Browsing by Subject "Mild traumatic brain injury"
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Item Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary(MDPI, 2023-08-21) Pankatz, Lara; Rojczyk, Philine; Seitz-Holland, Johanna; Bouix, Sylvain; Jung, Leonard B.; Wiegand, Tim L. T.; Bonke, Elena M.; Sollmann, Nico; Kaufmann, Elisabeth; Carrington, Holly; Puri, Twishi; Rathi, Yogesh; Coleman, Michael J.; Pasternak, Ofer; George, Mark S.; McAllister, Thomas W.; Zafonte, Ross; Stein, Murray B.; Marx, Christine E.; Shenton, Martha E.; Koerte, Inga K.; Psychiatry, School of MedicineThe gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.Item Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium(Elsevier, 2023) Vorn, Rany; Devoto, Christina; Meier, Timothy B.; Lai, Chen; Yun, Sijung; Broglio, Steven P.; Mithani, Sara; McAllister, Thomas W.; Giza, Christopher C.; Kim, Hyung-Suk; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin M.; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; McCrea, Michael A.; Gill, Jessica M.; CARE Consortium Investigators; Psychiatry, School of MedicineBackground: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. Methods: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. Results: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. Conclusion: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.Item Clinical Reaction-Time Performance Factors in Healthy Collegiate Athletes(Allen Press, 2020-06-23) Caccese, Jaclyn B.; Eckner, James T.; Franco-MacKendrick, Lea; Hazzard, Joseph B.; Ni, Meng; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael; Buckley, Thomas A.; Psychiatry, School of MedicineContext: In the absence of baseline testing, normative data may be used to interpret postconcussion scores on the clinical reaction-time test (RTclin). However, to provide normative data, we must understand the performance factors associated with baseline testing. Objective: To explore performance factors associated with baseline RTclin from among candidate variables representing demographics, medical and concussion history, self-reported symptoms, sleep, and sport-related features. Design: Cross-sectional study. Setting: Clinical setting (eg, athletic training room). Patients or other participants: A total of 2584 National Collegiate Athletic Association student-athletes (n = 1206 females [47%], 1377 males [53%], and 1 unreported (<0.1%); mass = 76.7 ± 18.7 kg; height = 176.7 ± 11.3 cm; age = 19.0 ± 1.3 years) from 3 institutions participated in this study as part of the Concussion Assessment, Research and Education Consortium. Main outcome measure(s): Potential performance factors were sex; race; ethnicity; dominant hand; sport type; number of prior concussions; presence of anxiety, learning disability, attention-deficit disorder or attention-deficit/hyperactivity disorder, depression, or migraine headache; self-reported sleep the night before the test; mass; height; age; total number of symptoms; and total symptom burden at baseline. The primary study outcome measure was mean baseline RTclin. Results: The overall RTclin was 202.0 ± 25.0 milliseconds. Female sex (parameter estimate [B] = 8.6 milliseconds, P < .001, Cohen d = 0.54 relative to male sex), black or African American race (B = 5.3 milliseconds, P = .001, Cohen d = 0.08 relative to white race), and limited-contact (B = 4.2 milliseconds, P < .001, Cohen d = 0.30 relative to contact) or noncontact (B = 5.9 milliseconds, P < .001, Cohen d = 0.38 relative to contact) sport participation were associated with slower RTclin. Being taller was associated with a faster RTclin, although this association was weak (B = -0.7 milliseconds, P < .001). No other predictors were significant. When adjustments are made for sex and sport type, the following normative data may be considered (mean ± standard deviation): female, noncontact (211.5 ± 25.8 milliseconds), limited contact (212.1 ± 24.3 milliseconds), contact (203.7 ± 21.5 milliseconds); male, noncontact (199.4 ± 26.7 milliseconds), limited contact (196.3 ± 23.9 milliseconds), contact (195.0 ± 23.8 milliseconds). Conclusions: Potentially clinically relevant differences existed in RTclin for sex and sport type. These results provide normative data adjusting for these performance factors.Item Concussion-Recovery Trajectories Among Tactical Athletes: Results From the CARE Consortium(Allen Press, 2020-07) Van Pelt, Kathryn L.; Allred, C. Dain; Brodeur, Rachel; Cameron, Kenneth L.; Campbell, Darren E.; D’Lauro, Christopher J.; He, Xuming; Houston, Megan N.; Johnson, Brian R.; Kelly, Tim F.; McGinty, Gerald; Meehan, Sean K.; O’Donnell, Patrick G.; Peck, Karen Y.; Svoboda, Steven J.; Pasquina, Paul; McAllister, Thomas; McCrea, Michael; Broglio, Steven P.; Psychiatry, School of MedicineContext: Assessments of the duration of concussion recovery have primarily been limited to sport-related concussions and male contact sports. Furthermore, whereas durations of symptoms and return-to-activity (RTA) protocols encompass total recovery, the trajectory of each duration has not been examined separately. Objective: To identify individual (eg, demographics, medical history), initial concussion injury (eg, symptoms), and external (eg, site) factors associated with symptom duration and RTA-protocol duration after concussion. Design: Cohort study. Setting: Three US military service academies. Patients or other participants: A total of 10 604 cadets at participating US military service academies enrolled in the study and completed a baseline evaluation and up to 5 postinjury evaluations. A total of 726 cadets (451 men, 275 women) sustained concussions during the study period. Main outcome measure(s): Number of days from injury (1) until the participant became asymptomatic and (2) to complete the RTA protocol. Results: Varsity athlete cadets took less time than nonvarsity cadets to become asymptomatic (hazard ratio [HR] = 1.75, 95% confidence interval = 1.38, 2.23). Cadets who reported less symptom severity on the Sport Concussion Assessment Tool, third edition (SCAT3), within 48 hours of concussion had 1.45 to 3.77 times shorter symptom-recovery durations than those with more symptom severity. Similar to symptom duration, varsity status was associated with a shorter RTA-protocol duration (HR = 1.74, 95% confidence interval = 1.34, 2.25), and less symptom severity on the SCAT3 was associated with a shorter RTA-protocol duration (HR range = 1.31 to 1.47). The academy that the cadet attended was associated with the RTA-protocol duration (P < .05). Conclusions: The initial total number of symptoms reported and varsity athlete status were strongly associated with symptom and RTA-protocol durations. These findings suggested that external (varsity status and academy) and injury (symptom burden) factors influenced the time until RTA.Item Hybrid Diffusion Imaging in Mild Traumatic Brain Injury(Mary Ann Liebert, 2018-10-15) Wu, Yu-Chien; Mustafi, Sourajit M.; Harezlak, Jaroslaw; Kodiweera, Chandana; Flashman, Laura A.; McAllister, Thomas W.; Radiology and Imaging Sciences, School of MedicineMild traumatic brain injury (mTBI) is an important public health problem. Although conventional medical imaging techniques can detect moderate-to-severe injuries, they are relatively insensitive to mTBI. In this study, we used hybrid diffusion imaging (HYDI) to detect white matter alterations in 19 patients with mTBI and 23 other trauma control patients. Within 15 days (standard deviation = 10) of brain injury, all subjects underwent magnetic resonance HYDI and were assessed with a battery of neuropsychological tests of sustained attention, memory, and executive function. Tract-based spatial statistics (TBSS) was used for voxel-wise statistical analyses within the white matter skeleton to study between-group differences in diffusion metrics, within-group correlations between diffusion metrics and clinical outcomes, and between-group interaction effects. The advanced diffusion imaging techniques, including neurite orientation dispersion and density imaging (NODDI) and q-space analyses, appeared to be more sensitive then classic diffusion tensor imaging. Only NODDI-derived intra-axonal volume fraction (Vic) demonstrated significant group differences (i.e., 5-9% lower in the injured brain). Within the mTBI group, Vic and a q-space measure, P0, correlated with 6 of 10 neuropsychological tests, including measures of attention, memory, and executive function. In addition, the direction of correlations differed significantly between groups (R2 > 0.71 and pinteration < 0.03). Specifically, in the control group, higher Vic and P0 were associated with better performances on clinical assessments, whereas in the mTBI group, higher Vic and P0 were associated with worse performances with correlation coefficients >0.83. In summary, the NODDI-derived axonal density index and q-space measure for tissue restriction demonstrated superior sensitivity to white matter changes shortly after mTBI. These techniques hold promise as a neuroimaging biomarker for mTBI.Item In vivo Two-Photon Imaging Reveals Acute Cerebral Vascular Spasm and Microthrombosis After Mild Traumatic Brain Injury in Mice(Frontiers Media, 2020-03) Han, Xinjia; Chai, Zhi; Ping, Xingjie; Song, Li-Juan; Ma, Cungen; Ruan, Yiwen; Jin, Xiaoming; Anatomy and Cell Biology, School of MedicineMild traumatic brain injury (mTBI), or concussion, is reported to interfere with cerebral blood flow and microcirculation in patients, but our current understanding is quite limited and the results are often controversial. Here we used longitudinal in vivo two-photon imaging to investigate dynamic changes in cerebral vessels and velocities of red blood cells (RBC) following mTBI. Closed-head mTBI induced using a controlled cortical impact device resulted in a significant reduction of dwell time in a Rotarod test but no significant change in water maze test. Cerebral blood vessels were repeatedly imaged through a thinned skull window at baseline, 0.5, 1, 6 h, and 1 day following mTBI. In both arterioles and capillaries, their diameters and RBC velocities were significantly decreased at 0.5, 1, and 6 h after injury, and recovered in 1 day post-mTBI. In contrast, decreases in the diameter and RBC velocity of venules occurred only in 0.5–1 h after mTBI. We also observed formation and clearance of transient microthrombi in capillaries within 1 h post-mTBI. We concluded that in vivo two-photon imaging is useful for studying earlier alteration of vascular dynamics after mTBI and that mTBI induced reduction of cerebral blood flow, vasospasm, and formation of microthrombi in the acute stage following injury. These changes may contribute to early brain functional deficits of mTBI.Item King-Devick Sensitivity and Specificity to Concussion in Collegiate Athletes(Allen Press, 2023) Le, Rachel Khinh; Ortega, Justus; Chrisman, Sara P.; Kontos, Anthony P.; Buckley, Thomas A.; Kaminski, Thomas W.; Meyer, Briana P.; Clugston, James R.; Goldman, Joshua T.; McAllister, Thomas; McCrea, Michael; Broglio, Steven P.; Schmidt, Julianne D.; Psychiatry, School of MedicineContext: The King-Devick (K-D) test is used to identify oculomotor impairment after concussion. However, the diagnostic accuracy of the K-D test over time has not been evaluated. Objectives: To (1) examine the sensitivity and specificity of the K-D test at 0 to 6 hours postinjury, 24 to 48 hours postinjury, the beginning of a return-to-play (RTP) protocol (asymptomatic), unrestricted RTP, and 6 months postconcussion and (2) compare outcomes between athletes with and those without concussion across confounding factors (sex, age, sport contact level, academic year, learning disorder, attention-deficit/hyperactivity disorder, migraine history, concussion history, and test administration mode). Design: Retrospective, cross-sectional design. Setting: Multiple institutions in the Concussion Assessment, Research and Education Consortium. Patients or other participants: A total of 320 athletes with a concussion (162 men, 158 women; age = 19.80 ± 1.41 years) were compared with 1239 total collegiate athletes without a concussion (646 men, 593 women; age = 20.31 ± 1.18 years). Main outcome measure(s): We calculated the K-D test time difference (in seconds) by subtracting the baseline from the most recent time. Receiver operator characteristic (ROC) curve and area under the curve (AUC) analyses were used to determine the diagnostic accuracy across time points. We identified cutoff scores and corresponding specificity at both the 80% and 70% sensitivity levels. We repeated ROC with AUC analyses using confounding factors. Results: The K-D test predicted positive results at the 0- to 6-hour (AUC = 0.724, P < .001), 24- to 48-hour (AUC = 0.701, P < .001), RTP (AUC = 0.640, P < .001), and 6-month postconcussion (AUC = 0.615, P < .001) tim points but not at the asymptomatic time point (AUC = 0.513, P = .497). The 0- to 6-hour and 24- to 48-hour time points yielded 80% sensitivity cutoff scores of -2.6 and -3.2 seconds (ie, faster), respectively, but 46% and 41% specificity, respectively. The K-D test had a better AUC when administered using an iPad (AUC = 0.800, 95% CI = 0.747, 0.854) compared with the spiral-bound card system (AUC = 0.646, 95% CI = 0.600, 0.692; P < .001). Conclusions: The diagnostic accuracy of the K-D test was greatest at 0 to 6 hours and 24 to 48 hours postconcussion but declined across subsequent postconcussion time points. The AUCs did not differentiate between groups across confounding factors. Our negative cutoff scores indicated that practice effects contributed to improved performance, requiring athletes to outperform their baseline scores.Item A National Study on the Effects of Concussion in Collegiate Athletes and US Military Service Academy Members: The NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium Structure and Methods(Springer, 2017-07) Broglio, Steven P.; McCrea, Michael; McAllister, Thomas; Harezlak, Jaroslaw; Katz, Barry; Hack, Dallas; Hainline, Brian; CARE Consortium Investigators; Psychiatry, School of MedicineBACKGROUND: The natural history of mild traumatic brain injury (TBI) or concussion remains poorly defined and no objective biomarker of physiological recovery exists for clinical use. The National Collegiate Athletic Association (NCAA) and the US Department of Defense (DoD) established the Concussion Assessment, Research and Education (CARE) Consortium to study the natural history of clinical and neurobiological recovery after concussion in the service of improved injury prevention, safety and medical care for student-athletes and military personnel. OBJECTIVES: The objectives of this paper were to (i) describe the background and driving rationale for the CARE Consortium; (ii) outline the infrastructure of the Consortium policies, procedures, and governance; (iii) describe the longitudinal 6-month clinical and neurobiological study methodology; and (iv) characterize special considerations in the design and implementation of a multicenter trial. METHODS: Beginning Fall 2014, CARE Consortium institutions have recruited and enrolled 23,533 student-athletes and military service academy students (approximately 90% of eligible student-athletes and cadets; 64.6% male, 35.4% female). A total of 1174 concussions have been diagnosed in participating subjects, with both concussion and baseline cases deposited in the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. CONCLUSIONS: Challenges have included coordinating regulatory issues across civilian and military institutions, operationalizing study procedures, neuroimaging protocol harmonization across sites and platforms, construction and maintenance of a relational database, and data quality and integrity monitoring. The NCAA-DoD CARE Consortium represents a comprehensive investigation of concussion in student-athletes and military service academy students. The richly characterized study sample and multidimensional approach provide an opportunity to advance the field of concussion science, not only among student athletes but in all populations at risk for mild TBI.Item Physical activity behavior in the first month after mild traumatic brain injury is associated with physiological and psychological risk factors for chronic pain(Wolters Kluwer, 2021-10-29) Naugle, Kelly M.; Corrona, Sam; Smith, Jared A.; Nguyen, Tyler; Saxe, Jonathan; White, Fletcher A.; Kinesiology, School of Health and Human SciencesObjective: The purpose of this study was to determine whether self-reported physical activity (PA) in the first month after mild traumatic brain injury (mTBI) predicts endogenous pain modulatory function and pain catastrophizing at 1 to 2 weeks and 1 month after injury in patients with mTBI. Methods: Patients with mild traumatic brain injury completed study sessions at 1 to 2 weeks and 1 month after injury. Assessments included a headache survey, Pain Catastrophizing Scale, International Physical Activity Questionnaire-Short Form, and several quantitative sensory tests to measure endogenous pain modulatory function including conditioned pain modulation (CPM), temporal summation, and pressure pain thresholds of the head. Hierarchical linear regressions determined the relationship between the PA variables (predictors) and pain catastrophizing and pain modulation variables (dependent variables) cross-sectionally and longitudinally, while controlling for potential covariates. Results: In separate hierarchical regression models, moderate PA, walking, and total PA at 1 to 2 weeks after injury predicted pain inhibition on the CPM test at 1 month, after controlling for significant covariates. In addition, a separate regression revealed that minutes sitting at 1 month predicted CPM at 1 month. Regarding predicting pain catastrophizing, the regression results showed that sitting at 1 to 2 weeks after injury significantly predicted pain catastrophizing at 1 month after injury. Conclusion: Greater self-reported PA, especially moderate PA, 1 to 2 weeks after injury longitudinally predicted greater pain inhibitory capacity on the CPM test at 1 month after injury in patients with mTBI. In addition, greater sedentary behavior was associated with worse pain inhibition on the CPM test and greater pain catastrophizing at 1 month after injury.Item Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts(Frontiers Media, 2023-08-17) Devoto, Christina; Vorn, Rany; Mithani, Sara; Meier, Timothy B.; Lai, Chen; Broglio, Steven P.; McAllister, Thomas; Giza, Christopher C.; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; Turtzo, Christine; Latour, Lawrence; McCrea, Michael A.; Gill, Jessica M.; Psychiatry, School of MedicineObjective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.