Associations of prior concussion severity with brain microstructure using mean apparent propagator magnetic resonance imaging.

Magnetic resonance imaging (MRI) diffusion studies have shown chronic microstructural tissue abnormalities in athletes with history of concussion, but with inconsistent findings. Concussions with post-traumatic amnesia (PTA) and/or loss of consciousness (LOC) have been connected to greater physiological injury. The novel mean apparent propagator (MAP) MRI is expected to be more sensitive to such tissue injury than the conventional diffusion tensor imaging. This study examined effects of prior concussion severity on microstructure with MAP-MRI. Collegiate-aged athletes (N = 111, 38 females; ≥6 months since most recent concussion, if present) completed semistructured interviews to determine the presence of prior concussion and associated injury characteristics, including PTA and LOC. MAP-MRI metrics (mean non-Gaussian diffusion [NG Mean], return-to-origin probability [RTOP], and mean square displacement [MSD]) were calculated from multi-shell diffusion data, then evaluated for associations with concussion severity through group comparisons in a primary model (athletes with/without prior concussion) and two secondary models (athletes with/without prior concussion with PTA and/or LOC, and athletes with/without prior concussion with LOC only). Bayesian multilevel modeling estimated models in regions of interest (ROI) in white matter and subcortical gray matter, separately. In gray matter, the primary model showed decreased NG Mean and RTOP in the bilateral pallidum and decreased NG Mean in the left putamen with prior concussion. In white matter, lower NG Mean with prior concussion was present in all ROI across all models and was further decreased with LOC. However, only prior concussion with LOC was associated with decreased RTOP and increased MSD across ROI. Exploratory analyses conducted separately in male and female athletes indicate associations in the primary model may differ by sex. Results suggest microstructural measures in gray matter are associated with a general history of concussion, while a severity-dependent association of prior concussion may exist in white matter.

The effects of cytomegalovirus on brain structure following sport-related concussion.

The neurotrophic herpes virus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of traumatic brain injury, including sport-related concussion, are major physiological stressors that produce neuroinflammation. In theory, concussion could predispose to the reactivation of cytomegalovirus and amplify the effects of physical injury on brain structure. However, to our knowledge this hypothesis remains untested. This study evaluated the effect of cytomegalovirus serostatus on white and grey matter structure in a prospective study of athletes with concussion and matched contact-sport controls. Athletes who sustained concussion (n = 88) completed MRI at 1, 8, 15 and 45 days post-injury; matched uninjured athletes (n = 73) completed similar visits. Cytomegalovirus serostatus was determined by measuring serum IgG antibodies (n = 30 concussed athletes and n = 21 controls were seropositive). Inverse probability of treatment weighting was used to adjust for confounding factors between athletes with and without cytomegalovirus. White matter microstructure was assessed using diffusion kurtosis imaging metrics in regions previously shown to be sensitive to concussion. T1-weighted images were used to quantify mean cortical thickness and total surface area. Concussion-related symptoms, psychological distress, and serum concentration of C-reactive protein at 1 day post-injury were included as exploratory outcomes. Planned contrasts compared the effects of cytomegalovirus seropositivity in athletes with concussion and controls, separately. There was a significant effect of cytomegalovirus on axial and radial kurtosis in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion showed greater axial (P = 0.007, d = 0.44) and radial (P = 0.010, d = 0.41) kurtosis than cytomegalovirus negative athletes with concussion. Similarly, there was a significant association of cytomegalovirus with cortical thickness in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion had reduced mean cortical thickness of the right hemisphere (P = 0.009, d = 0.42) compared with cytomegalovirus negative athletes with concussion and showed a similar trend for the left hemisphere (P = 0.036, d = 0.33). There was no significant effect of cytomegalovirus on kurtosis fractional anisotropy, surface area, symptoms and C-reactive protein. The results raise the possibility that cytomegalovirus infection contributes to structural brain abnormalities in the aftermath of concussion perhaps via an amplification of concussion-associated neuroinflammation. More work is needed to identify the biological pathways underlying this process and to clarify the clinical relevance of this putative viral effect.

A dominance analysis of subjective cognitive complaint comorbidities in former professional football players with and without mild cognitive impairment.

OBJECTIVES: Subjective cognitive difficulties (SCDs) are associated with factors commonly reported in older adults and former contact sport athletes, regardless of objective cognitive decline. We investigated the relative contribution of these factors to SCD in former National Football League (NFL)-players with and without a diagnosis of mild cognitive impairment (MCI). METHODS: Former NFL players (n = 907) aged ≥ 50 years (mean = 64.7 ± 8.9), with (n = 165) and without (n = 742) a diagnosis of MCI completed health questionnaires. Multivariable regression and dominance analyses determined the relative importance of SCD factors on SCD: 1) depression, 2) anxiety, 3) sleep disturbance, 4) pain interference, 5) ability to participate in social roles and activities, 6) stress-related events, 7) fatigue, 8) concussion history, and 9) education. SCD outcomes included Neuro-QoL Emotional-Behavioral Dyscontrol and the PROMIS Cognitive Function. Fisher's z-transformation compared comorbid contributing factors to SCD across MCI and non-MCI groups. RESULTS: Complete dominance of anxiety was established over most comorbid factors across the MCI and non-MCI groups. Fatigue also exhibited complete dominance over most comorbid factors, though its influence in the MCI group was less robust (general dominance). Average contributions to variance accounted for by comorbid factors to ratings of SCD across MCI and non-MCI groups did not statistically differ (Z-statistics <1.96, ps>.05). CONCLUSIONS: Anxiety and fatigue are the most robust factors associated with SCD in former professional football players across various combinations of clinical presentations (different combinations of comorbid factors), regardless of documented cognitive impairment. Self-reported deficits may be less reliable in detecting objective impairment in the presence of these factors, with multidimensional assessment being ideal.

Cognitive decline and quality of life after resective epilepsy surgery.

OBJECTIVES: The objectives of this study were to examine the association between cognitive decline and quality of life (QoL) change in a large sample of individuals with drug-resistant epilepsy who underwent resective surgery and to examine whether the association between cognitive decline and QoL is differentially affected by seizure classification outcome (Engel Class 1 vs. 2-4) or side of surgery (left vs. right hemisphere). MATERIALS AND METHODS: The sample comprised 224 adults (ages ≥ 18) with drug-resistant focal epilepsy treated with resective surgery who underwent comprehensive pre-operative and post-operative evaluations including neuropsychological testing and the Quality of Life in Epilepsy Inventory - 31 between 1991 and 2020. Linear mixed-effects models were fit to examine subject-specific trajectories and assess the effects of time (pre- to post-operative), cognitive decline (number of measures that meaningfully declined), and the interaction between time and cognitive decline on pre- to post-operative change in QoL. RESULTS: Increases in QoL following resection were observed (B = -10.72 [SE = 1.22], p < .001; mean difference between time point 1 and time point 2 QoL rating = 8.11). There was also a main effect of cognitive decline on QoL (B = -.85 [SE = .27], p = .002). Follow-up analyses showed that the number of cognitive measures that declined was significantly associated with post-surgical QoL, (r = -.20 p = .003), but not pre-surgical QoL, (r = -.04 p = .594), and with pre-to post-surgery raw change in QoL score, (r = -.18 p = .009). A cognitive decline by time point interaction was observed, such that those who had greater cognitive decline had less improvement in overall QoL following resection (B = .72 [SE = .27], p = .009). Similar results were observed within the Engel Class 1 outcome subgroup. However, within the Engel Class 2-4 outcome subgroup, QoL improved following resection, but there was no main effect of cognitive decline or interaction between cognitive decline and time point on QoL change. There was no main effect of resection hemisphere on overall QoL, nor were there interactions with hemisphere by time, hemisphere by cognitive decline, or hemisphere by time by cognitive decline. CONCLUSIONS: Quality of life improves following epilepsy surgery. Participants who had cognitive decline across a greater number of measures experienced less improvement in QoL post-operatively overall, but there was no clear pattern of domain-specific cognitive decline associated with change in QoL. Our results indicate that cognitive decline in a diffuse set of cognitive domains negatively influences post-operative QoL, particularly for those who experience good seizure outcomes (i.e., seizure freedom), regardless of the site or side of resection.

Relationship Between Neighborhood Disadvantage and Mild Traumatic Brain Injury Symptoms.

OBJECTIVE: To test the hypotheses that (1) higher neighborhood disadvantage is associated with greater injury-related symptom severity in civilians with mild traumatic brain injury (mTBI) and (2) neighborhood disadvantage remains predictive after controlling for other established predictors. SETTING: Level 1 trauma center and affiliated academic medical center. PARTICIPANTS: N = 171 individuals with mTBI. DESIGN: Prospective cohort study. MAIN MEASURES: Rivermead Post Concussion Symptoms Questionnaire (RPQ) total score assessed less than 24 hours and at 2 weeks, 3 months, and 6 months postinjury. Linear mixed-effects models were used to assess the relationship between predictor variables and mTBI-related symptom burden (RPQ score). Neighborhood disadvantage was quantified by the Area Deprivation Index (ADI), a composite of 17 markers of socioeconomic position (SEP) scored at the census block group level. RESULTS: Individuals in the upper ADI quartile of the national distribution displayed higher RPQ symptoms than those in the lower 3 quartiles ( P < .001), with a nonsignificant ADI × visit interaction ( P = .903). In a multivariable model, the effect of ADI remained significant ( P = .034) after adjusting for demographics, individual SEP, and injury factors. Other unique predictors in the multivariable model were gender (gender × visit P = .035), health insurance type ( P = .017), and injury-related litigation ( P = .012). CONCLUSION: Neighborhood disadvantage as quantified by the ADI is robustly associated with greater mTBI-related symptom burden throughout the first 6 months postinjury. That the effect of ADI remained after controlling for demographics, individual SEP, and injury characteristics implies that neighborhood disadvantage is an important, understudied factor contributing to clinical recovery from mTBI.

Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review.

OBJECTIVE: Determine the role of fluid-based biomarkers, advanced neuroimaging, genetic testing and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion (SRC). DESIGN: Systematic review. DATA SOURCES: Searches of seven databases from 1 January 2001 through 24 March 2022 using keywords and index terms relevant to concussion, sports and neurobiological recovery. Separate reviews were conducted for studies involving neuroimaging, fluid biomarkers, genetic testing and emerging technologies. A standardised method and data extraction tool was used to document the study design, population, methodology and results. Reviewers also rated the risk of bias and quality of each study. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they: (1) were published in English; (2) represented original research; (3) involved human research; (4) pertained only to SRC; (5) included data involving neuroimaging (including electrophysiological testing), fluid biomarkers or genetic testing or other advanced technologies used to assess neurobiological recovery after SRC; (6) had a minimum of one data collection point within 6 months post-SRC; and (7) contained a minimum sample size of 10 participants. RESULTS: A total of 205 studies met inclusion criteria, including 81 neuroimaging, 50 fluid biomarkers, 5 genetic testing, 73 advanced technologies studies (4 studies overlapped two separate domains). Numerous studies have demonstrated the ability of neuroimaging and fluid-based biomarkers to detect the acute effects of concussion and to track neurobiological recovery after injury. Recent studies have also reported on the diagnostic and prognostic performance of emerging technologies in the assessment of SRC. In sum, the available evidence reinforces the theory that physiological recovery may persist beyond clinical recovery after SRC. The potential role of genetic testing remains unclear based on limited research. CONCLUSIONS: Advanced neuroimaging, fluid-based biomarkers, genetic testing and emerging technologies are valuable research tools for the study of SRC, but there is not sufficient evidence to recommend their use in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020164558.

Acute evaluation of sport-related concussion and implications for the Sport Concussion Assessment Tool (SCAT6) for adults, adolescents and children: a systematic review.

OBJECTIVES: To systematically review the scientific literature regarding the acute assessment of sport-related concussion (SRC) and provide recommendations for improving the Sport Concussion Assessment Tool (SCAT6). DATA SOURCES: Systematic searches of seven databases from 2001 to 2022 using key words and controlled vocabulary relevant to concussion, sports, SCAT, and acute evaluation. ELIGIBILITY CRITERIA: (1) Original research articles, cohort studies, case-control studies, and case series with a sample of >10; (2) ≥80% SRC; and (3) studies using a screening tool/technology to assess SRC acutely (<7 days), and/or studies containing psychometric/normative data for common tools used to assess SRC. DATA EXTRACTION: Separate reviews were conducted involving six subdomains: Cognition, Balance/Postural Stability, Oculomotor/Cervical/Vestibular, Emerging Technologies, and Neurological Examination/Autonomic Dysfunction. Paediatric/Child studies were included in each subdomain. Risk of Bias and study quality were rated by coauthors using a modified SIGN (Scottish Intercollegiate Guidelines Network) tool. RESULTS: Out of 12 192 articles screened, 612 were included (189 normative data and 423 SRC assessment studies). Of these, 183 focused on cognition, 126 balance/postural stability, 76 oculomotor/cervical/vestibular, 142 emerging technologies, 13 neurological examination/autonomic dysfunction, and 23 paediatric/child SCAT. The SCAT discriminates between concussed and non-concussed athletes within 72 hours of injury with diminishing utility up to 7 days post injury. Ceiling effects were apparent on the 5-word list learning and concentration subtests. More challenging tests, including the 10-word list, were recommended. Test-retest data revealed limitations in temporal stability. Studies primarily originated in North America with scant data on children. CONCLUSION: Support exists for using the SCAT within the acute phase of injury. Maximal utility occurs within the first 72 hours and then diminishes up to 7 days after injury. The SCAT has limited utility as a return to play tool beyond 7 days. Empirical data are limited in pre-adolescents, women, sport type, geographical and culturally diverse populations and para athletes. PROSPERO REGISTRATION NUMBER: CRD42020154787.

Incorporation of concussion history as part of the LIfestyle for BRAin Health (LIBRA) modifiable factors risk score and associations with cognition in older former National Football League players.

OBJECTIVE: Investigate associations between the LIfestyle for BRAin Health (LIBRA) risk score with odds of mild cognitive impairment (MCI) diagnosis and cognitive function, incorporating concussion history. METHODS: Former National Football League (NFL) players (N = 1050; mean age = 64.8 ± 9.0-years) completed initial testing for integration of concussion history into LIBRA scores (i.e., modified-LIBRA) and completed the Brief Test of Adult Cognition by Telephone (BTACT). Modified-LIBRA score (including concussion history) associations with odds of MCI and cognitive dysfunction were assessed via logistic and linear regression. RESULTS: The highest quartile LIBRA scores were six times more likely to have a diagnosis of MCI compared to the lowest quartile (OR = 6.27[3.61, 10.91], p < 0.001). Modified-LIBRA scores significantly improved model fit for odds of MCI above original LIBRA scores (χ2 (1) = 7.76, p = 0.005) and accounted for a greater fraction of variance in executive function (ΔR2  = 0.02, p = 0.003) and episodic memory (ΔR2  = 0.02, p = 0.002). CONCLUSIONS: Modified-LIBRA score, incorporating concussion history, may help monitoring risk status in former contact sport athletes, by targeting modifiable, lifestyle-related risk factors.

Cumulative Concussion and Odds of Stroke in Former National Football League Players.

BACKGROUND AND PURPOSE: Postmortem and experimental studies indicate a potential association between repeated concussions and stroke risk in older contact sport athletes. We examined the relationship between concussion and stroke history in former National Football League players aged ≥50 years. METHODS: Former professional football players aged ≥50 years who played ≥1 year in the National Football League were enrolled in the cross-sectional study. Indirect standardization was used to calculate overall and decade-specific standardized prevalence ratios. Logistic regression using Firth's bias reduction method examined the association between lifetime concussion history 0 (n=119; 12.2%), 1 to 2 (n=152; 15.5%), 3 to 5 (n=242; 24.7%), 6 to 9 (201; 20.5%), and 10+(n=265; 27.1%) and stroke. Adjusted odds ratios for stroke were calculated for concussion history groups, age, and coronary artery disease and/or myocardial infarction. RESULTS: The 979 participants who met inclusion criteria had a mean age of 65.0±9.0 years (range, 50-99). The prevalence of stroke was 3.4% (n=33), significantly lower than expected based on rates of stroke in US men aged 50 and over (standardized prevalence ratio=0.56, Z= -4.56, P<0.001). Greater odds of stroke history were associated with concussion history (10+ versus 0, adjusted odds ratio [95% CI]=5.51 [1.61-28.95]), cardiovascular disease (adjusted odds ratio [95% CI]=2.24 [1.01-4.77]), and age (1-year-increase adjusted odds ratio [95% CI]=1.07 [1.02-1.11]). CONCLUSIONS: The prevalence of stroke among former National Football League players aged ≥50 years was lower than the general population, with significantly increased risk among those with 10 or more prior concussions. Findings add to the evidence suggesting that traumatic brain injuries are associated with increased risk of stroke. Clinically, management of cardio- and cerebrovascular health may be pertinent to those with a history of multiple prior concussions.

Psychometric Properties of Computerized Cognitive Tools and Standard Neuropsychological Tests Used to Assess Sport Concussion: A Systematic Review.

Athletic programs are more frequently turning to computerized cognitive tools in order to increase efficiencies in concussion assessment. However, assessment using a traditional neuropsychological test battery may provide a more comprehensive and individualized evaluation. Our goal was to inform sport clinicians of the best practices for concussion assessment through a systematic literature review describing the psychometric properties of standard neuropsychological tests and computerized tools. We conducted our search in relevant databases including Ovid Medline, Web of Science, PsycINFO, and Scopus. Journal articles were included if they evaluated psychometric properties (e.g., reliability, sensitivity) of a cognitive assessment within pure athlete samples (up to 30 days post-injury). Searches yielded 4,758 unique results. Ultimately, 103 articles met inclusion criteria, all of which focused on adolescent or young adult participants. Test-retest reliability estimates ranged from .14 to .93 for computerized tools and .02 to .95 for standard neuropsychological tests, with strongest correlations on processing speed tasks for both modalities, although processing speed tasks were most susceptible to practice effects. Reliability was improved with a 2-factor model (processing speed and memory) and by aggregating multiple baseline exams, yet remained below acceptable limits for some studies. Sensitivity to decreased cognitive performance within 72 h of injury ranged from 45%-93% for computerized tools and 18%-80% for standard neuropsychological test batteries. The method for classifying cognitive decline (normative comparison, reliable change indices, regression-based methods) affected sensitivity estimates. Combining computerized tools and standard neuropsychological tests with the strongest psychometric performance provides the greatest value in clinical assessment. To this end, future studies should evaluate the efficacy of hybrid test batteries comprised of top-performing measures from both modalities.

Longitudinal trajectory of depression symptom severity and the influence of concussion history and physical function over a 19-year period among former National Football League (NFL) players: an NFL-LONG Study.

OBJECTIVE: This study investigated the longitudinal course of depressive symptom severity over 19 years in former American football players and the influence of concussion history, contact sport participation and physical function on observed trajectories. METHODS: Former American football players completed a general health questionnaire involving demographic information, medical/psychiatric history, concussion/football history and validated measures of depression and physical function at three time points (2001, 2010 and 2019). Parallel process latent growth curve modelling tested associations between concussion history, years of football participation, and overall and change in physical function on the overall level and trajectory of depressive symptoms. RESULTS: Among the 333 participants (mean(SD) age, 48.95 (9.37) at enrolment), there was a statistically significant, but small increase in depressive symptom severity from 2001 (48.34 (7.75)) to 2019 (49.77 (9.52)), slope=0.079 (SE=0.11), p=0.007. Those with greater concussion history endorsed greater overall depressive symptom severity, B=1.38 (SE=0.33), p<0.001. Concussion history, B<0.001 (SE=0.02), p=0.997 and years of participation, B<0.001 (SE=0.01), p=0.980, were not associated with rate of change (slope factor) over 19 years. Greater decline in physical function, B=-0.71 (SE=0.16), p<0.001, was predictive of a faster growth rate (ie, steeper increase) of depression symptom endorsement over time. CONCLUSIONS: Concussion history, not years of participation, was associated with greater depressive symptom severity. Neither factor was predictive of changes over a 19-year period. Decline in physical function was a significant predictor of a steeper trajectory of increased depressive symptoms, independent of concussion effects. This represents one viable target for preventative intervention to mitigate long-term neuropsychiatric difficulties associated with concussion across subsequent decades of life.

Disparate Associations of Years of Football Participation and a Metric of Head Impact Exposure with Neurobehavioral Outcomes in Former Collegiate Football Players.

OBJECTIVES: Years of sport participation (YoP) is conventionally used to estimate cumulative repetitive head impacts (RHI) experienced by contact sport athletes. The relationship of this measure to other estimates of head impact exposure and the potential associations of these measures with neurobehavioral functioning are unknown. We investigated the association between YoP and the Head Impact Exposure Estimate (HIEE), and whether associations between the two estimates of exposure and neurobehavioral functioning varied. METHODS: Former American football players (N = 58; age = 37.9 ± 1.5 years) completed in-person evaluations approximately 15 years following sport discontinuation. Assessments consisted of neuropsychological assessment and structured interviews of head impact history (i.e., HIEE). General linear models were fit to test the association between YoP and the HIEE, and their associations with neurobehavioral outcomes. RESULTS: YoP was weakly correlated with the HIEE, p = .005, R2 = .13. Higher YoP was associated with worse performance on the Symbol Digit Modalities Test, p = .004, R2 = .14, and Trail Making Test-B, p = .001, R2 = .18. The HIEE was associated with worse performance on the Delayed Recall trial of the Hopkins Verbal Learning Test-Revised, p = .020, R2 = .09, self-reported cognitive difficulties (Neuro-QoL Cognitive Function), p = .011, R2 = .10, psychological distress (Brief Symptom Inventory-18), p = .018, R2 = .10, and behavioral regulation (Behavior Rating Inventory of Executive Function for Adults), p = .017, R2 = .10. CONCLUSIONS: YoP was marginally associated with the HIEE, a comprehensive estimate of head impacts sustained over a career. Associations between each exposure estimate and neurobehavioral functioning outcomes differed. Findings have meaningful implications for efforts to accurately quantify the risk of adverse long-term neurobehavioral outcomes potentially associated with RHI.

The Association Between Concussion History and Increased Symptom Severity Reporting Is Independent of Common Medical Comorbidities, Personality Factors, and Sleep Quality in Collegiate Athletes.

OBJECTIVE: We investigated the degree to which the association between history of concussion with psychological distress and general symptom severity is independent of several factors commonly associated with elevated symptom severity. We also examined whether symptom severity endorsement was associated with concussion injury specifically or response to injury in general. SETTING: Academic medical center. PARTICIPANTS: Collegiate athletes ( N = 106; age: M = 21.37 ± 1.69 years; 33 female) were enrolled on the basis of strict medical/psychiatric exclusion criteria. DESIGN: Cross-sectional single-visit study. Comprehensive assessment, including semistructured interviews to retrospectively diagnose the number of previous concussions, was completed. Single-predictor and stepwise regression models were fit to examine the predictive value of prior concussion and orthopedic injuries on symptom severity, both individually and controlling for confounding factors. MAIN OUTCOME MEASURES: Psychological distress was operationalized as Brief Symptom Inventory-18 Global Severity Index (BSI-GSI) ratings; concussion-related symptom severity was measured using the Sport Concussion Assessment Tool. RESULTS: Controlling for baseline factors associated with the symptom outcomes (agreeableness, neuroticism, negative emotionality, and sleep quality), concussion history was significantly associated with psychological distress ( B = 1.25 [0.55]; P = .025, Δ R2 = 0.034) and concussion-like symptom severity ( B = 0.22 [0.08]; P = .005, Δ R2 = 0.064) and accounted for a statistically significant amount of unique variance in symptom outcomes. Orthopedic injury history was not individually predictive of psychological distress ( B = -0.06 [0.53]; P = .905) or general symptom severity ( B = 0.06 [0.08]; P = .427) and did not explain the relationship between concussion history and symptom outcomes. CONCLUSIONS: Concussion history is associated with subtle elevations in symptom severity in collegiate-aged athletes; this relationship is independent of medical, lifestyle (ie, sleep), and personality factors. Furthermore, this relationship is associated with brain injury (ie, concussion) and is not a general response to injury history.

The stability of self-reported professional football concussion history among former players: A longitudinal NFL-LONG study.

OBJECTIVES: To examine the stability of former National Football League (NFL) players' recall of professional football concussion. METHODS: Two-hundred-and-nine former NFL players (ceasing football participation before/in 2001) completed surveys in 2001, 2010, and 2019 and reported the number of concussions sustained during their professional careers (0, 1 … 10, >10). Participants were categorized into four 'recall stability' groups, based upon concussion recall [e.g., 'Same' (same number recalled), 'Increased' (more recalled than in prior time point)]. In 2019, participants completed measures of functioning (e.g., PROMIS Cognitive Function, Anxiety, Depression). Fleiss Kappa and generalized linear mixed models (GLMM)-based ordinal measures Kappa assessed stability across time points. 'Recall stability group' functioning scores were compared. RESULTS: Overall, 45.9% recalled more concussions over time; 14.8% reported the same number. Fleiss Kappa and GLMM-based ordinal measures Kappa suggested fair (0.22, 95% CI: 0.26, 0.38) and moderate stability (0.41, 95% CI: 0.35, 0.46), respectively. Higher cognitive functioning (P = 0.002), lower anxiety (P = 0.003), and lower depression (P = 0.007) were observed in the 'Same' vs 'Increased' groups. CONCLUSIONS: Despite subtle time-based variations in reporting, professional football concussion history recall was relatively stable. Better cognitive and psychological functioning was associated with greater stability in concussion recall.

Age-Group Differences and Annual Variation in Return-To-Play Practices After Sport-Related Concussion.

OBJECTIVE: To examine return-to-play (RTP) practice differences between high school and collegiate athletes, as well as the stability (ie, year-by-year) in these practices over a 5-year period. We hypothesized that similar protocols for treatment will be comparable across competition levels and that these practices will vary year-to-year. DESIGN: Prospective cohort study. SETTING: Nine high schools and 4 National Collegiate Athletic Association Division III colleges in Southeastern Wisconsin. PARTICIPANTS AND INDEPENDENT VARIABLES: Two-hundred seventy-three (N = 273) athletes with sport-related concussions (SRCs). Independent predictors included competition level (high school, n = 88 vs collegiate, n = 185) and year-of-injury. OUTCOME MEASURES: Athletes were evaluated prospectively for differences in symptom duration, symptom free waiting period (SFWP), and time to RTP, as well as longitudinal changes in management. RESULTS: High school and collegiate athletes experienced comparable median symptom duration (high school, 6.0 days, interquartile range (IQR) = 3.5-11.0; college, 6.0 days, IQR = 4.0-9.0, P = 0.95), SFWP (high school, 5.0 days, IQR = 3.0-8.0; college, 5.0 days, IQR = 3.0-7.0, P = 0.12), and total time to RTP (high school, 10.5 days, IQR = 7.0-16.0; college, 11.0 days, IQR = 8.0-14.0 days, P = 0.94). A Cox regression analysis revealed a nonsignificant trend toward longer SFWPs in high school athletes (P = 0.055; hazard ratio = 1.347, confidence interval = 0.99-1.83). Among football players, SFWPs in 2017 (Median = 3.5 days, IQR = 1.5-5.0 days) were significantly longer than those in 2014 (Median = 5.0 days, IQR = 4.0-8.5 days, P = 0.029) after correction for multiple comparisons. CONCLUSION: Similar postinjury and RTP management practices were observed at the high school and collegiate levels after SRCs. Symptom duration and time from injury to unrestricted RTP were comparable, although high school athletes may have longer SFWPs.

Transition-Related Psychosocial Factors and Mental Health Outcomes in Former National Football League Players: An NFL-LONG Study.

Transition from professional sport to nonsport endeavors has implications for postcareer health and well-being of athletes. The purpose of the current study was to examine associations among transition-related psychosocial factors and current mental health outcomes in former National Football League (NFL) players. Participants were former NFL players (n = 1,784; mean age = 52.3 ± 16.3 years) who responded to a questionnaire assessing the nature of their discontinuation from professional football (i.e., any degree of voluntary choice vs. forced discontinuation), prediscontinuation transition planning (yes vs. no), and current symptoms of depression and anxiety. After adjusting for relevant covariates, having an involuntary discontinuation and no transition plan prior to discontinuation were associated with greater depressive and anxiety symptom severity. Autonomy in discontinuation and pretransition planning are important to former NFL football players' mental health. Increasing autonomy in the discontinuation decision and pretransition planning represent psychoeducational intervention targets for this population.

Patterns and predictors of concussion symptom presentations in NCAA athletes.

Sport-related concussion (SRC) is a complex injury, and SRCs are notably prevalent among National Collegiate Athletic Association (NCAA) athletes. We analysed SRCs and associated exposure data collected within the NCAA Injury Surveillance Program during 2014-2019. A total of 1,709 SRCs were reported with complete symptom profiles during the study period (Women's sports n = 499; Men's sports n = 1,210). Event type and academic class year most commonly predicted specific symptom presentations among athletes in men's sports, while symptom presentation among athletes in women's sports was most commonly predicted by class year and sport classification. We observed 78 and 69 significant pairwise symptom dependencies in men's and women's sports athletes, respectively; odds of longer symptom resolution time were higher with greater counts of symptoms with strongest cross-domain associations. Our findings highlight several contextual predictors of specific symptom presentations and identify parsimonious symptom subsets that may indicate protracted recovery among men's and women's sports athletes.

Distinct latent profiles based on neurobehavioural, physical and psychosocial functioning of former National Football League (NFL) players: an NFL-LONG Study.

OBJECTIVE: To identify subgroups of former National Football League (NFL) players using latent profile analysis (LPA) and examine their associations with total years of participation (TYP) and self-reported lifetime sport-related concussion history (SR-CHx). METHODS: Former NFL players (N=686) aged 50-70 years, with an average 18.0 TYP (±4.5) completed a questionnaire. SR-CHx distributions included: low (0-3; n=221); intermediate (4-8; n=209) and high (9+; n=256). LPA measures included: Quality of Life in Neurological Disorders Emotional-Behavioral Dyscontrol, Patient Reported Outcomes Measurement Information System Cognitive Function, Emotional Support, Self-Efficacy, Meaning and Purpose, Physical Function, Pain Interference, Participation in Social Roles and Activities, Anxiety, Depression, Fatigue, and Sleep Disturbance. Demographic, medical/psychiatric history, current psychosocial stressors, TYP and SR-CHx were compared across latent profiles (LPs). RESULTS: A five profile solution emerged: (LP1) global higher functioning (GHF; 26.5%); (LP2) average functioning (10.2%); (LP3) mild somatic (pain and physical functioning) concerns (22.0%); (LP4) somatic and cognitive difficulties with mild anxiety (SCA; 27.5%); LP5) global impaired functioning (GIF; 13.8%). The GIF and SCA groups reported the largest number ofe- medical/psychiatric conditions and higher psychosocial stressor levels. SR-CHx was associated with profile group (χ2(8)=100.38, p<0.001); with a higher proportion of GIF (72.6%) and SCA (43.1%) groups reporting being in the high SR-CHx category, compared with GHF (23.1%), average (31.4%) and somatic (27.8%) groups. TYP was not significantly associated with group (p=0.06), with greater TYP reported by the GHF group. CONCLUSIONS: Five distinct profiles of self-reported functioning were identified among former NFL players. Several comorbid factors (ie, medical/psychiatric diagnoses and psychosocial stressors) and SR-CHx were associated with greater neurobehavioural and psychosocial dysfunction.

Positive association between serum quinolinic acid and functional connectivity following concussion.

The molecular mechanisms underlying the diverse psychiatric and neuropathological sequalae documented in subsets of athletes with concussion have not been identified. We have previously reported elevated quinolinic acid (QuinA), a neurotoxic kynurenine pathway metabolite, acutely following concussion in football players with prior concussion. Similarly, work from our group and others has shown that increased functional connectivity strength, assessed using resting state fMRI, occurs following concussion and is associated with worse concussion-related symptoms and outcome. Moreover, other work has shown that repetitive concussion may have cumulative effects on functional connectivity and is a risk factor for adverse outcomes. Understanding the molecular mechanisms underlying these cumulative effects may ultimately be important for therapeutic interventions or the development of prognostic biomarkers. Thus, in this work, we tested the hypothesis that the relationship between QuinA in serum and functional connectivity following concussion would depend on the presence of a prior concussion. Concussed football players with prior concussion (N = 21) and without prior concussion (N = 16) completed a MRI session and provided a blood sample at approximately 1 days, 8 days, 15 days, and 45 days post-injury. Matched, uninjured football players with (N = 18) and without prior concussion (N = 24) completed similar visits. The association between QuinA and global connectivity strength differed based on group (F(3, 127) = 3.46, p = 0.019); post-hoc analyses showed a positive association between QuinA and connectivity strength in concussed athletes with prior concussion (B = 16.05, SE = 5.06, p = 0.002, 95%CI[6.06, 26.03]), but no relationship in concussed athletes without prior concussion or controls. Region-specific analyses showed that this association was strongest in bilateral orbitofrontal cortices, insulae, and basal ganglia. Finally, exploratory analyses found elevated global connectivity strength in concussed athletes with prior concussion who reported depressive symptoms at the 1-day visit compared to those who did not report depressive symptoms (t(15) = 2.37, mean difference = 13.50, SE = 5.69, p = 0.032, 95%CI[1.36, 25.63], Cohen's d = 1.15.). The results highlight a potential role of kynurenine pathway (KP) metabolites in altered functional connectivity following concussion and raise the possibility that repeated concussion has a "priming" effect on KP metabolism.

Research Letter: Sleep Mediates the Association Between Prior Concussion and Depressive Symptoms.

OBJECTIVE: To test sleep quality as one mechanistic pathway through which repeated concussion increases risk of depression later in life among former contact sport athletes. SETTING: Multicenter study enrolled former American collegiate football players from 16 different National Collegiate Athletic Association member institutions. PARTICIPANTS: Fifty-eight former American collegiate football players approximately 15 years following sport discontinuation. DESIGN: Participants completed in-person evaluations including comprehensive semistructured interviews with detailed concussion history and sport history, as well as self-reported measures of depression symptom severity (Beck Depression Inventory-II) and sleep quality (Pittsburgh Sleep Quality Index). Years of football participation were included as a covariate. Mediation modeling examined the degree to which sleep quality accounted for the association between repeated concussion and depression symptoms. RESULTS: Within the mediation model, concussion history significantly predicted sleep quality (B = 1.03; 95% CI, 0.37 to 1.65; P = .002) and sleep quality significantly predicted depressive symptom severity (controlling for the effects of concussion history; B = 0.15; 95% CI, 0.06 to 0.24; P = .001). The association between prior concussion and depressive symptom severity was fully mediated by sleep quality. With inclusion of the indirect effects, concussion history did not predict depressive symptom severity (direct effect: B = 0.14; 95% CI, -0.09 to 0.41; P = .249; indirect effect: 0.15; 95% CI, 0.03 to 0.29; P = .016). CONCLUSIONS: Current findings raise the possibility that the greater risk of depression reported in those with a history of mTBI/concussion is mediated by sleep quality, a common sequela of mTBI. These findings highlight potential opportunities for prophylactic sleep-related intervention among individuals with multiple prior concussions to mitigate the risk of depression.