A Systematic Review of ASL Perfusion MRI in Mild TBI.

Mild traumatic brain injury (mTBI) is a major public health concern. Cerebrovascular alterations play a significant role in the evolution of injury sequelae and in the process of post-traumatic brain repair. Arterial spin labeling (ASL) is an advanced perfusion magnetic resonance imaging technique that permits noninvasive quantification of cerebral blood flow (CBF). This is the first systematic review of ASL research findings in patients with mTBI. Our approach followed the American Academy of Neurology (AAN) and PRISMA guidelines. We searched Ovid/MEDLINE, Web of Science, Scopus, and the Cochrane Index for relevant articles published as of February 20, 2020. Full-text results were combined into Rayyan software for further evaluation. Data extraction, including risk of bias ratings, was performed using American Academy of Neurology's four-tiered classification scheme. Twenty-three articles met inclusion criteria comprising data on up to 566 mTBI patients and 654 control subjects. Of the 23 studies, 18 reported some type of regional CBF abnormality in mTBI patients at rest or during a cognitive task, with more findings of decreased than increased CBF. The evidence supports the conclusion that mTBI likely causes ASL-derived CBF anomalies. However, synthesis of findings was challenging due to substantial methodological variations across studies and few studies with low risk of bias. Thus, larger-scale prospective cohort studies are needed to more definitively chart the course of CBF changes in humans after mTBI and to understand how individual difference factors contribute to post-injury CBF changes.

Association of obesity with mild traumatic brain injury symptoms, inflammatory profile, quality of life and functional outcomes: a TRACK-TBI Study.

OBJECTIVES: Obesity is associated with chronic inflammation, which may impact recovery from mild traumatic brain injury (mTBI). The objective was to assess the role of obesity in recovery of symptoms, functional outcome and inflammatory blood biomarkers after mTBI. METHODS: TRACK-TBI is a prospective study of patients with acute mTBI (Glasgow Coma Scale=13-15) who were enrolled ≤24 hours of injury at an emergency department of level 1 trauma centres and followed for 12 months. A total of 770 hospitalised patients who were either obese (body mass index (BMI) >30.0) or healthy mass (BMI=18.5-24.9) were enrolled. Blood concentrations of high-sensitivity C reactive protein (hsCRP), interleukin (IL) 6, IL-10, tumour necrosis factor alpha; Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Quality of Life After Brain Injury and Glasgow Outcome Score-Extended reflecting injury-related functional limitations at 6 and 12 months were collected. RESULTS: After adjusting for age and gender, obese participants had higher concentrations of hsCRP 1 day after injury (mean difference (MD)=0.65; 95% CI: 0.44 to 0.87, p<0.001), at 2 weeks (MD=0.99; 95% CI: 0.74 to 1.25, p<0.001) and at 6 months (MD=1.08; 95% CI: 0.79 to 1.37, p<0.001) compared with healthy mass participants. Obese participants had higher concentrations of IL-6 at 2 weeks (MD=0.37; 95% CI: 0.11 to 0.64, p=0.006) and 6 months (MD=0.42; 95% CI: 0.12 to 0.72, p=0.006). Obese participants had higher RPQ total score at 6 months (MD=2.79; p=0.02) and 12 months (MD=2.37; p=0.049). CONCLUSIONS: Obesity is associated with higher symptomatology at 6 and 12 months and higher concentrations of blood inflammatory markers throughout recovery following mTBI.

Linking Rivermead Post Concussion Symptoms Questionnaire (RPQ) and Sport Concussion Assessment Tool (SCAT) scores with item response theory.

OBJECTIVE: Despite the public health burden of traumatic brain injury (TBI) across broader society, most TBI studies have been isolated to a distinct subpopulation. The TBI research literature is fragmented further because often studies of distinct populations have used different assessment procedures and instruments. Addressing calls to harmonize the literature will require tools to link data collected from different instruments that measure the same construct, such as civilian mild traumatic brain injury (mTBI) and sports concussion symptom inventories. METHOD: We used item response theory (IRT) to link scores from the Rivermead Post Concussion Symptoms Questionnaire (RPQ) and the Sport Concussion Assessment Tool (SCAT) symptom checklist, widely used instruments for assessing civilian and sport-related mTBI symptoms, respectively. The sample included data from n = 397 patients who suffered a sports-related concussion, civilian mTBI, orthopedic injury control, or non-athlete control and completed the SCAT and/or RPQ. RESULTS: The results of several analyses supported sufficient unidimensionality to treat the RPQ + SCAT combined item set as measuring a single construct. Fixed-parameter IRT was used to create a cross-walk table that maps RPQ total scores to SCAT symptom severity scores. Linked and observed scores were highly correlated (r = .92). Standard errors of the IRT scores were slightly higher for civilian mTBI patients and orthopedic controls, particularly for RPQ scores linked from the SCAT. CONCLUSION: By linking the RPQ to the SCAT we facilitated efforts to effectively combine samples and harmonize data relating to mTBI.

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.

Salivary Cortisol Dynamics After Mild Traumatic Brain Injury.

OBJECTIVE: To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery. SETTING: Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community. PARTICIPANTS: Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed). DESIGN: A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]). MAIN OUTCOME MEASURE: Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample. RESULTS: Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT. CONCLUSIONS: Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent 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.

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.

Comparing Traumatic Brain Injury Symptoms Reported via Questionnaires Versus a Novel Structured Interview.

OBJECTIVE: Mild traumatic brain injury (mTBI) symptoms are typically assessed via questionnaires in research, yet questionnaires may be more prone to biases than direct clinical interviews. We compared mTBI symptoms reported on two widely used self-report inventories and the novel Structured Interview of TBI Symptoms (SITS). Second, we explored the association between acquiescence response bias and symptom reporting across modes of assessment. METHOD: Level 1 trauma center patients with mTBI (N = 73) were recruited within 2 weeks of injury, assessed at 3 months post-TBI, and produced nonacquiescent profiles. Assessments collected included the SITS (comprising open-ended and closed-ended questions), Rivermead Post Concussion Symptoms Questionnaire (RPQ), Sport Concussion Assessment Tool-3 (SCAT-3) symptom checklist, and Minnesota Multiphasic Personality Inventory-2 Restructured Form True Response Inconsistency (TRIN-r) scale. RESULTS: Current mTBI symptom burden and individual symptom endorsement were highly concordant between SITS closed-ended questions, the RPQ, and the SCAT-3. Within the SITS, participants reported significantly fewer mTBI symptoms to open-ended as compared to later closed-ended questions, and this difference was weakly correlated with TRIN-r. Symptom scales were weakly associated with TRIN-r. CONCLUSIONS: mTBI symptom reporting varies primarily by whether questioning is open- vs. closed-ended but not by mode of assessment (interview, questionnaire). Acquiescence response bias appears to play a measurable but small role in mTBI symptom reporting overall and the degree to which participants report more symptoms to closed- than open-ended questioning. These findings have important implications for mTBI research and support the validity of widely used TBI symptom inventories.

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.

Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference ( B ) = 0.25; 95% CI, 0.07 to 0.43; P = .005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, -2.07 to 2.60; P = .825. CONCLUSION: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed.

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.

Incidence of Neck Pain in Patients With Concussion in a Pediatric Emergency Department.

OBJECTIVES: The aims of the study were (1) to determine the frequency of neck pain in patients diagnosed with mild traumatic brain injury (mTBI) or concussion in a pediatric level 1 trauma center emergency department (ED), (2) to identify variables associated with neck pain in this population, and (3) to report on aspects of care received in the ED including imaging and medication use. METHODS: This is a retrospective chart review of 652 patients presenting to a pediatric ED with diagnosis of concussion/mTBI. Charts were reviewed for the following information: baseline demographic information, mechanism of injury, cause of mTBI, presence or absence of neck pain, point tenderness in the neck on physical examination, and whether the patient followed up within our health system in the 6 months after injury. Charts were also reviewed for other concussion-related symptoms, medication given in the ED, imaging performed in the ED, cervical spine clearance in the ED, and referrals made. For those patients who did have follow-up appointments within our system, additional chart review was performed to determine whether they sought follow-up treatment for symptoms related to concussion/neck pain and the duration of follow-up. Statistical analyses focused on the prevalence of neck pain in the sample. We subsequently explored the degree to which neck pain was associated with other collected variables. RESULTS: Of 652 patients, 90 (13.8%) reported neck pain. Acceleration/deceleration injury and motor vehicle accident were predictive of neck pain. Neck pain was less common in those reporting nausea and vomiting. Direct impact of the head against an object was associated with reduced odds of neck pain, but after adjusting for other variables, this was no longer statistically significant. Patients with neck pain were older than those without neck pain. Patients with neck pain were more likely to receive ibuprofen or morphine and undergo imaging of the spine. They were also more likely to receive a referral and follow-up with neurosurgery. There was no significant difference between groups with respect to concussion-related follow-up visits or follow-up visits to a dedicated concussion clinic. CONCLUSIONS: Neck pain is a common symptom in pediatric patients with mTBI, although it was more likely in older patients and those presenting with acceleration/deceleration mechanisms. Although patients with neck pain were more likely to receive a referral and follow-up with neurosurgery, they were not more likely to have concussion-related follow-up visits. Indeed, most patients had no follow-up visits related to their concussion, which supports the notion that concussion is a self-limiting condition.

A Prospective Study of Acute Blood-Based Biomarkers for Sport-Related Concussion.

OBJECTIVE: Prospectively characterize changes in serum proteins following sport-related concussion and determine whether candidate biomarkers discriminate concussed athletes from controls and are associated with duration of symptoms following concussion. METHODS: High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at preinjury baseline and within 6 hours (early acute) and at 24 to 48 hours (late acute) following concussion in football players (n = 106), matched uninjured football players (n = 84), and non-contact-sport athletes (n = 50). Glial fibrillary acidic protein, ubiquitin c-terminal hydrolase-L1, S100 calcium binding protein B, alpha-II-spectrin breakdown product 150, interleukin 6, interleukin 1 receptor antagonist, and c-reactive protein were measured in serum. Linear models assessed changes in protein concentrations over time. Receiver operating curves quantified the discrimination of concussed athletes from controls. A Cox proportional hazard model determined whether proteins were associated with symptom recovery. RESULTS: All proteins except glial fibrillary acidic protein and c-reactive protein were significantly elevated at the early acute phase postinjury relative to baseline and both control groups and discriminated concussed athletes from controls with areas under the curve of 0.68 to 0.84. The candidate biomarkers also significantly improved the discrimination of concussed athletes from noncontact controls compared to symptom severity alone. Glial fibrillary acidic protein was elevated postinjury relative to baseline in concussed athletes with a loss of consciousness or amnesia. Finally, early acute levels of interleukin 1 receptor antagonist were associated with the number of days to symptom recovery. INTERPRETATION: Brain injury and inflammatory proteins show promise as objective diagnostic biomarkers for sport-related concussion, and inflammatory markers may provide prognostic value. ANN NEUROL 2020;87:907-920.

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.

Personality Characteristics and Acute Symptom Response Predict Chronic Symptoms After Mild Traumatic Brain Injury.

OBJECTIVE: Despite consensus that personality influences mild traumatic brain injury (mTBI) recovery, it has been underexamined. We evaluated the extent to which diverse personality and psychiatric symptom dimensions predict mTBI recovery. METHODS: This prospective cohort study involved psychological assessments of hospital patients with mTBI (n = 75; median = 2 days post-injury, range = 0-12 days) and orthopedic trauma controls (OTC; n = 79) who were used for comparison in mediation modeling. Chronic symptoms were evaluated at 3 months after mTBI (n = 50) using the Sport Concussion Assessment Tool (SCAT) symptom checklist. Linear regression analyses were used to identify the predominant predictors of chronic symptoms in mTBI. Modern mediation analyses tested the hypothesis that personality traits predict chronic symptoms through acute psychological response to injury. RESULTS: In mTBI, trait psychoticism directly predicted chronic mTBI symptoms and was the strongest personality predictor overall. Furthermore, an internalizing personality dimension emphasizing negative affect/emotionality and detachment predicted chronic mTBI symptoms indirectly through enhancement of acute somatic complaints. In OTC, internalizing personality acted through the same mediator as in mTBI, whereas the effect of psychoticism was also mediated through acute somatic complaints. There was varying support for a moderated direct effect of personality traits at low levels of positive emotionality across models. CONCLUSION: These causal models provide novel insights about the role of personality in mTBI symptom recovery, highlighting the complexity of how psychological processes may interact to affect recovery and revealing that some of these processes may be non-specific to brain injury.

Risk Factors for Suicidal Ideation Following Mild Traumatic Brain Injury: A TRACK-TBI Study.

OBJECTIVE: To identify risk factors for suicidal ideation (SI) following mild traumatic brain injury (mTBI). SETTING: Eleven US level 1 trauma centers. PARTICIPANTS: A total of 1158 emergency department patients with mTBI (Glasgow Coma Scale score = 13-15) enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. DESIGN: Prospective observational study; weights-adjusted multivariable logistic regression models (n's = 727-883) estimated associations of baseline factors and post-TBI symptoms with SI at 2 weeks and 3, 6, and 12 months postinjury. MAIN MEASURES: Patient Health Questionnaire, Rivermead Post-Concussion Symptoms Questionnaire. RESULTS: Preinjury psychiatric history predicted SI at all follow-ups (adjusted odds ratios [AORs] = 2.26-6.33, P values <.05) and history of prior TBI predicted SI at 2 weeks (AOR = 2.36, 95% confidence interval [CI] = 1.16-4.81, P = .018), 3 months (AOR = 2.62, 95% CI = 1.33-5.16, P = .005), and 6 months postinjury (AOR = 2.54, 95% CI = 1.19-5.42, P = .016). Adjusting for these baseline factors, post-TBI symptoms were strongly associated with SI at concurrent (AORs = 1.91-2.88 per standard deviation unit increase in Rivermead Post-Concussion Symptoms Questionnaire score; P values <.0005) and subsequent follow-up visits (AORs = 1.68-2.53; P values <.005). Most of the associations between post-TBI symptoms and SI were statistically explained by co-occurring depression. CONCLUSION: Screening for psychiatric and prior TBI history may help identify patients at risk for SI following mTBI. Awareness of the strong associations of post-TBI symptoms with SI may facilitate interventions to prevent suicide-related outcomes in patients with mTBI.

Systemic inflammation moderates the association of prior concussion with hippocampal volume and episodic memory in high school and collegiate athletes.

BACKGROUND: There is a need to determine why prior concussion has been associated with adverse outcomes in some retired and active athletes. We examined whether serum inflammatory markers moderate the associations of prior concussion with hippocampal volumes and neurobehavioral functioning in active high school and collegiate athletes. METHODS: Athletes (N = 201) completed pre-season clinical testing and serum collection (C-reactive protein [CRP]; Interleukin-6 [IL]-6; IL-1 receptor antagonist [RA]) and in-season neuroimaging. Linear mixed-effects models examined associations of prior concussion with inflammatory markers, self-reported symptoms, neurocognitive function, and hippocampal volumes. Models examined whether inflammatory markers moderated associations of concussion history and hippocampal volume and/or clinical measures. RESULTS: Concussion history was significantly associated with higher symptom severity, p = 0.012, but not hippocampal volume or inflammatory markers (ps > 0.05). A significant interaction of prior concussion and CRP was observed for hippocampal volume, p = 0.006. Follow-up analyses showed that at high levels of CRP, athletes with two or more prior concussions had smaller hippocampal volume compared to athletes without prior concussion, p = 0.008. There was a significant interaction between prior concussion and levels of IL-1RA on memory scores, p = 0.044, i.e., at low levels of IL-1RA, athletes with two or more concussions had worse memory performance than those without prior concussion (p = 0.014). CONCLUSION: Findings suggest that certain markers of systemic inflammation moderate the association between prior concussion and hippocampal volume and episodic memory performance. Current findings highlight potential markers for predicting at-risk individuals and identify therapeutic targets for mitigating the long-term adverse consequences of cumulative concussion.

Prospective study of the effects of sport-related concussion on serum kynurenine pathway metabolites.

Reports of neurodegenerative and psychiatric disease in former athletes have increased public concern about the acute and chronic effects of sport-related concussions (SRC). The biological factors underlying individual differences in the psychiatric sequalae of SRC and their role in potential long-term negative outcomes have not been determined. One understudied biological consequence of the known inflammatory response to concussion is the activation of a key immunoregulatory pathway, the kynurenine pathway (KP). Activation of the KP produces several neuroactive metabolites that have been associated with psychiatric and neurodegenerative diseases. We tested the hypothesis that SRC results in an elevation of serum KP metabolites with neurotoxic properties (quinolinic acid [QuinA], 3-hydroxykynurenine [3HK]) together with a reduction in the neuroprotective metabolite kynurenic acid (KynA), and that these metabolites would predict post-concussion psychological symptoms. Additionally, because brain injury is thought to prime the immune system, a secondary goal was to test the hypothesis that athletes with acute SRC and a history of prior SRC would have elevated neurotoxic relative to neuroprotective KP metabolites compared to athletes that were concussed for the first time. High school and collegiate football players (N = 1136) were enrolled at a preseason baseline visit that included clinical testing and blood specimen collection. Athletes that suffered a SRC (N = 59) completed follow-up visits within 6-hours (early-acute), at 24-48 h (late-acute) and at 8, 15, and 45 days post-injury. Uninjured contact sport (CC; N = 54) and non-contact sport athletes completed similar visits and served as controls (NCC; N = 30). SRC athletes had significantly elevated psychological symptoms, assessed using the Brief Symptom Inventory-18 (BSI), acutely following injury relative to both control groups. There was a group-by-visit interaction on the ratio of KynA to 3HK in serum, a neuroprotective index, with elevated KynA/3HK in athletes with SRC at the early-acute visit relative to later visits. Importantly, athletes with greater elevation in this neuroprotective index at the early-acute visit reported fewer depressive symptoms at the late-acute visit. Finally, SRC athletes with prior concussion had significantly lower serum KynA/QuinA at all visits compared to SRC athletes with no prior concussion, an effect driven by elevated QuinA in SRC athletes with prior concussion. These results suggest that early-acute activation of the KynA branch of the KP may protect against the development of depressive symptoms following concussion. Furthermore, they highlight the potential of serum QuinA as a biomarker for repetitive head injury and provide insight into possible mechanisms linking prior concussion with subsequent injury.

Frequency of Primary Neck Pain in Mild Traumatic Brain Injury/Concussion Patients.

OBJECTIVES: To determine (1) the frequency of neck pain overall and relative to other symptoms in patients presenting to a level I trauma center emergency department (ED) with mild traumatic brain injury (mTBI) and (2) the predictors of primary neck pain in this population. DESIGN: Cohort study. SETTING: Level I trauma center ED. PARTICIPANTS: Patients presenting to the ED with symptoms of mTBI having been exposed to an event that could have caused mTBI (N=95). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Frequency of self-reported neck pain as measured by Sport Concussion Assessment Tool 3 (SCAT3) symptom questionnaire at <3, 8, 15, and 45 days post injury. Primary neck pain was defined in 2 ways: (1) neck pain rated as equal or greater in severity than all other SCAT3 symptoms and (2) neck pain worse than all other symptoms. RESULTS: The frequency of any reported neck pain was 68.4%, 50.6%, 49%, and 41.9% within 72 hours and at 8, 15, and 45 days, respectively. Frequency of primary neck pain (equal or worse/worse definitions) was 35.8%/17.9%, 34.9%/14.5%, 37%/14.8%, and 39.2%/10.8% across the 4 follow-up assessments. Participants who sustained their injuries in motor vehicle collisions had a higher rate of primary neck pain than those with other mechanisms of injury. CONCLUSIONS: A sizable percentage of patients who present to level I trauma center EDs with mTBI report neck pain, which is commonly rated as similar to or worse than other mTBI-related symptoms. Primary neck pain is more common after motor vehicle collisions than with other mechanisms of injury. These findings support consensus statements identifying cervical injury as an important potential concurrent diagnosis in patients with mTBI.