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.

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.

Functional Movement Screen Task Scores and Joint Range-of-motion: A Construct Validity Study.

Little is known about the construct validity of the Functional Movement Screen (FMS). We aimed to assess associations between FMS task scores and measures of maximum joint range-of-motion (ROM) among university varsity student-athletes from 4 sports (volleyball, basketball, ice hockey, and soccer). Athletes performed FMS tasks and had their maximum ankle, hip and shoulder ROM measured. Multivariable linear regression was used to estimate associations between FMS task scores and ROM measurements. 101 university student-athletes were recruited (52 W/49 M; mean age 20.4±1.9 years). In general, athletes with higher FMS task scores had greater ROM compared to those with lower task scores. For example, athletes who scored 2 on the FMS squat task had 4° (95% CI, 1° to 7°) more uni-articular ankle dorsiflexion ROM compared with those who scored 1, while those who scored 3 on the FMS squat task had 10° (4° to 17°) more uni-articular ankle dorsiflexion ROM compared with those who scored 1. Large variation in ROM measurements was observed. In sum, substantial overlap in joint ROM between groups of athletes with different FMS task scores weakens the construct validity of the FMS as an indicator of specific joint ROM.

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.

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.

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.

Feasibility of a postacute structured aerobic exercise intervention following sport concussion in symptomatic adolescents: a randomised controlled study.

OBJECTIVE: The utility of structured exercise for rehabilitation purposes early in the postacute phase (ie, beyond the initial 24-48 hours of advised rest) following sport-related concussion (SRC) remains largely unexplored. This study examined the feasibility of implementing a standardised aerobic exercise (AE) intervention in the postacute stage of SRC recovery in a sample of adolescent students with SRC compared with usual care. METHODS: Symptomatic adolescents with SRC were randomised to one of two groups: Aerobic Exercise (n=8) or Usual Care (n=7). The AE intervention, beginning on day 6 postinjury, comprised eight sessions with progressive increases in intensity and duration on a cycle ergometer. Usual care consisted of rest followed by physician-advised progressions in activity levels in an unsupervised setting. All participants were evaluated by physician at weeks 1, 2, 3 and 4 postconcussion. Outcome measures included: (1) Intervention feasibility: symptom status pre-post exercise sessions and completion of intervention and (2) Clinical recovery: symptom status at weeks 1, 2, 3 and 4 postinjury and medical clearance date. RESULTS: All participants completed the exercise sessions as part of the AE intervention and symptom exacerbation was not associated with any exercise session. The AE group experienced greater symptom resolution compared with the Usual Care Group across the recovery timeline. CONCLUSION: A structured AE protocol appears to be safe and feasible to administer in the postacute stage of SRC recovery in adolescents and should be explored as part of a full Phase III Clinical Trial.

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.

Earlier time to aerobic exercise is associated with faster recovery following acute sport concussion.

OBJECTIVE: To determine whether earlier time to initiation of aerobic exercise following acute concussion is associated with time to full return to (1) sport and (2) school or work. METHODS: A retrospective stratified propensity score survival analysis of acute (≤14 days) concussion was used to determine whether time (days) to initiation of aerobic exercise post-concussion was associated with, both, time (days) to full return to (1) sport and (2) school or work. RESULTS: A total of 253 acute concussions [median (IQR) age, 17.0 (15.0-20.0) years; 148 (58.5%) males] were included in this study. Multivariate Cox regression models identified that earlier time to aerobic exercise was associated with faster return to sport and school/work adjusting for other covariates, including quintile propensity strata. For each successive day in delay to initiation of aerobic exercise, individuals had a less favourable recovery trajectory. Initiating aerobic exercise at 3 and 7 days following injury was associated with a respective 36.5% (HR, 0.63; 95% CI, 0.53-0.76) and 73.2% (HR, 0.27; 95% CI, 0.16-0.45) reduced probability of faster full return to sport compared to within 1 day; and a respective 45.9% (HR, 0.54; 95% CI, 0.44-0.66) and 83.1% (HR, 0.17; 95% CI, 0.10-0.30) reduced probability of faster full return to school/work. Additionally, concussion history, symptom severity, LOC deleteriously influenced concussion recovery. CONCLUSION: Earlier initiation of aerobic exercise was associated with faster full return to sport and school or work. This study provides greater insight into the benefits and safety of aerobic exercise within the first week of the injury.

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.

Neuroimaging of sport concussion: persistent alterations in brain structure and function at medical clearance.

The medical decision of return to play (RTP) after a sport concussion is largely based on symptom status following a graded exercise protocol. However, it is currently unknown how objective markers of brain structure and function relate to clinical recovery. The goal of this study was to determine whether differences in brain structure and function at acute injury remain present at RTP. In this longitudinal study, 54 active varsity athletes were scanned using magnetic resonance imaging (MRI), including 27 with recent concussion, imaged at both acute injury and medical clearance, along with 27 matched controls. Diffusion tensor imaging was used to measure fractional anisotropy (FA) and mean diffusivity (MD) of white matter and resting-state functional MRI was used to measure global functional connectivity (Gconn). At acute injury, concussed athletes had reduced FA and increased MD, along with elevated Gconn; these effects remained present at RTP. Athletes who took longer to reach RTP also showed elevated Gconn in dorsal brain regions, but no significant white matter effects. This study presents the first evidence of altered brain structure and function at the time of medical clearance to RTP, with greater changes in brain function for athletes with a longer recovery time.

The first week after concussion: Blood flow, brain function and white matter microstructure.

Concussion is a major health concern, associated with short-term deficits in physical function, emotion and cognition, along with negative long-term health outcomes. However, we remain in the early stages of characterizing MRI markers of concussion, particularly during the first week post-injury when symptoms are most severe. In this study, 52 varsity athletes were scanned using Magnetic Resonance Imaging (MRI), including 26 athletes with acute concussion (scanned 1-7 days post-injury) and 26 matched control athletes. A comprehensive set of functional and structural MRI measures were analyzed, including cerebral blood flow (CBF) and global functional connectivity (Gconn) of grey matter, along with fractional anisotropy (FA) and mean diffusivity (MD) of white matter. An analysis comparing acutely concussed athletes and controls showed limited evidence for reliable mean effects of acute concussion, with only MD showing spatially extensive differences between groups. We subsequently demonstrated that the number of days post-injury explained a significant proportion of inter-subject variability in MRI markers of acutely concussed athletes. Athletes scanned at early acute injury (1-3 days) had elevated CBF and Gconn and reduced FA, but those scanned at late acute injury (5-7 days) had the opposite response. In contrast, MD showed a more complex, spatially-dependent relationship with days post-injury. These novel findings highlight the variability of MRI markers during the acute phase of concussion and the critical importance of considering the acute injury time interval, which has significant implications for studies relating acute MRI data to concussion outcomes.

Psychological and Physiological Markers of Stress in Concussed Athletes Across Recovery Milestones.

BACKGROUND: Sport-related concussions are associated with a range of physical, cognitive, and behavioral disturbances that are highly variable across individuals. Much remains unknown about the effects of sport concussion, and changes in markers of psychological and physiological stress over the recovery timeline. OBJECTIVE: To examine psychological (mood, stress, sleep quality, and symptoms) and physiological (heart rate variability and salivary cortisol) measures in concussed athletes over clinical recovery milestones. SETTING: University athletic program, sport medicine clinic, Canada. PARTICIPANTS: A sample of 52 interuniversity athletes (32 male and 20 female), 26 with concussion and 26 healthy controls. DESIGN: Case-control repeated measures study at 3 time points of the clinical recovery process. Measures were administered to a matched control sample of uninjured athletes as well. MAIN MEASURES: Physiological measures were heart rate variability and salivary cortisol; psychological measures were mood, perceived stress, and quality of sleep. RESULTS: Psychological measures were significantly worse for concussed athletes relative to controls at the symptomatic phase (acute injury), but significantly better at return-to-play (RTP). Multivariate analysis of heart rate variability identified main effects of sex and concussion, with reduced high-frequency heart rate variability for females and concussed athletes extending into the post-RTP phase. An interaction effect was also observed, showing the cardiac response of female athletes was more sensitive to concussion compared with males. Conversely, male athletes showed greater suppression of low-frequency heart rate variability associated with mood disturbances. CONCLUSION: This integrated study of psychological and physiological markers in concussed athletes confirmed the resolution of mood disturbances, symptoms, and sleep quality by RTP, but identified autonomic nervous system disturbances, as measured by depressed heart rate variability beyond RTP.

Brain Structure and Function Associated with a History of Sport Concussion: A Multi-Modal Magnetic Resonance Imaging Study.

There is growing concern about the potential long-term consequences of sport concussion for young, currently active athletes. However, there remains limited information about brain abnormalities associated with a history of concussion and how they relate to clinical factors. In this study, advanced MRI was used to comprehensively describe abnormalities in brain structure and function associated with a history of sport concussion. Forty-three athletes (21 male, 22 female) were recruited from interuniversity teams at the beginning of the season, including 21 with a history of concussion and 22 without prior concussion; both groups also contained a balanced sample of contact and noncontact sports. Multi-modal MRI was used to evaluate abnormalities in brain structure and function. Athletes with a history of concussion showed frontal decreases in brain volume and blood flow. However, they also demonstrated increased posterior cortical volume and elevated markers of white matter microstructure. A greater number of prior concussions was associated with more extensive decreases in cerebral blood flow and insular volume, whereas recovery time from most recent concussion was correlated with reduced frontotemporal volume. White matter showed limited correlations with clinical factors, predominantly in the anterior corona radiata. This study provides the first evidence of the long-term effects of concussion on gray matter volume, blood flow, and white matter microstructure within a single athlete cohort. This was examined for a mixture of male and female athletes in both contact and noncontact sports, demonstrating the relevance of these findings for the overall sporting community.

Correction: Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts.

[This corrects the article DOI: 10.1371/journal.pone.0159929.].

Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts.

The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27) were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries). Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage.