History of traumatic brain injury is associated with increased grey-matter loss in patients with mild cognitive impairment.

OBJECTIVES: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). METHODS: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. RESULTS: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction (PD) = 90-99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%). CONCLUSIONS: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.

A Multimodal Exertional Test for concussion: a pilot study in healthy athletes.

Introduction: Exertional tests have become a promising tool to assist clinicians in the management of concussions, however require expensive equipment, extensive spaces, and specialized clinician expertise. As such, we developed a test with minimal resource requirements encompassing key elements of sport and physical activity. The purpose of this study was to pilot test the Multimodal Exertional Test (MET) protocol in a sample of healthy interuniversity athletes. Methods: The MET comprises four stages, each featuring three distinct tasks. The test begins with engaging in squats, alternating reverse lunges, and hip hinges (Stage 1). The next stage progressively evolves into executing these tasks within specified time limits (Stage 2). Following this, the test advances to a stage that incorporates cognitive tasks (Stage 3), and the final stage demands greater levels of physical exertion, cognition, and multi-directional movements (Stage 4). Heart rate (HR) was obtained during each stage of the MET and participants' symptom severity scores were recorded following each task. Results: Fourteen healthy interuniversity athletes (n = 8 female, n = 6 male) participated in the study. HR was obtained for 10 of the 14 athletes (females: n = 6, males: n = 4). Increases in average and maximum HR were identified between pre-MET and Stage 1, and between Stages 3 and 4. Consistent with the tasks in each stage, there were no increases in average and maximum HR observed between MET Stages 1 to 3. Female athletes exhibited higher average and maximum HRs compared to male athletes during all four stages. All 14 athletes reported minimal changes in symptom severity following each task. Conclusion: Among healthy athletes, the MET elicits an increase in average and maximum HR throughout the protocol without symptom provocation. Female athletes exhibit higher HRs during all four stages in comparison to male athletes.

Whole blood stimulation provides preliminary evidence of altered immune function following SRC.

PURPOSE: To implement an approach combining whole blood immune stimulation and causal modelling to estimate the impact of sport-related concussion (SRC) on immune function. METHODS: A prospective, observational cohort study was conducted on athletes participating across 13 university sports at a single academic institute; blood was drawn from 52 athletes, comprised of 22 athletes (n = 11 male, n = 11 female) within seven days of a physician-diagnosed SRC, and 30 healthy athletes (n = 18 female, n = 12 male) at the beginning of their competitive season. Blood samples were stimulated for 24 h under two conditions: (1) lipopolysaccharide (lps, 100ng/mL) or (2) resiquimod (R848, 1uM) using the TruCulture® system. The concentration of 45 cytokines and chemokines were quantitated in stimulated samples by immunoassay using the highly sensitive targeted Proximity Extension Assays (PEA) on the Olink® biomarker platform. A directed acyclic graph (DAG) was used as a heuristic model to make explicit scientific assumptions regarding the effect of SRC on immune function. A latent factor analysis was used to derive two latent cytokine variables representing immune function in response to LPS and R848 stimulation, respectively. The latent variables were then modelled using student-t regressions to estimate the total causal effect of SRC on immune function. RESULTS: There was an effect of SRC on immune function in males following SRC, and it varied according to prior concussion history. In males with no history of concussion, those with an acute SRC had lower LPS reactivity compared to healthy athletes with 93% posterior probability (pprob), and lower R848 reactivity with 77% pprob. Conversely, in males with a history of SRC, those with an acute SRC had higher LPS reactivity compared to healthy athletes with 85% pprob and higher R848 reactivity with 82%. In females, irrespective of concussion history, SRC had no effect on LPS reactivity. However, in females with no concussion history, those with an acute SRC had higher R848 reactivity compared to healthy athletes with 86% pprob. CONCLUSION: Whole blood stimulation can be used within a causal framework to estimate the effect of SRC on immune function. Preliminary evidence suggests that SRC affects LPS and R848 immunoreactivity, that the effect is stronger in male athletes, and differs based on concussion history. Replication of this study in a larger cohort with a more sophisticated causal model is necessary.

Concussion Characteristics in the National Hockey League Before and After the Introduction of Rule 48.

Importance: A rule prohibiting a direct hit to the lateral side of the head (ie, Rule 48-Illegal Check to the Head) was introduced in the National Hockey League (NHL) in the 2010-2011 season and refined in the 2011-2012 season to widen the application to include direct contact to all areas of the head. Objective: To compare the incidence and proportion of concussions that occurred following hits to the head before and after the implementation of Rule 48. Design, Setting, and Participants: This retrospective cohort study used a before and after design to evaluate concussions among NHL players in regular season games. Data from the 4 seasons preceding the implementation of Rule 48 (2006-2007 to 2009-2010) were compared with data from 5 seasons following its implementation (2014-2015 to 2018-2019). Data were analyzed from October 31, 2021, to November 30, 2022. Main Outcomes and Measures: The incidence and relative proportion of concussion characteristics and mechanisms before and after the introduction of Rule 48. Results: In the analysis of 688 concussions for NHL seasons spanning 2006 to 2010 (n = 231) and 2014 to 2019 (n = 457), there was an overall increase in the incidence of concussion between the 2 time frames, although the incidence of concussions due to hits to the lateral aspect of the head decreased from 1.6/100 games to 1.0/100 games (estimated difference, 0.6/100 games [90% credible interval (CrI), 0.30/100 games to 0.90/100 games). There was also a reduction of 18.8 (90% CrI, 13.0-23.7) percentage points in the proportion of concussions due to hits to the lateral aspect of the head from 80 of 231 concussions (34.6%) to 61 of 457 concussions (13.3%). The incidence of concussions following hits to the head from body checks using the shoulder, arm, and glove was similar before and following the implementation of Rule 48. However, the proportion was reduced 14.7 percentage points from 113 of 231 concussions (48.9%) before to 149 of 457 concussions (32.6%) after implementation of Rule 48 (90% CrI of the difference, 8.9-20.7 percentage points). Conclusions and Relevance: The findings of this cohort study of NHL players suggest that after the introduction of Rule 48, the incidence rate and proportion of concussions from contact to the lateral aspect of the head decreased, as did the proportion of concussions following direct hits to the head.

A Continuous Aerobic Resistance Exercise Protocol for Concussion Rehabilitation Delivered Remotely via a Mobile App: Feasibility Study.

BACKGROUND: In recent years, several studies have consistently reported the beneficial effects of aerobic exercise in alleviating symptoms following concussion. However, exercise modality recommendations by practitioners are often limited to traditional exercise equipment (eg, treadmills and stationary bikes). Advances in digital technologies may help to overcome this limitation, as mobile apps can now provide users with high-quality instructional videos, programs, and monitoring capabilities using alternative modalities such as resistance exercises. Mobile technologies are also rapidly expanding to deliver and complement in-person clinical care. Thus, it is imperative to evaluate this emerging technology on its feasibility, safety, and clinical utility for concussion care. OBJECTIVE: The objective of the study was to determine the feasibility of a mobile app to deliver a resistance exercise protocol with minimal equipment to individuals following concussion. Feasibility was defined by retention, adverse events, and achievement of a target heart rate (HR) of 60%±5% (age-adjusted percentage of max: 220 - age). HR data were collected using an Apple Watch, Series 6. Symptoms were evaluated before and after 3 exercise sessions. METHODS: A 2-week, prospective, single-arm pilot study was conducted on 21 adults diagnosed with a concussion. Users were provided a continuous aerobic resistance exercise (CARE) protocol through a mobile app. RESULTS: A total of 18 participants (14 female and 4 male) completed a 3-session exercise plan. The median age-adjusted percent of HR max for session 1 was 55.5% (IQR 49%-63%), 58.1% (IQR 50.8%-65.2%) for session 2, and 57.4% (IQR 49.5%-64.7%) for session 3. Individual median HR% across all sessions ranged from 46.9% to 67.4%; furthermore, 10 participants (55.5%) had a total mean HR% within the target HR%, 7 participants had a mean HR% below 55%, and 1 participant had a mean HR% above 65%. In addition, adherence to the plan resulted in a decrease in reported symptom burden with 94% posterior probability. CONCLUSIONS: Following concussion, a CARE protocol delivered through a mobile app resulted in no adverse effects with 14% (n=3/21) attrition over 3 sessions. CARE was successful in achieving an aerobic exercise intensity of 55%-65% of age-adjusted maximum HR in the majority of participants and resulted in a decrease in reported symptom burden. The potential for this platform in concussion rehabilitation warrants further investigation. Future studies are needed to assess the use of this technology throughout concussion recovery in both individuals with acute concussion, and those with persistent symptoms.

Incidence of Remote Near-Point of Convergence in University Athletes After Sport-Related Concussion.

OBJECTIVE: Near-point of convergence (NPC) testing is an attractive screening tool in the sport setting because it is rapid, requires few resources, and is easy to administer. Remote NPC has been reported after sport-related concussion (SRC), although the incidence among a university-aged population is not well defined. The purpose of the study was to examine the incidence of remote NPC after SRC in a cohort of Canadian interuniversity athletes. DESIGN: Cross-sequential. SETTING: University. PARTICIPANTS: One hundred thirty-two university athletes [SRC, n = 68; musculoskeletal (MSK) injury, n = 64] were tested before the beginning of their competitive season and again after their injury. INDEPENDENT VARIABLES: Healthy athletes measured preseason were compared with athletes after SRC or MSK injury using both longitudinal and cross-sectional designs. MAIN OUTCOME MEASURES: Remote NPC (pass/fail), measured at 6 cm or greater, repeated 3 times. RESULTS: After SRC, 22% of athletes failed their test postinjury (95% CI, 14%-33%). Comparatively, in the MSK group, 3% of athletes failed their test postinjury (95% CI, 1%-7%). A direct comparison of both injury groups yielded a mean 19% higher prevalence of failed NPC tests after SRC versus MSK injury (95% CI, 10%-30%). There seems to be no relationship between reported symptom burden and NPC performance after SRC. CONCLUSION: Remote NPC occurs in approximately 1 of 5 athletes after SRC and is rarely observed after MSK injury.

Randomized controlled trial of early aerobic exercise following sport-related concussion: Progressive percentage of age-predicted maximal heart rate versus usual care.

OBJECTIVE: To examine the effect of a readily accessible, structured aerobic exercise intervention on days to asymptomatic status and days to medical clearance compared to usual care exercise prescription in a cohort of adolescents and young adults following sport-related concussion (SRC). METHODS: A longitudinal, randomized, non-blinded clinical trial consisting of a structured aerobic exercise protocol (SAEP) group and a usual care exercise prescription (UCEP) group. Participants in the SAEP group underwent an exercise protocol including 8 sessions over 11 days progressing in duration and intensity stepwise based on participants' age-predicted maximal heart rate. Symptom follow-ups were on days 7, 14, 21, and 28. The primary outcome measures of the study were days to asymptomatic status and days to medical clearance, while the secondary outcome measure was symptom severity on days 7, 14, 21, and 28. RESULTS: 38 participants (SAEP, n = 20; UCEP, n = 19) were recruited and completed all follow-up appointments. Compared to the UCEP group, the SAEP had a faster time to asymptomatic status with 96% posterior probability. In addition, the SAEP group displayed an earlier time to medical clearance with 93% posterior probability. While symptom severity scores did not differ between groups at enrolment (SAEP symptom severity, 30; UCEP, 29), they were subsequently lower in the SAEP group at all assessments throughout the trial with 100% posterior probability. CONCLUSIONS: An aerobic exercise protocol based on percentages of age-predicted maximum heart rate is a safe and effective treatment for reducing symptoms and can be initiated during the first week following SRC. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02969824.

Ten-Word List Performance in Healthy Athletes and Athletes at 3-to-5 Days Following Concussion.

OBJECTIVE: Although the word recall component of the Sport Concussion Assessment Tool (SCAT) was updated from 5-to-10 words, its clinical utility across athletic populations remains unknown. The purpose of this study was to provide normative data on the SCAT-5 10-word test and examine its discriminative ability between healthy university level athletes and those with sport-related concussion (SRC). DESIGN: Cross-sectional. SETTING: University. PARTICIPANTS: Three hundred sixty-three (363, M = 220, F = 153) healthy athletes and 49 (M = 30, F = 19) athletes following SRC. INDEPENDENT VARIABLE: Healthy athletes measured preseason were compared with athletes following an SRC (median = 4.0 days postinjury). MAIN OUTCOME MEASURE: Ten-word list performance from the SCAT-5. RESULTS: There were no significant differences in either immediate ( P = 0.228, Cohen's D = 0.18) or delayed ( P = 0.908, Cohen's D = 0.02) recall tests between athletes with SRC and healthy athletes; the null findings extended to both the male and female subset comparisons. Among healthy athletes, females outperformed males on both immediate (mean difference = 1.0, P < 0.001) and delayed (mean difference = 0.5, P = 0.006) recall tasks. CONCLUSION: Concussion does not seem to impact immediate or delayed recall of the 10-word list in the subacute period following injury. Practitioners should be mindful of sex differences and the time point of administration following injury.

Cerebral blood flow is associated with matrix metalloproteinase levels during the early symptomatic phase of concussion.

Concussion is associated with disrupted cerebral blood flow (CBF), although there appears to be substantial inter-individual variability in CBF response. At present, the mechanisms of variable CBF response remain incompletely understood, but one potential contributor is matrix metalloproteinase (MMP) expression. In more severe forms of acquired brain injury, MMP up-regulation contributes to CBF impairments via increased blood-brain barrier permeability. A similar relationship is hypothesized for concussion, where recently concussed individuals with higher MMP levels have lower CBF. To test this hypothesis, 35 concussed athletes were assessed longitudinally at early symptomatic injury (median: 5 days post-injury) and at medical clearance (median: 24 days post-injury), along with 71 athletic controls. For all athletes, plasma MMPs were measured and arterial spin labelling was used to measure CBF. Consistent with our hypothesis, higher concentrations of MMP-2 and MMP-3 were correlated with lower global CBF. The correlations between MMPs and global CBF were also significantly diminished for concussed athletes at medical clearance and for athletic controls. These results indicate an inverse relationship between plasma MMP levels and CBF that is specific to the symptomatic phase of concussion. Analyses of regional CBF further showed that correlations with MMP levels exhibited some spatial specificity, with greatest effects in occipital, parietal and temporal lobes. These findings provide new insights into the mechanisms of post-concussion cerebrovascular dysfunction.

Blast in Context: The Neuropsychological and Neurocognitive Effects of Long-Term Occupational Exposure to Repeated Low-Level Explosives on Canadian Armed Forces' Breaching Instructors and Range Staff.

Currently, there is strong interest within the military to better understand the effects of long-term occupational exposure to repeated low-level blast on health and performance. To gain traction on the chronic sequelae of blast, we focused on breaching-a tactical technique for gaining entry into closed/blocked spaces by placing explosives and maintaining a calculated safe distance from the detonation. Using a cross-sectional design, we compared the neuropsychological and neurocognitive profiles of breaching instructors and range staff to sex- and age-matched Canadian Armed Forces (CAF) controls. Univariate tests demonstrated that breaching was associated with greater post-concussive symptoms (Rivermead Post Concussion Symptoms Questionnaire) and lower levels of energy (RAND SF-36). In addition, breaching instructors and range staff were slower on a test that requires moving and thinking simultaneously (i.e., cognitive-motor integration). Next, using a multivariate approach, we explored the impact of other possible sources of injury, including concussion and prior war-zone deployment on the same outcomes. Concussion history was associated with higher post-concussive scores and musculoskeletal problems, whereas deployment was associated with higher post-concussive scores, but lower energy and greater PTSD symptomatology (using PCL-5). Our results indicate that although breaching, concussion, and deployment were similarly correlated with greater post-concussive symptoms, concussion history appears to be uniquely associated with altered musculoskeletal function, whereas deployment history appears to be uniquely associated with lower energy and risk of PTSD. We argue that the broader injury context must, therefore, be considered when studying the impact of repetitive low-level explosives on health and performance in military members.

A history of concussion is associated with minimal perturbations to heart rate variability in athletes.

PURPOSE: To compare heart rate variability (HRV) in healthy male and female athletes with versus without a history of concussion. METHODS: A cross-sectional study of 113 healthy interuniversity athletes (n = 62 female; n = 51 male) across nine sports from a single institution, participating within the first half of their respective athletic seasons. Concussion history was determined by self-report (males: yes = 20, no = 31; females: yes = 21, no = 41). HRV was measured over five-minute time intervals in both seated and supine positions. All analyses were adjusted for age. RESULTS: No differences in HRV were observed in female athletes with versus without a history of concussion; male athletes with a history of concussion displayed a significantly lower mean RR in the seated position compared to athletes with no history of concussion. CONCLUSION: In the months-to-years following a concussion, HRV does not appear to be significantly perturbed. However, males with a history of concussion may have a slightly lower mean RR. Future studies evaluating HRV and concussion history should be mindful of the confounding influence of sex and age.

An investigation of plasma interleukin-6 in sport-related concussion.

BACKGROUND: Increasing evidence suggests inflammation is an important component of concussion pathophysiology. However, its etiology, restitution, and potential clinical repercussions remain unknown. The purpose of the current study was to compare the blood concentrations of interleukin (IL) -6, a prominent inflammatory cytokine, between healthy athletes and athletes with a sport-related concussion (SRC), while addressing the potential confounds of sex, recent physical activity, and the interacting effect of concussion history. METHOD: A prospective, observational cohort study was conducted on athletes at a single academic institute participating across 13 interuniversity sports. Follow-up of 96 athletes who agreed to provide a blood sample was completed: 41 athletes with a physician diagnosed SRC, and 55 healthy athletes. Ella™, the high sensitivity immunoassay system by ProteinSimple was used to measure peripheral plasma concentrations of IL-6 within the first week (median = 4 days, range = 2-7) following injury. A resampled ordinary least squares regression was used to evaluate the relationship between IL-6 concentrations and concussion status, while partial least squares regression was used to evaluate the relationship between IL-6 and both symptom burden and time to clinical recovery. RESULTS: Regression analysis identified a negative relationship between plasma IL-6 concentrations and the interaction between an acute SRC and a history of concussion (ß = -0.29, p = 0.029). IL-6 did not differ between healthy athletes and those with an acute SRC independent of concussion history, and was not correlated with either recovery time or symptom burden in athletes with SRC. CONCLUSION: Perturbations to circulating IL-6 concentrations, a key inflammatory cytokine, may be more pronounced following SRC in athletes who have a history of concussion. These results add to a growing body of evidence supporting the involvement of inflammation at all phases of recovery following SRC, and potentially support a concomitant effect of prior concussion on acute SRC pathophysiology.

The relationship between symptom burden and systemic inflammation differs between male and female athletes following concussion.

BACKGROUND: Inflammation appears to be an important component of concussion pathophysiology. However, its relationship to symptom burden is unclear. Therefore, the purpose of this study was to evaluate the relationship between symptoms and inflammatory biomarkers measured in the blood of male and female athletes following a sport-related concussion (SRC). RESULTS: Forty athletes (n = 20 male, n = 20 female) from nine interuniversity sport teams at a single institution provided blood samples within one week of an SRC. Twenty inflammatory biomarkers were quantitated by immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms. Partial least squares (PLS) analyses were used to evaluate the relationship(s) between biomarkers and symptoms. In males, a positive correlation between interferon (IFN)-γ and symptom severity was observed following SRC. The relationship between IFN-γ and symptoms was significant among all symptom clusters, with cognitive symptoms displaying the largest effect. In females, a significant negative relationship was observed between symptom severity and cytokines IFN-γ, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO); a positive relationship was observed between symptom severity and MCP-4. Inflammatory mediators were significantly associated with all symptom clusters in females; the somatic symptom cluster displayed the largest effect. CONCLUSION: These results provide supportive evidence of a divergent relationship between inflammation and symptom burden in male and female athletes following SRC. Future investigations should be cognizant of the potentially sex-specific pathophysiology underlying symptom presentation.

Massage Therapy Modulates Inflammatory Mediators Following Sprint Exercise in Healthy Male Athletes.

Massage therapy is a common postexercise muscle recovery modality; however, its mechanisms of efficacy are uncertain. We evaluated the effects of massage on systemic inflammatory responses to exercise and postexercise muscle performance and soreness. In this crossover study, nine healthy male athletes completed a high-intensity intermittent sprint protocol, followed by massage therapy or control condition. Inflammatory markers were assessed pre-exercise; postexercise; and at 1, 2, and 24 h postexercise. Muscle performance was measured by squat and drop jump, and muscle soreness on a Likert scale. Significant time effects were observed for monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor alpha (TNFα), drop jump performance, squat jump performance, and soreness. No significant effects for condition were observed. However, compared with control, inflammatory marker concentrations (IL-8, TNFα, and MCP-1) returned to baseline levels earlier following the massage therapy condition (p < 0.05 for all). IL-6 returned to baseline levels earlier following the control versus massage therapy condition (p < 0.05). No differences were observed for performance or soreness variables. MCP-1 area under the curve (AUC) was negatively associated with squat and drop jump performance, while IL-10 AUC was positively associated with drop jump performance (p < 0.05 for all). In conclusion, massage therapy promotes resolution of systemic inflammatory signaling following exercise but does not appear to improve performance or soreness measurements.

Peripheral blood neuroendocrine hormones are associated with clinical indices of sport-related concussion.

The purpose of this study was to evaluate the relationship between neuroendocrine hormones and clinical recovery following sport-related concussion (SRC). Ninety-five athletes (n = 56 male, n = 39 female) from a cohort of 11 interuniversity sport teams at a single institution provided blood samples; twenty six athletes with SRC were recruited 2-7 days post-injury, and 69 uninjured athletes recruited prior to the start of their competitive season. Concentrations of seven neuroendocrine hormones were quantitated in either plasma or serum by solid-phase chemiluminescent immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms at the time of blood sampling in all athletes. Multivariate partial least squares (PLS) analyses were used to evaluate the relationship between blood hormone concentrations and both (1) time to physician medical clearance and (2) initial symptom burden. A negative relationship was observed between time to medical clearance and both dehydroepiandrosterone sulfate (DHEA-S) and progesterone; a positive relationship was found between time to medical clearance and prolactin. Cognitive, somatic, fatigue and emotion symptom clusters were associated with distinct neuroendocrine signatures. Perturbations to the neuroendocrine system in athletes following SRC may contribute to initial symptom burden and longer recovery times.

Evidence of a distinct peripheral inflammatory profile in sport-related concussion.

BACKGROUND: Inflammation is considered a hallmark of concussion pathophysiology in experimental models, yet is understudied in human injury. Despite the growing use of blood biomarkers in concussion, inflammatory biomarkers have not been well characterized. Furthermore, it is unclear if the systemic inflammatory response to concussion differs from that of musculoskeletal injury. The purpose of this paper was to characterize systemic inflammation after injury in athletes with sport-related concussion or musculoskeletal injury. METHODS: A prospective, observational cohort study was conducted employing 175 interuniversity athletes (sport-related concussion, n = 43; musculoskeletal injury, n = 30; healthy, n = 102) from 12 sports at a sports medicine clinic at an academic institution. High-sensitivity immunoassay was used to evaluate 20 inflammatory biomarkers in the peripheral blood of athletes within 7 days of injury (subacute) and at medical clearance. Healthy athletes were sampled prior to the start of their competitive season. Partial least squares regression analyses were used to identify salient biomarker contributions to class separation between injured and healthy athletes, as well as to evaluate the relationship between biomarkers and days to recovery in injured athletes. RESULTS: In the subacute period after injury, compared to healthy athletes, athletes with sport-related concussion had higher levels of the chemokines' monocyte chemoattractant protein-4 (p < 0.001) and macrophage inflammatory protein-1ß (p = 0.001); athletes with musculoskeletal injury had higher levels of thymus and activation-regulated chemokine (p = 0.001). No significant differences in biomarker profiles were observed at medical clearance. Furthermore, concentrations of monocyte chemoattractant protein-1 (p = 0.007) and monocyte chemoattractant protein-4 (p < 0.001) at the subacute time point were positively correlated with days to recovery in athletes with sport-related concussion, while thymus and activation-regulated chemokine was (p = 0.001) positively correlated with days to recovery in athletes with musculoskeletal injury. CONCLUSION: Sport-related concussion is associated with perturbations to systemic inflammatory chemokines that differ from those observed in athletes with a musculoskeletal injury. These results support inflammation as an important facet of secondary injury after sport-related concussion that can be measured systemically in a human model of injury.

High-Intensity Interval Training Is Associated With Alterations in Blood Biomarkers Related to Brain Injury.

Purpose: Blood biomarkers are a useful tool to study concussion. However, their interpretation is complicated by a number of potential biological confounds, including exercise. This is particularly relevant in military and athletic settings where injury commonly occurs during physical exertion. The impact of high-intensity interval training (HIIT) on putative brain injury biomarkers remains under-examined. The purpose of this study was to observe the effects of HIIT on a panel of blood biomarkers associated with brain injury. Methods: Eleven healthy, recreationally active males (median age = 29.0, interquartile range = 26.0-31.5) performed HIIT on a bicycle ergometer (8-12 × 60-s intervals at 100% of peak power output, interspersed by 75-s recovery at 50 W) three times/week for 2 weeks. Peripheral blood samples were collected before and immediately after HIIT during the first and last training sessions. Plasma concentrations of s100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurogranin (NRGN), peroxiredoxin (PRDX)-6, creatine kinase-BB isoenzyme (CKBB), visinin-like protein (VILIP)-1, von Willebrand factor (vWF), monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-9, and total tau (T-tau) were quantitated by high-sensitivity MULTI-SPOT® immunoassay, on the MesoScale Diagnostics electrochemiluminescence detection platform. Differences in biomarker concentrations in response to HIIT were evaluated by partial least squares discriminant analysis (PLSDA) within a repeated-measures bootstrapped framework. Results: Ten of 12 biomarkers were increased pre-to-post HIIT; VILIP-1 remained unchanged, and GFAP was not statistically evaluated due to insufficient detectability. After 2 weeks of HIIT, T-tau was no longer significantly elevated pre-to-post HIIT, and significant attenuation was noted in the acute responses of NRGN, PRDX-6, MMP-9, and vWF. In addition, compared to session 1, session 6 pre-exercise concentrations of NSE and VILIP-1 were significantly lower and higher, respectively. Conclusion: Blood biomarkers commonly associated with brain injury are significantly elevated in response to a single bout of HIIT. After a 2-week, six-session training protocol, this response was attenuated for some, but not all markers. While biomarkers continue to provide promise to concussion research, future studies are necessary to disentangle the common biological sequelae to both exercise and brain injury.

Blood biomarkers are associated with brain function and blood flow following sport concussion.

BACKGROUND: Secondary injury pathophysiology after sport-related concussion (SRC) is poorly understood. Blood biomarkers may be a useful tool for characterizing these processes, yet there are limitations in their application as a single modality. Combining blood biomarker analysis with advanced neuroimaging may help validate their continued utility in brain injury research by elucidating important secondary injury mechanisms. Hence, the purpose of this study was to evaluate co-modulation between peripheral blood biomarkers and advanced functional brain imaging after SRC. METHODS: Forty-three university level athletes from 7 sports were recruited (16 recently concussed athletes; 15 healthy athletes with no prior history of concussion; 12 healthy athletes with a history of concussion). Seven blood biomarkers were evaluated: s100B, total tau (T-tau), von Willebrand factor (vWF), brain derived neurotrophic factor (BDNF), peroxiredoxin (PRDX)-6, monocyte chemoattractant protein (MCP)-1 and -4. Resting-state functional MRI was employed to assess global neural connectivity (Gconn), and arterial spin labelling was used to evaluate cerebral blood flow (CBF). We tested for concurrent alterations in blood biomarkers and MRI measures of brain function between athlete groups using a non-parametric, bootstrapped resampling framework. RESULTS: Compared to healthy athletes, recently concussed athletes showed greater concurrent alterations in several peripheral blood biomarker and MRI measures: a decrease in T-Tau and Gconn, a decrease in T-Tau and CBF, a decrease in Gconn with elevated PRDX-6, a decrease in CBF with elevated PRDX-6, and a decrease in Gconn with elevated MCP-4. In addition, compared to healthy athletes with no concussion history, healthy athletes with a history of concussion displayed greater concurrent alterations in blood biomarkers and Gconn; lower GConn covaried with higher blood levels of s100B and MCP-4. CONCLUSION: We identified robust relationships between peripheral blood biomarkers and MRI measures in both recently concussed athletes and healthy athletes with a history of concussion. The results from this combinatorial approach further support that human concussion is associated with inflammation, oxidative stress, and cellular damage, and that physiological perturbations may extend chronically beyond recovery. Finally, our results support the continued implementation of blood biomarkers as a tool to investigate brain injury, particularly in a multimodal framework.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery.

OBJECTIVES: To characterise a panel of neuroinjury-related blood biomarkers after sport-related concussion (SRC). We hypothesised significant differences in biomarker profiles between athletes with SRC and healthy controls at both subacute and medical clearance time points. METHODS: Thirty-eight interuniversity athletes were recruited over two athletic seasons (n = 19 SRC; n = 19 healthy matched-control). High-sensitivity immunoassay was used to evaluate 11 blood analytes at both the subacute phase after SRC and at medical clearance. RESULTS: Univariate analysis identified elevated circulating peroxiredoxin-6 (PRDX-6) in athletes with SRC compared to healthy controls at the subacute time point. Multivariate analyses yielded similar results in the subacute phase, but identified both PRDX-6 and T-tau as significant contributors to class separation between athletes with SRC and controls at medical clearance. CONCLUSIONS: Our results are consistent with the increasing recognition that physiological recovery after SRC extends beyond clinical recovery. Blood biomarkers appear to be useful in elucidating the biology of brain restitution after SRC. However, their implementation requires mindfulness of factors such as academic stress, exercise, and injury heterogeneity.

Systematic review of mental health measures associated with concussive and subconcussive head trauma in former athletes.

Public concern has been a catalyst for an emerging body of research investigating the potential long-term negative health consequences associated with sport-related concussion and subconcussive impacts. We conducted a systematic review of the literature on mental health measures associated with sport-related brain injuries in former athletes. Ovid MEDLINE, EMBASE, CINAHL, and PsychINFO databases were used. Thirteen studies were included in the final review. We identified a consistent positive association between a history of concussion and depression among former athletes, although the underlying causation remains unclear. Limited and inconsistent findings were observed in studies that evaluated subconcussive impacts. Overall, several methodological shortcomings were noted, including selection bias, research design, operational definitions, and measurement tools. Future research will benefit from employing prospective longitudinal studies, surveillance data systems and standardized collection methods, and should attempt to account for psychosocial modifiers or confounders when reporting the mental health status of former athletes. This area would also benefit from studies that include equal representation of male and female athletes, examine mental health disorders beyond depression, and assess a variety of sports and competition levels.