title: Cerebral Perfusion Changes in Post-Concussion Syndrome: A Prospective Controlled Cohort Study Cerebral Blood Flow During Treadmill Exercise Is a Marker of Physiological Postconcussion Syndrome in Female Athletes Professional Rugby Union players have a 60% greater risk of time loss injury after concussion: a 2-season prospective study of clinical outcomes Autonomic Nervous System Responses to Concussion: Arterial Pulse Contour Analysis Temporal Profile of Cerebrovascular Reactivity Impairment, Gray Matter Volumes, and Persistent Symptoms after Mild Traumatic Head Injury Subject-Specific Increases in Serum S-100B Distinguish Sports-Related Concussion from Sports-Related Exertion Functional abnormalities in symptomatic concussed athletes: an fMRI study Myelin Water Fraction Is Transiently Reduced after a Single Mild Traumatic Brain Injury – A Prospective Cohort Study in Collegiate Hockey Players FUNCTIONAL BRAIN ABNORMALITIES ARE RELATED TO CLINICAL RECOVERY AND TIME TO RETURN‐TO‐PLAY IN ATHLETES Persistent motor system abnormalities in formerly concussed athletes. Acute Effects and Recovery After Sport‐Related Concussion: A Neurocognitive and Quantitative Brain Electrical Activity Study Evaluating the cognitive consequences of mild traumatic brain injury and concussion by using electrophysiology. Recovery From Mild Head Injury in Sports: Evidence From Serial Functional Magnetic Resonance Imaging Studies in Male Athletes Reliability of a Graded Exercise Test for Assessing Recovery From Concussion Brain magnetic resonance imaging CO2 stress testing in adolescent postconcussion syndrome. Serum Tau Fragments Predict Return to Play in Concussed Professional Ice Hockey Players. Blood biomarkers for brain injury in concussed professional ice hockey players. Recovery of cerebral blood flow following sports-related concussion.
abstract: Abstract The biology of post-concussive symptoms is unclear . Symptoms are often increased during activities , and have been linked to decreased cerebrovascular reactivity and perfusion . The aim of this study was to examine cerebral blood flow ( CBF ) in children with different clinical recovery patterns following mild traumatic brain injury ( mTBI ) . This was a prospect i ve controlled cohort study of children with mTBI ( ages 8 to 18 years ) who were symptomatic with post-concussive symptoms at one month post-injury ( symptomatic , n = 27 ) and children who had recovered quickly ( asymptomatic , n = 24 ) .  Pseudo continuous arterial spin labeling magnetic resonance imaging ( MRI ) was used to quantify CBF . The mTBI groups were imaged at 40 days post-injury . Global and regional CBF were compared with healthy controls of similar age and sex but without a history of mTBI ( n = 21 ) . Seventy-two participants ( mean age : 14.1 years ) underwent neuroimaging . Significant differences in CBF were found : global CBF was higher in the symptomatic group and lower in the asymptomatic group compared with controls , ( F(2,69 ) 9.734 ; p < 0.001 ) . Post-injury symptom score could be predicted by pre-injury symptoms and CBF in presence of mTBI ( adjusted R2 = 0.424 ; p < 0.001 ) . Altered patterns of cerebral perfusion are seen following mTBI and are associated with the recovery trajectory . Symptomatic children have higher CBF . Children who “ recovered ” quickly , have decreased CBF suggesting that clinical recovery precedes the cerebral recovery . Further longitudinal studies are required to determine if these perfusion patterns continue to change over time Objective : Some patients with postconcussion syndrome ( PCS ) have reduced exercise capacity that may reflect altered central cardiorespiratory control . The purpose of this study was to evaluate control of cerebral blood flow ( CBF ) during exercise in females with PCS . Setting : University Concussion Clinic . Participants : Nine female Division 1 collegiate team athletes with PCS ( 23 ± 6 years ) and a reference group of 13 healthy female recreational aerobic athletes ( 21 ± 3 years ) . Design : A prospect i ve experimental study . All PCS athletes were compared with the reference group at the beginning of the study . Six of the PCS athletes were subsequently measured before and after a subsymptom threshold aerobic exercise treatment program . Main Measures : Exercise treadmill test  during which blood pressure ( BP ) , minute ventilation ( E ) , end-tidal CO2 ( PETCO2 ) , and CBF velocity ( CBFV , by transcranial Doppler ) were measured . Results : Participants with PCS had significantly lower E ( by 18 % ) and greater PETCO2 ( 5 % ) and CBFV ( 14 % ) versus the reference group at similar workloads in association with appearance of symptoms and premature exercise cessation . Subthreshold exercise normalized E , PETCO2 , CBFV and exercise tolerance . Before treatment , PCS had low CO2 sensitivity that blunted their exercise ventilation . CO2 sensitivity and ventilation improved after exercise treatment . Conclusion : Some PCS patients have exercise intolerance due to abnormal CBF regulation that may be the result of concussion-induced altered sensitivity to CO2 . Return of normal CBF control and exercise tolerance may be physiological markers of recovery from concussion Aim To investigate incidence of concussion , clinical outcomes and subsequent injury risk following concussion . Methods In a two-season ( 2012/2013 , 2013/2014 ) prospect i ve cohort study , incidence of diagnosed match concussions ( injuries/1000 h ) , median time interval to subsequent injury of any type ( survival time ) and time spent at each stage of the graduated return to play pathway were determined in 810 professional Rugby Union players ( 1176 player seasons ) . Results Match concussion incidence was 8.9/1000 h with over 50 % occurring in the tackle . Subsequent incidence of any injury for players who returned to play in the same season following a diagnosed concussion ( 122/1000 h , 95 % CI 106 to 141 ) was 60 % higher ( IRR 1.6 , 95 % CI 1.4 to 1.8 ) than for those who did not sustain a concussion ( 76/1000 h , 95 % CI 72 to 80 ) . Median time to next injury following return to play was shorter following concussion ( 53 days , 95 % CI 41 to 64 ) than following non-concussive injuries ( 114 days , 95 % CI 85 to 143 ) . 38 % of players reported recurrence of symptoms or failed to match their baseline neurocognitive test during the graduated return to play protocol . Summary and conclusions Players who returned to play in the same season after a diagnosed concussion had a 60 % greater risk of time-loss injury than players without concussion . A substantial proportion of players reported recurrence of symptoms or failed to match baseline neurocognitive test scores during graduated return to play . These data pave the way for trials of more conservative and comprehensive graduated return to play protocol s , with a greater focus on active rehabilitation The arterial pulse wave ( APW ) has a distinct morphology whose contours reflect dynamics in cardiac function and peripheral vascular tone as a result of sympathetic nervous system ( SNS ) control . With a transition from rest to increased metabolic dem and , the expected augmentation of SNS outflow will not only affect arterial blood pressure and heart rate but it will also induce changes to the contours of the APW . Following a sports concussion , a transient state cardiovascular autonomic dysfunction is present . How this state affects the APW has yet to be described . A prospect i ve , parallel-group study on cardiovascular autonomic control ( i.e. , digital electrocardiogram and continuous beat-to-beat blood pressure ) was performed in the seated upright position in 10 athletes with concussion and 7 non-injured control athletes .  Changes in APW were compared at rest and during the first 60 s ( F60 ) of an isometric h and grip test ( IHGT ) in concussed athletes and non-injured controls within 48 h and 1 week of injury . The concussion group was further separated by the length of time until they were permitted to return to play ( RTP > 1week ; RTP ≤ 1week ) . SysSlope , an indirect measurement of stroke volume , was significantly lower in the concussion group at rest and during F60 at 48 h and 1week ; a paradoxical decline in SysSlope occurred at each visit during the transition from rest to IHGT F60 . The RTP > 1week group had lower SysSlope ( 405 ± 200 ; 420 ± 88 ; 454 ± 236 mmHg/s , respectively ) at rest 48 h compared to the RTP ≤ 1week and controls . Similarly at 48 h rest , several measurements of arterial stiffness were abnormal in RTP > 1week compared to RTP ≤ 1week and controls : peak-to-notch latency ( 0.12 ± 0.04 ; 0.16 ± 0.02 ; 0.17 ± 0.05 , respectively ) , notch relative amplitude ( 0.70 ± 0.03 ; 0.71 ± 0.04 ; 0.66 ± 0.14 , respectively ) , and stiffness index ( 6.4 ± 0.2 ; 5.7 ± 0.4 ; 5.8 ± 0.5 , respectively ) . Use of APW revealed that concussed athletes have a transient increase in peripheral artery stiffness , which may be a compensatory adaptation to a paradoxical decline of stroke volume during the transition from rest to a state of increased metabolic dem and within 48 h of concussion . This dysfunction of the SNS appeared to be more pronounced among concussed athletes who were removed from participation for > 1 week compared to those who resumed play within 7 days Objective Increased awareness around neurocognitive deficits after mild traumatic brain injury ( mTBI ) has progressed the search for objective , diagnostic , and monitoring tools , yet imaging biomarkers for mTBI and recovery are not established in clinical use . It has been suggested that mTBI impairs cerebrovascular reactivity ( CVR ) to CO2 , which could be related to post-concussive syndrome ( PCS ) . We investigate CVR evolution after mTBI using blood-oxygen-level dependent ( BOLD ) magnetic resonance imaging ( MRI ) and possible correlation with PCS . Methods A prospect i ve cohort of 25 mTBI patients and 18 matched controls underwent BOLD MRI CVR measurements . A subset of 19 mTBI patients underwent follow-up testing . Visits took place at a mean of 63 and 180 days after injury . Symptoms were assessed with the  Sport Concussion Assessment Tool 2 ( SCAT2 ) . Symptoms , CVR and brain volume [ gray matter ( GM ) , white matter ( WM ) , and whole brain ( WB ) ] , age , and sex , were examined between groups and longitudinally within traumatic brain injury ( TBI ) patients . Results Traumatic brain injury participants were 72 % males , mean age being 42.7 years . Control participants were 61 % with mean age of 38.7 years .  SCAT2 scores tended to improve among those mTBI patients with follow-up visits ( p = 0.07 ) ; however , they did not tend to recover to scores of the healthy controls . Brain volumes were not statistically different between groups at the first visit ( WM p = 0.71 ; GM p = 0.36 ) . In mTBI patients , there was a reduction in GM volume between visits 1 and 2 ( p = 0.0046 ) . Although mean CVR indexes were similar ( WM p = 0.27 ; GM p = 0.36 ; and WB p = 0.35 ) , the correlation between SCAT2 and CVR was negative in controls ( WM-r = −0.59 ; p = 0.010 ; GM-r = −0.56 ; p = 0.016 ; brain-r = −0.58 ; p = 0.012 ) and weaker and positive in mTBI ( brain-r = 0.4 ; p = 0.046 ; GM-r = 0.4 ; p = 0.048 ) . SCAT2 correlated with GM volume ( r = 0.5215 , p = 0.0075 ) in mTBI but not in controls ( r = 0.2945 , p = 0.2355 ) . Conclusion There is a correlation between lower GM CVR indexes and lower performance on SCAT2 in patients with mTBI , which seems to be associated with more symptoms . This correlation seems to persist well beyond 120 days . mTBI may lead to a decrease in GM volume in these patients Background The on-field diagnosis of sports-related concussion ( SRC ) is complicated by the lack of an accurate and objective marker of brain injury . Purpose To compare subject-specific changes in the astroglial protein , S100B , before and after SRC among collegiate and semi-professional contact sport athletes , and compare these changes to differences in S100B before and after non-contact exertion . Study Design Longitudinal cohort study . Methods From 2009–2011 , we performed a prospect i ve study of athletes from Munich , Germany , and Rochester , New York , USA .  Serum S100B was measured in all SRC athletes at pre-season baseline , within 3 hours of injury , and at days 2 , 3 and 7 post-SRC . Among a subset of athletes , S100B was measured after non-contact exertion but before injury . All sample s were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels . Results Forty-six athletes ( 30 Munich , 16 Rochester ) underwent baseline testing . Thirty underwent additional post-exertion S100B testing . Twenty-two athletes ( 16 Rochester , 6 Munich ) sustained a SRC , and 17 had S100B testing within 3 hours post-injury . The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline ( 0.099±0.008 µg/L vs. 0.058±0.006 µg/L , p = 0.0002 ) . Mean post-exertion S100B was not significantly different than the preseason baseline . S100B levels at post-injury days 2 , 3 and 7 were significantly lower than the 3-hour level , and not different than baseline . Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC ( AUC 0.772 and 0.904 , respectively ) . A 3-hour post-concussion S100B > 0.122 µg/L and a proportional S100B increase of > 45.9 % over baseline were both 96.7 % specific for SRC . Conclusions Relative and absolute increases in serum S100B can accurately distinguish SRC from sports-related exertion , and may be a useful adjunct to the diagnosis of SRC Our aim was to quantify with functional magnetic resonance imaging ( fMRI ) changes in brain activity in concussed athletes and compare the results with those of normal control subjects . Regional brain activations associated with a working memory task were obtained from a group of concussed athletes ( 15 symptomatic , 1 asymptomatic ) and eight matched control subjects , using blood oxygen level dependent ( BOLD ) fMRI .  The average percent signal change from baseline to working memory condition in each region of interest was computed . Symptomatic concussed athletes demonstrated task-related activations in some but not all the regions of interest , even when they performed as well as the control subjects . Furthermore , several concussed athletes had additional increases in activity outside the regions of interest , not seen in the control group . Quantitative analysis of BOLD signals within regions of interest revealed that , in general , concussed athletes had different BOLD responses compared to the control subjects . The task-related activation pattern of the one symptom-free athlete was comparable to that of the control group . We also repeated the study in one athlete whose symptoms had resolved . On the first study , when he was still symptomatic , less task-related activations were observed . On follow-up , once his symptoms had disappeared , the task-related activations became comparable to those of the control group . These results demonstrate the potential of fMRI , in conjunction with the working memory task , to identify an underlying pathology in symptomatic concussed individuals with normal structural imaging results Impact-related mild traumatic brain injuries ( mTBI ) are a major public health concern , and remain as one of the most poorly understood injuries in the field of neuroscience . Currently , the diagnosis and management of such injuries are based largely on patient-reported symptoms . An improved underst and ing of the underlying pathophysiology of mTBI is urgently needed in order to develop better diagnostic and management protocol s. Specifically , dynamic post-injury changes to the myelin sheath in the human brain have not been examined , despite ‘ compromised white matter integrity ’ often being described as a consequence of mTBI . In this preliminary cohort study ,  myelin water imaging was used to prospect ively evaluate changes in myelin water fraction , derived from the T2 decay signal , in two varsity hockey teams ( 45 players ) over one season of athletic competition . 11 players sustained a concussion during competition , and were scanned at 72 hours , 2 weeks , and 2 months post-injury . Results demonstrated a reduction in myelin water fraction at 2 weeks post-injury in several brain areas relative to preseason scans , including the splenium of the corpus callosum , right posterior thalamic radiation , left superior corona radiata , left superior longitudinal fasciculus , and left posterior limb of the internal capsule . Myelin water fraction recovered to pre-season values by 2 months post-injury . These results may indicate transient myelin disruption following a single mTBI , with subsequent remyelination of affected neurons . Myelin disruption was not apparent in the athletes who did not experience a concussion , despite exposure to repetitive subconcussive trauma over a season of collegiate hockey . These findings may help to explain many of the metabolic and neurological deficits observed clinical ly following mTBI OBJECTIVE The relationship between athlete reports of symptoms , neurophysiological activation , and neuropsychological functioning is investigated in a sample of high school athletes . METHODS All athletes were evaluated using functional magnetic resonance imaging ( fMRI ) , a computer-based battery of neurocognitive tests , and a subjective symptom scale . Athletes were evaluated within approximately 1 week of injury and again after clinical recovery using all assessment modalities . RESULTS This study found that abnormal fMRI results during the first week of recovery predicted clinical recovery . As a group , athletes who demonstrated hyperactivation on fMRI scans at the time of their first fMRI scan demonstrated a more prolonged clinical recovery than athletes who did not demonstrate hyperactivation at the time of their first fMRI scan . CONCLUSION These results demonstrate the relationship between neurophysiological , neuropsychological , and subjective symptom data in a relatively large sample composed primarily of concussed high school athletes .  fMRI represents an important evolving technology for the underst and ing of brain recovery after concussion and may help shape return-to-play guidelines in the future CONTEXT The known detrimental effects of sport concussions on motor system function include balance problems , slowed motor execution , and abnormal motor cortex excitability . OBJECTIVE To assess whether these concussion-related alterations of motor system function are still evident in collegiate football players who sustained concussions but returned to competition more than 9 months before testing . DESIGN Case-control study . SETTING University laboratory . PATIENTS OR OTHER PARTICIPANTS A group of 21 active , university-level football players who had experienced concussions was compared with 15 university football players who had not sustained concussions . INTERVENTION(S ) A force platform was used to assess center-of-pressure ( COP ) displacement and COP oscillation regularity ( approximate entropy ) as measures of postural stability in the upright position . A rapid alternating-movement task was also used to assess motor execution speed . Transcranial magnetic stimulation over the motor cortex was used to measure long-interval intracortical inhibition and the cortical silent period , presumably reflecting y-aminobutyric acid subtype B receptor-mediated intracortical inhibition . MAIN OUTCOME MEASURE(S ) COP displacement and oscillation regularity , motor execution speed , long-interval intracortical inhibition , cortical silent period . RESULTS Relative to controls , previously concussed athletes showed persistently lower COP oscillation r and omness , normal performance on a rapid alternating-movement task , and more M1 intracortical inhibition that was related to the number of previous concussions . CONCLUSIONS Sport concussions were associated with pervasive changes in postural control and more M1 intracortical inhibition , providing neurophysiologic and behavioral evidence of lasting , sub clinical changes in motor system integrity in concussed athletes Objective To investigate the clinical utility and sensitivity of a portable , automatic , frontal quantitative electroencephalographic ( QEEG ) acquisition device currently in development in detecting abnormal brain electrical activity after sport-related concussion . Design This was a prospect i ve , non-r and omized study of 396 high school and college football players , including cohorts of 28 athletes with concussion and 28 matched controls . All subjects underwent preseason baseline testing on measures of postconcussive symptoms , postural stability , and cognitive functioning , as well as QEEG . Clinical testing and QEEG were repeated on day of injury and days 8 and 45 postinjury for the concussion and control groups . Main Outcomes and Results The injured group reported more significant postconcussive symptoms during the first 3 days postinjury , which resolved by days 5 and 8 . Injured subjects also performed poorer than controls on neurocognitive testing on the day of injury , but no differences were evident on day 8 or day 45 . QEEG studies revealed significant abnormalities in electrical brain activity in the injured group on day of injury and day 8 postinjury , but not on day 45 . Conclusions Results from the current study on clinical recovery after sport-related concussion are consistent with early reports indicating a typical course of full recovery in symptoms and cognitive dysfunction within the first week of injury . QEEG results , however , suggest that the duration of physiological recovery after concussion may extend longer than observed clinical recovery . Further study is required to replicate and extend these findings in a larger clinical sample , and further demonstrate the utility of QEEG as a marker of recovery after sport-related concussion OBJECT Mild traumatic brain injury ( MTBI ) , often referred to as concussion when it occurs in sports , produces persistent cognitive problems in at least 15 % of patients . Unfortunately , conventional neuropsychological tests usually yield results within normal limits in this population . The main objective of this event-related potential ( ERP ) study was to underst and brain functioning during the performance of a working memory ( WM ) task in patients who have sustained an MTBI , mostly due to motor vehicle accident or sports concussion . This study also aim ed for a better underst and ing of the association between brain functioning as measured with ERP , behavioral performance on the WM task , postconcussion symptoms , type of injury ( that is , sports concussion vs other types ) , and time since the injury . METHODS Forty-four patients with MTBI ( 7.6 ± 8.4 months postinjury ) were tested on a visual WM task with simultaneous recording of ERP , and were compared with 40 control volunteers who were their equivalent for age and sex . Amplitude and latency of frontal ( N200 and N350 ) and parietal ( P200 and P300 ) ERP waves were measured and were compared between groups . Correlation analyses were also performed between ERP characteristics , clinical variables , and behavioral performance . RESULTS A significant group difference was found for behavioral performance on the WM task , in which the MTBI group had a lower percentage of correct answers than the control group ( p < 0.05 ) . The patients with MTBI also had smaller amplitudes of both frontal N350 and parietal P300 ERP components when compared with control volunteers ( p < 0.05 ) . No changes were found for latency of ERP components . Smaller ERP amplitudes were associated with slower reaction times and worse accuracy on the WM task among patients with MTBI ( p < 0.05 ) . Types of injury ( that is , sports concussion vs other mechanisms ) were not associated with different ERP characteristics . CONCLUSIONS Abnormal ERP results are observed in patients after MTBI or sports concussion , even for those in the nonacute stage after their injury . Current st and ard clinical evaluations most often fail to detect cerebral dysfunction after MTBI , even when patients or athletes report symptoms . Clinicians should be aware that patients with MTBI , including sports concussion , probably have underlying mild but persistent cerebral dysfunctions that require further investigation Objective : To examine functional brain activation patterns before and after postconcussive symptoms ( PCS ) resolution . Design : Prospect i ve serial study with male athletes using functional magnetic resonance imaging ( fMRI ) . Setting : Hospital laboratory and imaging facility . Participants : 9 symptomatic concussed athletes who experienced persisting PCS at least 1 month postinjury and 6 healthy athletes . Interventions : All athletes filled out a PCS checklist and underwent an fMRI session during which they performed a working-memory task . Main outcome measurements : Behavioral outcomes were response speed and accuracy on the working memory tasks performed during the fMRI session . Functional imaging outcomes were blood oxygen level-dependent fMRI activation patterns associated with a working memory task . Results : There was no difference in behavioral performance between the groups . Despite normal structural MRI findings , all symptomatic concussed athletes initially showed atypical brain activation patterns in the dorsolateral prefrontal cortex ( DLPC ) . Compared to the initial postinjury evaluation , those athletes at follow-up with PCS resolved showed significant increases in activation in the left DLPC . Concussed athletes whose PCS status remained unchanged at follow-up continued to show atypical activation in DLPC . Healthy athletes showed remarkably clear and consistent brain activations in DLPC initially as well as in follow-up , highlighting the test-retest reliability of fMRI . Conclusions : The results demonstrate the feasibility of using fMRI to detect an underlying pathology in symptomatic concussed athletes with normal structural imaging results and its potential to document recovery . Such information may be of considerable value for clinical judgment and patient management Objective : To evaluate a grade d treadmill test for retest reliability ( RTR ) and interrater reliability ( IRR ) in the evaluation of the physiologic effects of symptom exacerbation from concussion . Design : Prospect i ve case series ( RTR ) and blinded rater assessment of 10 actors portraying patients with and without symptom exacerbation ( IRR ) . Setting : University Sports Medicine Concussion Clinic . Participants : For RTR , 21 refractory concussed patients ( 11 athletes and 10 nonathletes ) and 10 healthy subjects ; for IRR , 32 raters representing a variety of health care disciplines . Intervention : For RTR , a Balke protocol treadmill test to symptom exacerbation before and after 2 to 3 weeks . For IRR , video recordings of actors during the treadmill test viewed by raters blinded to condition . Main Outcome Measures : For RTR , agreement of the tests for maximal heart rate ( HR ) , systolic blood pressure , diastolic blood pressure , and rating of perceived exertion . For IRR , presence or absence of symptom exacerbation and the symptom exacerbation HR . Results : Raters achieved a sensitivity of 99 % for identifying actors with symptom exacerbation and a specificity of 89 % for ruling out concussion symptoms and agreed on 304 of 320 observations ( accuracy of 95 % ) . The intraclass correlation coefficient for the symptom exacerbation HR was large at 0.90 ( 95 % confidence interval , 0.78 - 0.98 ) . The treadmill test had good RTR for maximum HR ( intraclass correlation coefficient , 0.79 ) but not for systolic blood pressure , diastolic blood pressure , or rating of perceived exertion . Conclusions : The Balke exercise treadmill protocol has very good IRR and sufficient RTR for identifying patients with symptom exacerbation from concussion OBJECT A neuroimaging assessment tool to visualize global and regional impairments in cerebral blood flow ( CBF ) and cerebrovascular responsiveness in individual patients with concussion remains elusive . Here the authors summarize the safety , feasibility , and results of brain CO2 stress testing in adolescents with postconcussion syndrome ( PCS ) and healthy controls . METHODS This study was approved by the Biomedical Research Ethics Board at the University of Manitoba . Fifteen adolescents with PCS and 17 healthy control subjects underwent anatomical MRI , pseudo-continuous arterial spin labeling MRI , and brain stress testing using controlled CO2 challenge and blood oxygen level-dependent ( BOLD ) MRI . Post hoc processing was performed using statistical parametric mapping to determine voxel-by-voxel regional resting CBF and cerebrovascular responsiveness of the brain to the CO2 stimulus ( increase in BOLD signal ) or the inverse ( decrease in BOLD signal ) . Receiver operating characteristic ( ROC ) curves were generated to compare voxel counts categorized by control ( 0 ) or PCS ( 1 ) . RESULTS Studies were well tolerated without any serious adverse events . Anatomical MRI was normal in all study participants . No differences in CO2 stimuli were seen between the 2 participant groups . No group differences in global mean CBF were detected between PCS patients and healthy controls . Patient-specific differences in mean regional CBF and CO2 BOLD responsiveness were observed in all PCS patients . The ROC curve analysis for brain regions manifesting a voxel response greater than and less than the control atlas ( that is , abnormal voxel counts ) produced an area under the curve of 0.87 ( p < 0.0001 ) and 0.80 ( p = 0.0003 ) , respectively , consistent with a clinical ly useful predictive model . CONCLUSIONS Adolescent PCS is associated with patient-specific abnormalities in regional mean CBF and BOLD cerebrovascular responsiveness that occur in the setting of normal global resting CBF . Future prospect i ve studies are warranted to examine the utility of brain MRI CO2 stress testing in the longitudinal assessment of acute sports-related concussion and PCS The diagnosis of sports-related concussion is mainly based on subjective clinical symptoms and neuropsychological tests . Therefore , reliable brain injury biomarkers to assess when it is safe to return to play are highly desirable . The overall objective of this study was to evaluate the utility of two newly described tau fragments for diagnosis and prognosis of sports-related concussions . This multi-center prospect i ve cohort study involved all 12 teams of the top professional ice hockey league in Sweden . A total of 288 players consented to participate in the study . Thirty-five players sustained concussions , of whom 28 underwent repeated blood samplings at 1 , 12 , 36 , and 144 h after the trauma , or when the player returned to play ( 7 to > 90 days ) . There was no significant increase in the levels of Tau-A in post-concussion sample s compared with preseason values . However , serum levels of Tau-C were significantly higher in post-concussion sample s compared with preseason . Further , levels of Tau-A correlated with the duration of post-concussive symptoms . Tau-A in serum , which is newly discovered biomarker , could be used to predict when it is safe to return to play after a sports-related concussion IMPORTANCE Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion . OBJECTIVES To determine whether sports-related concussion is associated with elevated levels of blood biochemical markers of injury to the central nervous system and to assess whether plasma levels of these biomarkers predict return to play in professional ice hockey players with sports-related concussion . DESIGN , SETTING , AND PARTICIPANTS Multicenter prospect i ve cohort study involving all 12 teams of the top professional ice hockey league in Sweden , the Swedish Hockey League . Two hundred eighty-eight professional ice hockey players from 12 teams contesting during the 2012 - 2013 season consented to participate . All players underwent clinical preseason baseline testing regarding concussion assessment measures . Forty-seven players from 2 of the 12 ice hockey teams underwent blood sampling prior to the start of the season . Thirty-five players had a concussion from September 13 , 2012 , to January 31 , 2013 ; of these players , 28 underwent repeated blood sampling at 1 , 12 , 36 , and 144 hours and when the players returned to play . MAIN OUTCOMES AND MEASURES Total tau , S-100 calcium-binding protein B , and neuron-specific enolase concentrations in plasma and serum were measured . RESULTS Concussed players had increased levels of the axonal injury biomarker total tau(median , 10.0 pg/mL ; range , 2.0 - 102 pg/mL ) compared with preseason values ( median , 4.5pg/mL ; range , 0.06 - 22.7 pg/mL ) ( P < .001 ) . The levels of the astroglial injury biomarker S-100 calcium-binding protein B were also increased in players with sports-related concussion(median , 0.075 μg/L ; range , 0.037 - 0.24 μg/L ) compared with preseason values ( median,0.045 μg/L ; range , 0.005 - 0.45 μg/L ) ( P < .001 ) . The highest biomarker concentrations of total tau and S-100 calcium-binding protein B were measured immediately after a concussion , and they decreased during rehabilitation . No significant changes were detected in the levels of neuron-specific enolase from preseason values ( median , 6.5 μg/L ; range,3.45 - 18.0 μg/L ) to postconcussion values ( median , 6.1 μg/L ; range , 3.6 - 12.8 μg/L ) ( P = .10 ) . CONCLUSIONS AND RELEVANCE Sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury . This can be monitored using blood biomarkers , which may be developed into clinical tools to guide sport physicians in the medical counseling of athletes in return-to-play decisions IMPORTANCE Animal models suggest that reduced cerebral blood flow ( CBF ) is one of the most enduring physiological deficits following concussion . Despite this , longitudinal studies documenting serial changes in regional CBF following human concussion have yet to be performed . OBJECTIVE To longitudinally assess the recovery of CBF in a carefully selected sample of collegiate athletes and compare time course of CBF recovery with that of cognitive and behavioral symptoms . DESIGN , SETTING , AND PARTICIPANTS A cohort of collegiate football athletes ( N = 44 ) participated in this mixed longitudinal and cross-sectional study at a private research institute specializing in neuroimaging between March 2012 and December 2013 .  Serial imaging occurred approximately 1 day , 1 week , and 1 month postconcussion for a subset of participants ( n = 17 ) . All athletes reported no premorbid mood disorders , anxiety disorders , substance abuse , or alcohol abuse . MAIN OUTCOMES AND MEASURES  Arterial spin labeling magnetic resonance imaging  was used to collect voxelwise relative CBF at each visit . Neuropsychiatric evaluations and a brief cognitive screen  were also performed at all 3 points . Clinicians trained in sports medicine provided an independent measure of real-world concussion outcome ( ie , number of days withheld from competition ) . RESULTS The results indicated both cognitive ( simple reaction time ) and neuropsychiatric symptoms at 1 day postinjury that resolved at either 1 week ( cognitive ; P < .005 ) or 1 month ( neuropsychiatric ; P < .005 ) postinjury . Imaging data suggested both cross-sectional ( ie , healthy vs concussed athletes ; P < .05 ) and longitudinal ( 1 day and 1 week vs 1 month postinjury ; P < .001 ) evidence of CBF recovery in the right insular and superior temporal cortex . Importantly , CBF in the dorsal midinsular cortex was both decreased at 1 month postconcussion in slower-to-recover athletes ( t11 = 3.45 ; P = .005 ) and was inversely related to the magnitude of initial psychiatric symptoms ( Hamilton Depression Scale : r = -0.64 , P = .02 ; Hamilton Anxiety Scale : r = -0.56 , P = .046 ) , suggesting a potential prognostic indication for CBF as a biomarker . CONCLUSIONS AND RELEVANCE To our knowledge , these results provide the first prospect i ve evidence of reduced CBF in human concussion and subsequent recovery . The resolution of CBF abnormalities closely mirrors previous reports from the animal literature and show real-world validity for predicting outcome following concussion
target: Due to differences in modalities , time course , study design and outcomes , it is not possible to define a single ‘ physiological time window ’ for SRC recovery .
  Multiple studies suggest physiological dysfunction may outlast current clinical measures of recovery , supporting a buffer zone of gradually increasing activity before full contact risk .
background: Aim or objective The aim of this study is to consoli date studies of physiological measures following sport-related concussion ( SRC ) to determine if a time course of postinjury altered neurobiology can be outlined .
  This biological time course was considered with respect to clinical ly relevant outcomes such as vulnerability to repeat injury and safe timing of return to physical contact risk .