Browsing by Author "Duma, Stefan M."
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Item Acute White-Matter Abnormalities in Sports-Related Concussion: A Diffusion Tensor Imaging Study from the NCAA-DoD CARE Consortium(Mary Ann Liebert, 2018-11-15) Mustafi, Sourajit Mitra; Harezlak, Jaroslaw; Koch, Kevin M.; Nencka, Andrew S.; Meier, Timothy B.; West, John D.; Giza, Christopher C.; DiFiori, John P.; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; Saykin, Andrew J.; McCrea, Michael; McAllister, Thomas W.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of MedicineSports-related concussion (SRC) is an important public health issue. Although standardized assessment tools are useful in the clinical management of acute concussion, the underlying pathophysiology of SRC and the time course of physiological recovery after injury remain unclear. In this study, we used diffusion tensor imaging (DTI) to detect white matter alterations in football players within 48 h after SRC. As part of the NCAA-DoD CARE Consortium study of SRC, 30 American football players diagnosed with acute concussion and 28 matched controls received clinical assessments and underwent advanced magnetic resonance imaging scans. To avoid selection bias and partial volume effects, whole-brain skeletonized white matter was examined by tract-based spatial statistics to investigate between-group differences in DTI metrics and their associations with clinical outcome measures. Mean diffusivity was significantly higher in brain white matter of concussed athletes, particularly in frontal and subfrontal long white matter tracts. In the concussed group, axial diffusivity was significantly correlated with the Brief Symptom Inventory and there was a similar trend with the symptom severity score of the Sport Concussion Assessment Tool. In addition, concussed athletes with higher fractional anisotropy performed better on the cognitive component of the Standardized Assessment of Concussion. Overall, the results of this study are consistent with the hypothesis that SRC is associated with changes in white matter tracts shortly after injury, and these differences are correlated clinically with acute symptoms and functional impairments.Item The Association Between Persistent White-Matter Abnormalities and Repeat Injury After Sport-Related Concussion(Frontiers Media, 2020-01-21) Brett, Benjamin L.; Wu, Yu-Chien; Mustafi, Sourajit M.; Saykin, Andrew J.; Koch, Kevin M.; Nencka, Andrew S.; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; Duma, Stefan M.; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael A.; Meier, Timothy B.; Radiology and Imaging Sciences, School of MedicineObjective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion. Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (<48 h), at an asymptomatic time point, 7 days post-return to play (RTP), and 6 months relative to controls (n = 69). The relationship between MD in the identified ROI and likelihood of sustaining a subsequent concussion over a 1-year period was examined with a binary logistic regression (re-injured, yes/no). Results: Eleven of 82 concussed athletes (13.4%) sustained a second concussion within 12 months of initial injury. Mean MD at 7 days post-RTP was significantly higher in those athletes who went on to sustain a repeat concussion within 1 year of initial injury than those who did not (p = 0.048; d = 0.75). In this underpowered sample, the relationship between MD at 7 days post-RTP and likelihood of sustaining a secondary injury approached significance [χ2 (1) = 4.17, p = 0.057; B = 0.03, SE = 0.017; OR = 1.03, CI = 0.99, 1.07]. Conclusions: These preliminary findings raise the hypothesis that persistent signal abnormalities in diffusion imaging metrics at RTP following concussion may be predictive of a repeat concussion. This may reflect a window of cerebral vulnerability or increased susceptibility following concussion, though understanding the clinical significance of these findings requires further study.Item Bifactor Model of the Sport Concussion Assessment Tool Symptom Checklist: Replication and Invariance Across Time in the CARE Consortium Sample(Sage, 2020-09) Brett, Benjamin L.; Kramer, Mark D.; McCrea, Michael A.; Broglio, Steven P.; McAllister, Thomas; Nelson, Lindsay D.; Hazzard, Joseph B., Jr.; Kelly, Louise A.; Ortega, Justus; Port, Nicholas; Pasquina, Paul F.; Jackson, Jonathan; Cameron, Kenneth L.; Houston, Megan N.; Goldman, Joshua T.; Giza, Christopher; Buckley, Thomas; Clugston, James R.; Schmidt, Julianne D.; Feigenbaum, Luis A.; Eckner, James T.; Master, Christina L.; Collins, Michael W.; Kontos, Anthony P.; Chrisman, Sara P.D.; Duma, Stefan M.; Miles, Christopher M.; Susmarski, Adam; Psychiatry, School of MedicineBackground: Identifying separate dimensions of concussion symptoms may inform a precision medicine approach to treatment. It was previously reported that a bifactor model identified distinct acute postconcussion symptom dimensions. Purpose: To replicate previous findings of a bifactor structure of concussion symptoms in the Concussion Assessment Research and Education (CARE) Consortium sample, examine measurement invariance from pre- to postinjury, and evaluate whether factors are associated with other clinical and biomarker measures. Study design: Cohort study (Diagnosis); Level of evidence, 2. Methods: Collegiate athletes were prospectively evaluated using the Sport Concussion Assessment Tool-3 (SCAT-3) during preseason (N = 31,557); 2789 were followed at <6 hours and 24 to 48 hours after concussion. Item-level SCAT-3 ratings were analyzed using exploratory and confirmatory factor analyses. Bifactor and higher-order models were compared for their fit and interpretability. Measurement invariance tested the stability of the identified factor structure across time. The association between factors and criterion measures (clinical and blood-based markers of concussion severity, symptom duration) was evaluated. Results: The optimal structure for each time point was a 7-factor bifactor model: a General factor, on which all items loaded, and 6 specific factors-Vestibulo-ocular, Headache, Sensory, Fatigue, Cognitive, and Emotional. The model manifested strict invariance across the 2 postinjury time points but only configural invariance from baseline to postinjury. From <6 to 24-48 hours, some dimensions increased in severity (Sensory, Fatigue, Emotional), while others decreased (General, Headache, Vestibulo-ocular). The factors correlated with differing clinical and biomarker criterion measures and showed differing patterns of association with symptom duration at different time points. Conclusion: Bifactor modeling supported the predominant unidimensionality of concussion symptoms while revealing multidimensional properties, including a large dominant General factor and 6 independent factors: Headache, Vestibulo-ocular, Sensory, Cognitive, Fatigue, and Emotional. Unlike the widely used SCAT-3 symptom severity score, which declines gradually after injury, the bifactor model revealed separable symptom dimensions that have distinct trajectories in the acute postinjury period and different patterns of association with other markers of injury severity and outcome. Clinical relevance: The SCAT-3 total score remains a valuable, robust index of overall concussion symptom severity, and the specific factors identified may inform management strategies. Because some symptom dimensions continue to worsen in the first 24 to 48 hours after injury (ie, Sensory, Fatigue, Emotional), routine follow-up in this time frame may be valuable to ensure that symptoms are managed effectively.Item Comparison of Head Impact Exposure Between Concussed Football Athletes and Matched Controls: Evidence for a Possible Second Mechanism of Sport-Related Concussion(Springer, 2018) Stemper, Brian D.; Shah, Alok S.; Harezlak, Jaroslaw; Rowson, Steven; Mihalik, Jason P.; Duma, Stefan M.; Riggen, Larry D.; Brooks, Alison; Cameron, Kenneth L.; Campbell, Darren; DiFiori, John P.; Giza, Christopher C.; Guskiewicz, Kevin M.; Jackson, Jonathan; McGinty, Gerald T.; Svoboda, Steven J.; McAllister, Thomas W.; Broglio, Steven P.; McCrea, Michael; Psychiatry, School of MedicineStudies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.Item Effects of White-Matter Tract Length in Sport-Related Concussion: A Tractography Study from the NCAA-DoD CARE Consortium(Mary Ann Liebert, Inc., 2022-11) Mustafi, Sourajit M.; Yang, Ho-Ching; Harezlak, Jaroslaw; Meier, Timothy B.; Brett, Benjamin L.; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; McCrea, Michael A.; McAllister, Thomas W.; Wu, Yu-Chien; Psychiatry, School of MedicineSport-related concussion (SRC) is an important public health issue. White-matter alterations after SRC are widely studied by neuroimaging approaches, such as diffusion magnetic resonance imaging (MRI). Although the exact anatomical location of the alterations may differ, significant white-matter alterations are commonly observed in long fiber tracts, but are never proven. In the present study, we performed streamline tractography to characterize the association between tract length and white-matter microstructural alterations after SRC. Sixty-eight collegiate athletes diagnosed with acute concussion (24–48 h post-injury) and 64 matched contact-sport controls were included in this study. The athletes underwent diffusion tensor imaging (DTI) in 3.0 T MRI scanners across three study sites. DTI metrics were used for tract-based spatial statistics to map white-matter regions-of-interest (ROIs) with significant group differences. Whole-brain white-mater streamline tractography was performed to extract “affected” white-matter streamlines (i.e., streamlines passing through the identified ROIs). In the concussed athletes, streamline counts and DTI metrics of the affected white-matter fiber tracts were summarized and compared with unaffected white-matter tracts across tract length in the same participant. The affected white-matter tracts had a high streamline count at length of 80–100 mm and high length-adjusted affected ratio for streamline length longer than 80 mm. DTI mean diffusivity was higher in the affected streamlines longer than 100 mm with significant associations with the Brief Symptom Inventory score. Our findings suggest that long fibers in the brains of collegiate athletes are more vulnerable to acute SRC with higher mean diffusivity and a higher affected ratio compared with the whole distribution.Item Effects of White-Matter Tract Length in Sport-Related Concussion: A Tractography Study from the NCAA-DoD CARE Consortium(Mary Ann Liebert, 2022) Mustafi, Sourajit M.; Yang, Ho-Ching; Harezlak, Jaroslaw; Meier, Timothy B.; Brett, Benjamin L.; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; McCrea, Michael A.; McAllister, Thomas W.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of MedicineSport-related concussion (SRC) is an important public health issue. White-matter alterations after SRC are widely studied by neuroimaging approaches, such as diffusion magnetic resonance imaging (MRI). Although the exact anatomical location of the alterations may differ, significant white-matter alterations are commonly observed in long fiber tracts, but are never proven. In the present study, we performed streamline tractography to characterize the association between tract length and white-matter microstructural alterations after SRC. Sixty-eight collegiate athletes diagnosed with acute concussion (24–48 h post-injury) and 64 matched contact-sport controls were included in this study. The athletes underwent diffusion tensor imaging (DTI) in 3.0 T MRI scanners across three study sites. DTI metrics were used for tract-based spatial statistics to map white-matter regions-of-interest (ROIs) with significant group differences. Whole-brain white-mater streamline tractography was performed to extract “affected” white-matter streamlines (i.e., streamlines passing through the identified ROIs). In the concussed athletes, streamline counts and DTI metrics of the affected white-matter fiber tracts were summarized and compared with unaffected white-matter tracts across tract length in the same participant. The affected white-matter tracts had a high streamline count at length of 80–100 mm and high length-adjusted affected ratio for streamline length longer than 80 mm. DTI mean diffusivity was higher in the affected streamlines longer than 100 mm with significant associations with the Brief Symptom Inventory score. Our findings suggest that long fibers in the brains of collegiate athletes are more vulnerable to acute SRC with higher mean diffusivity and a higher affected ratio compared with the whole distribution.Item Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study(Springer Nature, 2024-04) Simpson, Edward; Reiter, Jill L.; Ren, Jie; Zhang, Zhiqi; Nudelman, Kelly N.; Riggen, Larry D., Jr.; Menser, Michael D.; Harezlak, Jaroslaw; Foroud, Tatiana M.; Saykin, Andrew J.; Brooks, Alison; Cameron, Kenneth L.; Duma, Stefan M.; McGinty, Gerald; Rowson, Steven; Svoboda, Steven J.; Broglio, Steven P.; McCrea, Michael A.; Pasquina, Paul F.; McAllister, Thomas W.; Liu, Yunlong; CARE Consortium Investigators; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. Objective The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. Methods We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. Results Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. Conclusions Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.Item Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion(Wolters Kluwer, 2023) Wu, Yu-Chien; Wen, Qiuting; Thukral, Rhea; Yang, Ho-Ching; Gill, Jessica M.; Gao, Sujuan; Lane, Kathleen A.; Meier, Timothy B.; Riggen, Larry D.; Harezlak, Jaroslaw; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; Saykin, Andrew J.; Walker McAllister, Thomas; McCrea, Michael A.; Radiology and Imaging Sciences, School of MedicineBackground and objectives: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. Methods: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. Results: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (β = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (β = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|β|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (βs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. Discussion: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.Item Longitudinal white-matter abnormalities in sports-related concussion: A diffusion MRI study(Wolters Kluwer, 2020-08) Wu, Yu-Chien; Harezlak, Jaroslaw; Elsaid, Nahla M. H.; Lin, Zikai; Wen, Qiuting; Mustafi, Sourajit M.; Riggen, Larry D.; Koch, Kevin M.; Nencka, Andrew S.; Meier, Timothy B.; Mayer, Andrew R.; Wang, Yang; Giza, Christopher C.; DiFiori, John P.; Guskiewicz, Kevin M.; Mihalik, Jason P.; LaConte, Stephen M.; Duma, Stefan M.; Broglio, Steven P.; Saykin, Andrew J.; McCrea, Michael A.; McAllister, Thomas W.; Radiology and Imaging Sciences, School of MedicineObjective To study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC. Methods Collegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non–contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time. Results In the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non–contact-sport controls. Conclusions Changes in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery timeItem Prevalence of Potentially Clinically Significant Magnetic Resonance Imaging Findings in Athletes with and without Sport-Related Concussion(Mary Ann Liebert, 2019-05-22) Klein, Andrew P.; Tetzlaff, Julie E.; Bonis, Joshua M.; Nelson, Lindsay D.; Mayer, Andrew R.; Huber, Daniel L.; Harezlak, Jaroslaw; Mathews, Vincent P.; Ulmer, John L.; Sinson, Grant P.; Nencka, Andrew S.; Koch, Kevin M.; Wu, Yu-Chien; Saykin, Andrew J.; DiFiori, John P.; Giza, Christopher C.; Goldman, Joshua; Guskiewicz, Kevin M.; Mihalik, Jason P.; Duma, Stefan M.; Rowson, Steven; Brooks, Alison; Broglio, Steven P.; McAllister, Thomas; McCrea, Michael A.; Meier, Timothy B.; Radiology and Imaging Sciences, School of MedicinePrevious studies have shown that mild traumatic brain injury (mTBI) can cause abnormalities in clinically relevant magnetic resonance imaging (MRI) sequences. No large-scale study, however, has prospectively assessed this in athletes with sport-related concussion (SRC). The aim of the current study was to characterize and compare the prevalence of acute, trauma-related MRI findings and clinically significant, non-specific MRI findings in athletes with and without SRC. College and high-school athletes were prospectively enrolled and participated in scanning sessions between January 2015 through August 2017. Concussed contact sport athletes (n = 138; 14 female [F]; 19.5 ± 1.6 years) completed up to four scanning sessions after SRC. Non-concussed contact (n = 135; 15 F; 19.7 ± 1.6) and non-contact athletes (n = 96; 15 F; 20.0 ± 1.7) completed similar scanning sessions and served as controls. Board-certified neuroradiologists, blinded to SRC status, reviewed T1-weighted and T2-weighted fluid-attenuated inversion recovery and T2*-weighted and T2-weighted images for acute (i.e., injury-related) or non-acute findings that prompted recommendation for clinical follow-up. Concussed athletes were more likely to have MRI findings relative to contact (30.4% vs. 15.6%; odds ratio [OR] = 2.32; p = 0.01) and non-contact control athletes (19.8%; OR = 2.11; p = 0.04). Female athletes were more likely to have MRI findings than males (43.2% vs. 19.4%; OR = 2.62; p = 0.01). One athlete with SRC had an acute, injury-related finding; group differences were largely driven by increased rate of non-specific white matter hyperintensities in concussed athletes. This prospective, large-scale study demonstrates that <1% of SRCs are associated with acute injury findings on qualitative structural MRI, providing empirical support for clinical guidelines that do not recommend use of MRI after SRC.