2) season repetitive head impact exposure (RHIE), and (3) injury day RHIE. Median SRT was 6.1 days (IQR 5.8 days, n = 45) and median RTP time was 12.3 days (IQR 7.8 days, n = 36) across our study sample. RTP time was 86% (Ratio 1.86, 95% CI [1.05, 3.28]) longer in athletes with a concussion history. Offensive players had SRTs 49% shorter than defensive players (Ratio 0.51, 95% CI [0.29, 0.92]). Per-unit increases in season RHIE were associated with 22% longer SRT (Ratio 1.22, 95% CI [1.09, 1.36]) but 28% shorter RTP time (Ratio 0.72, 95% CI [0.56, 0.93]). No other head injury biomechanics predicted injury recovery.

Neuroinflammatory Biomarkers Associated With Mild Traumatic Brain Injury History in Special Operations Forces Combat Soldiers.

BACKGROUND: Special Operations Forces (SOF) combat soldiers are frequently exposed to blast and blunt neurotrauma, most often classified as mild traumatic brain injury (mTBI). Repetitive mTBI may increase the risk of developing long-term neurological sequelae. Identifying changes in neuroinflammatory biomarkers before chronic conditions emerge could serve as preliminary evidence of developing neuropathology. OBJECTIVE: To determine the effects of mTBI history, lifetime mTBI incidence, and recency on blood biomarker concentrations of axonal protein neurofilament light (NfL), glycolytic enzyme neuron-specific enolase (NSE), astrocyte-expressed S100 calcium-binding protein B (S100B), and neurotrophic cytokine interleukin-6 (IL-6) in healthy, active duty SOF combat soldiers. METHODS: Self-reported mTBI history/recency and fasted blood samples were collected in this cross-sectional study of 104 asymptomatic SOF combat soldiers. Biomarker concentrations were quantified using commercial enzyme-linked immunosorbent assays. Mann-Whitney U and Kruskal-Wallis tests were used to compare groups. Post hoc tests with appropriate corrections were conducted as warranted. RESULTS: Soldiers with mTBI history had higher NSE concentrations than those without (z = -2.60, P = .01). We also observed significant main effects of lifetime mTBI incidence on NSE (χ(3) = 9.52, P = .02) and S100B (χ(3) = 8.21, P = .04) concentrations and a significant main effect of mTBI recency on NfL concentration (χ(2) = 6.02, P = .049). CONCLUSION: The SOF combat soldiers with mTBI history had increased NSE. Longitudinal studies in this population are needed due to between-subject heterogeneity in biomarker concentrations. The NfL concentrations in our SOF combat soldiers-regardless of mTBI history or recency-were similar to values previously reported in civilian acute TBI patients.

Delayed Migration and Perforation of the Jugular Vein by a Peripherally Inserted Central Catheter.

We report a case of peripherally inserted central catheter (PICC) migration and perforation of the left internal jugular vein in a home health setting in an 80-year-old female. A left sided PICC was placed for treatment of diverticulitis following hospital discharge. She complained of sudden onset left sided neck pain immediately after starting an infusion of vancomycin. In the emergency department the injury was identified by portable chest radiograph and computed tomography of her neck. Following removal of the line, she had an uneventful course. Emergency physicians should be aware of this possible PICC line complication.