Acute white matter changes following sport‐related concussion: A serial diffusion tensor and diffusion kurtosis tensor imaging study

Recent neuroimaging studies have suggested that following sport‐related concussion (SRC) physiological brain alterations may persist after an athlete has shown full symptom recovery. Diffusion MRI is a versatile technique to study white matter injury following SRC, yet serial follow‐up studies in the very acute stages following SRC utilizing a comprehensive set of diffusion metrics are lacking. The aim of the current study was to characterize white matter changes within 24 hours of concussion in a group of high school and collegiate athletes, using Diffusion Tensor and Diffusion Kurtosis Tensor metrics. Participants were reassessed a week later. At 24 hours post‐injury, the concussed group reported significantly more concussion symptoms than a well‐matched control group and demonstrated poorer performance on a cognitive screening measure, yet these differences were nonsignificant at the 8‐day follow‐up. Similarly, within 24‐hours after injury, the concussed group exhibited a widespread decrease in mean diffusivity, increased axial kurtosis and, to a lesser extent, decreased axial and radial diffusivities compared with control subjects. At 8 days post injury, the differences in these diffusion metrics were even more widespread in the injured athletes, despite improvement of symptoms and cognitive performance. These MRI findings suggest that the athletes might not have reached full physiological recovery a week after the injury. These findings have significant implications for the management of SRC because allowing an athlete to return to play before the brain has fully recovered from injury may have negative consequences. Hum Brain Mapp 37:3821–3834, 2016. © 2016 Wiley Periodicals, Inc .     

Longitudinal assessment of white matter abnormalities following sports‐related concussion

There is great interest in developing physiological‐based biomarkers such as diffusion tensor imaging to aid in the management of concussion, which is currently entirely dependent on clinical judgment. However, the time course for recovery of white matter abnormalities following sports‐related concussion (SRC) is unknown. We collected diffusion tensor imaging and behavioral data in forty concussed collegiate athletes on average 1.64 days (T1; n = 33), 8.33 days (T2; n = 30), and 32.15 days post‐concussion (T3; n = 26), with healthy collegiate contact‐sport athletes (HA) serving as controls (n = 46). We hypothesized that fractional anisotropy (FA) would be increased acutely and partially recovered by one month post‐concussion. Mood symptoms were assessed using structured interviews. FA differences were assessed using both traditional and subject‐specific analyses. An exploratory analysis of tau plasma levels was conducted in a subset of participants. Results indicated that mood symptoms improved over time post‐concussion, but remained elevated at T3 relative to HA. Across both group and subject‐specific analyses, concussed athletes exhibited increased FA in several white matter tracts at each visit post‐concussion with no longitudinal evidence of recovery. Increased FA at T1 and T3 was significantly associated with an independent, real‐world outcome measure for return‐to‐play. Finally, we observed a nonsignificant trend for reduced tau in plasma of concussed athletes at T1 relative to HA, with tau significantly increasing by T2. These results suggest white matter abnormalities following SRC may persist beyond one month and have potential as an objective biomarker for concussion outcome. Hum Brain Mapp 37:833–845, 2016. © 2015 Wiley Periodicals, Inc.     

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.     

Relationship between the apolipoprotein E gene and headache following sports-related concussion

Introduction: Headache is one of the most commonly reported and longest lasting symptoms that concussed athletes report, yet the etiology of headache symptoms following concussion is not entirely clear. The purpose of this study was to determine whether the e4 allele of the apolipoprotein E (APOE) gene influences the presence and severity of postconcussion headache. Method: Participants were composed of 45 concussed athletes and 43 healthy/nonconcussed athletes who were involved in a clinically based sports concussion management program. All athletes completed the Post-Concussion Symptom Scale (PCSS). The “headache” symptom from the PCSS was the primary outcome variable. Buccal samples were collected and analyzed to determine APOE genotype. Results: A significantly greater proportion of concussed e4+ athletes than e4– athletes endorsed headache. Furthermore, concussed e4+ athletes endorsed more severe headaches than e4– athletes. When examining the healthy/nonconcussed sample (i.e., athletes at baseline), results showed no differences between e4 allele groups with respect to the presence and severity of headache. Conclusions: These findings show that when compared to concussed e4– athletes, e4+ athletes are more likely to (a) endorse postconcussion headache and (b) report more severe headache symptoms following concussion. Conversely, it appears that the e4 allele does not influence baseline reports of headache. Thus, results suggest that those with the e4 genotype may be at a higher risk for experiencing headache-related difficulties only after a concussion is sustained.     

Premorbid predictors of postconcussion symptoms in collegiate athletes

Introduction: In recent years, the sports community has been faced with the challenge of determining when it is safe to return concussed athletes to play. Given that return-to-play decisions are partially dependent upon athletes’ endorsement of symptoms, better understanding what factors contribute to the presence of symptoms following concussion is crucial. The purpose of the present study was to better characterize the symptoms that athletes endorse at baseline and to determine what impact various premorbid (or preinjury) characteristics have on the presence and severity of postconcussion symptoms in the acute injury period following concussion. Method: Two groups of participants with similar ages and levels of education were examined: athletes at baseline (N = 702) and postconcussion (N = 55). Athletes were administered a comprehensive battery of neuropsychological tests, consisting of neurocognitive and neurobehavioral measures, at both time periods. The main outcome measure was the Post-Concussion Symptoms Scale (PCSS). A factor analysis was conducted on the participants’ baseline PCSS data to determine the factor structure of the PCSS, and separate logistic regression analyses were conducted that examined the baseline PCSS symptom clusters (derived from the factor analysis), demographic variables, and baseline neurocognitive variables as predictors of dichotomized postconcussion PCSS total scores (i.e., low versus high symptom reporting following concussion). Results: Four distinct clusters emerged from the factor analysis measuring cognitive, physical, affective, and sleep symptoms. Logistic regression results indicated that the physical and affective symptom clusters at baseline reliably predicted athletes’ postconcussion symptom group, as did sex and the neurocognitive composite score. Conclusions: These findings show that certain baseline characteristics of athletes confer risk for greater symptomatology postconcussion. Knowledge of these risk factors can assist the management and treatment of sports-related concussion.     

Reduced brain glutamine in female varsity rugby athletes after concussion and in non‐concussed athletes after a season of play

The purpose of this study was to use non‐invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18–23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in‐season) and followed up at the end of the season (off‐season). Concussed athletes were additionally evaluated 24–72 hr (n = 14), three months (n = 11), and six months (n = 8) post‐concussion. Reduced glutamine at 24–72 hr and three months post‐concussion, and reduced glutamine/creatine at three months post‐concussion were observed. In non‐concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off‐season compared to in‐season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non‐concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re‐myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.     

Concussion history predicts self-reported symptoms before and following a concussive event

The authors evaluated how history of concussion affects symptom reporting prior to and after sustaining a concussion. At baseline, athletes with a positive concussion history reported more current symptomatology than athletes who had never been concussed. At 2 hours postinjury, concussed athletes with a history of previous concussion (PC) reported fewer symptoms than concussed athletes with no previous concussion history (NPC). By 1 week postinjury, however, PC athletes reported more symptoms than NPC athletes.     

Multimodal assessment of primary motor cortex integrity following sport concussion in asymptomatic athletes

ObjectiveRecent studies have shown, in asymptomatic concussed athletes, metabolic disruption in the primary motor cortex (M1) and abnormal intracortical inhibition lasting for more than six months. The present study aims to assess if these neurochemical and neurophysiological alterations are persistent and linked to M1 cortical thickness.MethodsSixteen active football players who sustained their last concussion, on average, three years prior to testing and 14 active football players who never sustained a concussion were recruited for a single session of proton magnetic resonance spectroscopy (¹H-MRS) and transcranial magnetic stimulation (TMS). Measures of M1 and whole brain cortical thickness were acquired, and ¹H-MRS data were acquired from left M1 using a MEGA-PRESS sequence. Cortical silent period (CSP) and long-interval intracortical inhibition (LICI) were measured with TMS applied over left M1.ResultsNo significant group differences were observed for metabolic concentrations, TMS measures, and cortical thickness. However, whereas GABA and glutamate levels were positively correlated in control athletes, this relationship was absent in concussed athletes.ConclusionThese data suggest the general absence of neurophysiologic, neurometabolic and neuroanatomical disruptions in M1 three years following the last concussive event. However, correlational analyses suggest the presence of a slight metabolic imbalance between GABA and glutamate concentrations in the primary motor cortex of concussed athletes.SignificanceThe present study highlights the importance of multimodal assesments of the impacts of sport concussions.     

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

Use of computer based testing of youth hockey players with concussions

Concussion is a potentially serious injury for athletes. Recent statistics suggest that approximately 300,000 sports-related traumatic brain injuries occur annually in the United States. Soccer, rugby, football, and ice hockey are all considered high-risk team sports for concussion. Hockey-related concussions are of particular concern in Canada, where over 500,000 players compete annually in ice hockey. The United States is now registering similar numbers of players. Return to play issues are one of the most difficult issues for physicians caring for concussed athletes. The advent of computerized neuropsychological testing adds another tool to assist in this process. It also appears to enhance the education process for players, coaches, and parents on the potential seriousness of concussion for these young athletes.     

Scale‐free functional brain dynamics during recovery from sport‐related concussion

Studies using blood‐oxygenation‐level‐dependent functional magnetic resonance imaging (BOLD fMRI) have characterized how the resting brain is affected by concussion. The literature to date, however, has largely focused on measuring changes in the spatial organization of functional brain networks. In the present study, changes in the temporal dynamics of BOLD signals are examined throughout concussion recovery using scaling (or fractal) analysis. Imaging data were collected for 228 university‐level athletes, 61 with concussion and 167 athletic controls. Concussed athletes were scanned at the acute phase of injury (1–7 days postinjury), the subacute phase (8–14 days postinjury), medical clearance to return to sport (RTS), 1 month post‐RTS and 1 year post‐RTS. The wavelet leader multifractal approach was used to assess scaling ( c₁ ) and multifractal ( c₂ ) behavior. Significant longitudinal changes were identified for c₁ , which was lowest at acute injury, became significantly elevated at RTS, and returned near control levels by 1 year post‐RTS. No longitudinal changes were identified for c₂ . Secondary analyses showed that clinical measures of acute symptom severity and time to RTP were related to longitudinal changes in c₁ . Athletes with both higher symptoms and prolonged recovery had elevated c₁ values at RTS, while athletes with higher symptoms but rapid recovery had reduced c₁ at acute injury. This study provides the first evidence for long‐term recovery of BOLD scale‐free brain dynamics after a concussion.     

The relation between post concussion symptoms and neurocognitive performance in concussed athletes

The objective of this study was to examine differences in neurocognitive performance between symptomatic concussed athletes, a group of concussed athletes with no subjective symptoms, and a non-concussed control group of athletes. All concussed athletes were evaluated within one week of injury using the ImPACT computerized test battery. Results indicate that concussed athletes who denied subjective symptoms demonstrated poorer performance than control subjects on all four composite scores of the ImPACT test batters (Verbal Memory, Visual Memory, Reaction Time and Processing Speed However, the concussed but asymptomatic group demonstrated significantly better performance than did the concussed and symptomatic group. Thus, concussed athletes who did not report subjective symptoms were not fully recovered based on neurocognitive testing. This study underscores the importance of neurocognitive testing in the assessment of concussion sequelae and recovery.     

White matter microstructure in athletes with a history of concussion: Comparing diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI)

Sport concussion is associated with disturbances in brain function in the absence of gross anatomical lesions, and may have long‐term health consequences. Diffusion‐weighted magnetic resonance imaging (MRI) methods provide a powerful tool for investigating alterations in white matter microstructure reflecting the long‐term effects of concussion. In a previous study, diffusion tensor imaging (DTI) showed that athletes with a history of concussion had elevated fractional anisotropy (FA) and reduced mean diffusivity (MD) parameters. To better understand these effects, this study compared DTI results to neurite orientation dispersion and density imaging (NODDI), which was used to estimate the intracellular volume fraction (V_IC) and orientation dispersion index (ODI). Sixty‐eight (68) varsity athletes were recruited, including 37 without a history of concussion and 31 with concussion >6 months prior to imaging. Univariate analyses showed elevated FA and decreased MD for concussed athletes, along with increased V_IC and reduced ODI, indicating greater neurite density and coherence of neurite orientation within white matter. Multivariate analyses also showed that for athletes with a history of concussion, white matter regions with increased FA had increased V_IC and decreased ODI, with greater effects among athletes who were imaged a longer time since their last concussion. These findings enhance our understanding of the relationship between the biophysics of water diffusion and concussion neurobiology for young, healthy adults. Hum Brain Mapp 38:4201–4211, 2017. © 2017 Wiley Periodicals, Inc.     

Sleep following sport-related concussions

ObjectivesSleep and vigilance disorders are among the most commonly reported symptoms following a concussion. The aim of the study was thus to investigate the effects of sport-related concussions on subjective and objective sleep quality.MethodsTen concussed athletes and 11 non-concussed athletes were included. Concussed athletes had a history of 4.6 ± 2.1 concussions with at least one concussion during the last year. They were recorded for two consecutive nights in the laboratory and during a 10-min period of wakefulness. They completed questionnaires related to sleep quality and symptoms as well as neuropsychological tests and the CogSport computer battery.ResultsConcussed athletes reported more symptoms and worse sleep quality than control athletes, but no between-group differences were found on polysomnographic variables or on REM and NREM sleep quantitative EEG variables. However, concussed athletes showed significantly more delta activity and less alpha activity during wakefulness than did control athletes.ConclusionIn spite of the subjective complaints in sleep quality of concussed athletes, no change was observed in objective sleep characteristics. However, concussions were associated with an increase in delta and a reduction in alpha power in the waking EEG. Sport-related concussions are thus associated with wakefulness problems rather than sleep disturbances.     

Cognition in the days following concussion: comparison of symptomatic versus asymptomatic athletes

BACKGROUND: Concussion is a common neurological injury occurring during contact sport. Current guidelines recommend that no athlete should return to play while symptomatic or displaying cognitive dysfunction. This study compared post-concussion cognitive function in recently concussed athletes who were symptomatic/asymptomatic at the time of assessment with that of non-injured (control) athletes. METHODS: Prospective study of 615 male Australian Rules footballers. Before the season, all participants (while healthy) completed a battery of baseline computerised (CogSport) and paper and pencil cognitive tasks. Sixty one injured athletes (symptomatic = 25 and asymptomatic = 36) were reassessed within 11 days of being concussed; 84 controls were also reassessed. The serial cognitive function of the three groups was compared using analysis of variance. RESULTS: The performance of the symptomatic group declined at the post-concussion assessment on computerised tests of simple, choice, and complex reaction times compared with the asymptomatic and control groups. The magnitude of changes was large according to conventional statistical criteria. On paper and pencil tests, the symptomatic group displayed no change at reassessment, whereas large improvements were seen in the other two groups. CONCLUSION: Injured athletes experiencing symptoms of concussion displayed impaired motor function and attention, although their learning and memory were preserved. These athletes displayed no change in performance on paper and pencil tests in contrast with the improvement observed in asymptomatic and non-injured athletes. Athletes experiencing symptoms of concussion should be withheld from training and competition until both symptoms and cognitive dysfunction have resolved.     

Resting‐state fMRI detects the effects of learning in short term: A visual search training study

Can resting‐state functional connectivity (rs‐FC) detect the impact of learning on the brain in the short term? To test this possibility, we have combined task‐FC and rs‐FC tested before and after a 30‐min visual search training. Forty‐two healthy adults (20 men) divided into no‐contact control and trained groups completed the study. We studied the connectivity between four different regions of the brain involved in visual search: the primary visual area, the right posterior parietal cortex (rPPC), the right dorsolateral prefrontal cortex (rDLPFC), and the dorsal anterior cingulate cortex (dACC). Task‐FC showed increased connectivity between the rPPC and rDLPFC and between the dACC and rDLPFC from pretraining to posttraining for both the control group and the trained group, suggesting that connectivity between these areas increased with task repetition. In rs‐FC, we found enhanced connectivity between these regions in the trained group after training, especially in those with better learning. Whole brain independent component analyses did not reveal any change in main networks after training. These results imply that rs‐FC may not only predict individual differences in task performance, but rs‐FC might also serve to monitor the impact of learning on the brain after short periods of cognitive training, localizing them in brain areas specifically involved in training.     

A novel approach to sports concussion assessment: Computerized multilimb reaction times and balance control testing

Introduction: Mild traumatic brain injuries (MTBI) or concussions often result in problems with attention, executive functions, and motor control. For better identification of these diverse problems, novel approaches integrating tests of cognitive and motor functioning are needed. The aim was to characterize minor changes in motor and cognitive performance after sports-related concussions with a novel test battery, including balance tests and a computerized multilimb reaction time test. The cognitive demands of the battery gradually increase from a simple stimulus response to a complex task requiring executive attention. Method: A total of 113 male ice hockey players (mean age = 24.6 years, SD = 5.7) were assessed before a season. During the season, nine concussed players were retested within 36 hours, four to six days after the concussion, and after the season. A control group of seven nonconcussed players from the same pool of players with comparable demographics were retested after the season. Performance was measured using a balance test and the Motor Cognitive Test battery (MotCoTe) with multilimb responses in simple reaction, choice reaction, inhibition, and conflict resolution conditions. Results: The performance of the concussed group declined at the postconcussion assessment compared to both the baseline measurement and the nonconcussed controls. Significant changes were observed in the concussed group for the multilimb choice reaction and inhibition tests. Tapping and balance showed a similar trend, but no statistically significant difference in performance. Conclusion: In sports-related concussions, complex motor tests can be valuable additions in assessing the outcome and recovery. In the current study, using subtasks with varying cognitive demands, it was shown that while simple motor performance was largely unaffected, the more complex tasks induced impaired reaction times for the concussed subjects. The increased reaction times may reflect the disruption of complex and integrative cognitive function in concussions.     

Investigating the effects of subconcussion on functional connectivity using mass-univariate and multivariate approaches

There are concerns about the effects of subconcussive head impacts in sport, but the effects of subconcussion on brain connectivity are not well understood. We hypothesized that college football players experience changes in brain functional connectivity not found in athletes competing in lower impact sports or healthy controls. These changes may be spatially heterogeneous across participants, requiring analysis methods that go beyond mass-univariate approaches commonly used in functional MRI (fMRI). To test this hypothesis, we analyzed resting-state fMRI data from college football (n?=?15), soccer (n?=?12), and lacrosse players (n?=?16), and controls (n?=?29) collected at preseason and postseason time points. Regional homogeneity (ReHo) and degree centrality (DC) were calculated as measures of local and long-range functional connectivity, respectively. Standard voxel-wise analysis and paired support vector machine (SVM) classification studied subconcussion’s effects on local and global functional connectivity. Voxel-wise analyses yielded minimal findings, but SVM classification had high accuracy for college football’s ReHo (87%, p?=?0.009) and no other group. The findings suggest subconcussion results in spatially heterogeneous changes in local functional connectivity that may only be detectible with multivariate analyses. To determine if voxel-wise and SVM analyses had similar spatial patterns, region-average t-statistic and SVM weight values were compared using a measure of ranking distance. T-statistic and SVM weight rankings exhibited significantly low ranking distance values for all groups and metrics, demonstrating that the analyses converged on a similar underlying effect. Overall, this research suggests that subconcussion in football may produce local functional connectivity changes similar to concussion.     

Standard regression-based methods for measuring recovery after sport-related concussion.

Clinical decision making about an athlete's return to competition after concussion is hampered by a lack of systematic methods to measure recovery. We applied standard regression-based methods to statistically measure individual rates of impairment at several time points after concussion in college football players. Postconcussive symptoms, cognitive functioning, and balance were assessed in 94 players with concussion (based on American Academy of Neurology Criteria) and 56 noninjured controls during preseason baseline testing, and immediately, 3 hr, and 1, 2, 3, 5, and 7 days postinjury. Ninety-five percent of injured players exhibited acute concussion symptoms and impairment on cognitive or balance testing immediately after injury, which diminished to 4% who reported elevated symptoms on postinjury day 7. In addition, a small but clinically significant percentage of players who reported being symptom free by day 2 continued to be classified as impaired on the basis of objective balance and cognitive testing. These data suggest that neuropsychological testing may be of incremental utility to subjective symptom checklists in identifying the residual effects of sport-related concussion. The implementation of neuropsychological testing to detect subtle cognitive impairment is most useful once postconcussive symptoms have resolved. This management model is also supported by practical and other methodological considerations.