Brian J. Blyth

Subject-specific changes in brain white matter on diffusion tensor imaging after sports-related concussion

BACKGROUND AND PURPOSE Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of individual-level changes in DTI indices. We investigated the ability of wild bootstrapping analysis to detect subject-specific changes in brain white matter (WM) before and after sports-related concussion. MATERIALS AND METHODS A prospective cohort study was performed in nine high school athletes engaged in hockey or football and six controls. Subjects underwent DTI pre- and postseason within a 3-month interval. One athlete was diagnosed with concussion (scanned within 72 h), and eight suffered between 26 and 399 subconcussive head blows. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in each WM voxel. Bootstrap samples were generated, and a permuted t test was used to compare voxel-wise FA/MD changes in each subject pre- vs. postseason. RESULTS The percentage of WM voxels with significant (p<.05) pre-post FA changes was highest for the concussion subject (3.2%), intermediary for those with subconcussive head blows (mean 1.05%±.15%) and lowest for controls (mean 0.28%±.01%). Similarly, the percentage of WM voxels with significant MD changes was highest for the concussion subject (3.44%), intermediary for those with subconcussive head blows (mean 1.48%±.17%) and lowest for controls (mean 0.48%±.05%). Significantly changed FA and MD voxels colocalized in the concussion subject to the right corona radiata and right inferior longitudinal fasciculus. CONCLUSIONS Wild bootstrap analysis detected significantly changed WM in a single concussed athlete. Athletes with multiple subconcussive head blows had significant changes in a percentage of their WM that was over three times higher than controls. Efforts to understand the significance of these WM changes and their relationship to head impact forces appear warranted.

Sex differences in outcome after mild traumatic brain injury.

The objective of this study was to estimate the independent association of sex with outcome after mild traumatic brain injury (mTBI). We performed an analysis of a subset of an established cohort involving 1425 mTBI patients presenting to an academic emergency department (ED). The associations between sex and three outcomes determined 3 months after the initial ED visit were examined: post-concussive symptom (PCS) score (0, 1-5, 6-16, and >16), the number of days to return of normal activities (0, 1-7, and >7), and the number of days of work missed (0, 1-7,and >7). Logistic regression analyses were used to determine the relationship between sex and each outcome after controlling for 12 relevant subject-level variables. Of the 1425 subjects, 643 (45.1%) were female and 782 (54.9%) were male. Three months after mTBI, males had significantly lower odds of being in a higher PCS score category (odds ratio [OR] 0.62, 95% confidence interval [CI]: 0.50, 0.78); this association appeared to be more prominent during child-bearing years for females. Males and females did not significantly differ with respect to the odds of poorer outcome as defined by the number of days to return of normal activities or the number of days of work missed. Female sex is associated with significantly higher odds of poor outcome after mTBI, as measured by PCS score, after control for appropriate confounders. The observed pattern of peak disability for females during the child-bearing years suggests disruption of endogenous estrogen or progesterone production. Attempts to better understand how mTBI affects production of these hormones acutely after injury and during the recovery period may shed light on the mechanism behind poorer outcome among females and putative therapeutic interventions.

Elevated Serum Ubiquitin Carboxy-Terminal Hydrolase L1 Is Associated with Abnormal Blood–Brain Barrier Function after Traumatic Brain Injury

Serum S100B elevations accurately reflect blood-brain barrier (BBB) damage. Because S100B is also present in peripheral tissues, release of this protein may not be specific to central nervous system (CNS) injury. Ubiquitin C-terminal hydrolase 1 (UCHL1), and phosphorylated neurofilament heavy chain (pNF-H) are found exclusively in neurons, but their relationship to BBB dysfunction has not been determined. The objective of this study was to determine the accuracy of serum UCHL1 and pNF-H as measures of BBB integrity after traumatic brain injury (TBI), to and compare them to S100B. We performed a prospective study of 16 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) and 6 patients with non-traumatic headache who had cerebrospinal fluid (CSF) collected by ventriculostomy or lumbar puncture (LP). Serum and CSF were collected at the time of LP for headache patients and at 12, 24, and 48 h after injury for TBI patients. BBB function was determined by calculating albumin quotients (Q(A)), where Q(A)=[albumin(CSF)]/[albumin(serum)]. S100B, UCHL1, and pNF-H were measured by enzyme-linked immunosorbent assay (ELISA). Pearsons correlation coefficient and area under the receiver operator characteristic (ROC) curve were used to determine relationships between serum markers and Q(A). At 12 hours after TBI, a significant relationship was found between Q(A) and serum UCHL1 concentrations (AUC=0.76; 95% CI 0.55,1.00), and between Q(A) and serum S100B concentrations (AUC=0.794; 95% CI 0.57,1.02). There was no significant relationship found between these markers and Q(A) at other time points, or between pNF-H and Q(A) at any time point. We conclude that serum concentrations of UCHL1 are associated with abnormal BBB status 12 h after moderate to severe TBI. This relationship is similar to that observed between serum S100B and Q(A,) despite the fact that S100B may be released from peripheral tissues after multi-trauma. We conclude that peripheral release of S100B after multi-trauma is probably negligible and that UCHL1 may have some utility to monitor BBB disruption following TBI.

Traumatic Alterations in Consciousness: Traumatic Brain Injury

Mild traumatic brain injury (mTBI) refers to the clinical condition of transient alteration of consciousness as a result of traumatic injury to the brain. The priority of emergency care is to identify and facilitate the treatment of rare but potentially life-threatening intracranial injuries associated with mTBI through the judicious application of appropriate imaging studies and neurosurgical consultation. Although post-mTBI symptoms quickly and completely resolve in the vast majority of cases, a significant number of patients will complain of lasting problems that may cause significant disability. Simple and early interventions such as patient education and appropriate referral can reduce the likelihood of chronic symptoms. Although definitive evidence is lacking, mTBI is likely to be related to significant long-term sequelae such as Alzheimer disease and other neurodegenerative processes.

Subject-Specific Increases in Serum S-100B Distinguish Sports-Related Concussion from Sports-Related Exertion

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 prospective 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 samples 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.

Classification accuracy of serum Apo A-I and S100B for the diagnosis of mild traumatic brain injury and prediction of abnormal initial head computed tomography scan.

The objective of the current study was to determine the classification accuracy of serum S100B and apolipoprotein (apoA-I) for mild traumatic brain injury (mTBI) and abnormal initial head computed tomography (CT) scan, and to identify ethnic, racial, age, and sex variation in classification accuracy. We performed a prospective, multi-centered study of 787 patients with mTBI who presented to the emergency department within 6 h of injury and 467 controls who presented to the outpatient laboratory for routine blood work. Serum was analyzed for S100B and apoA-I. The outcomes were disease status (mTBI or control) and initial head CT scan. At cutoff values defined by 90% of controls, the specificity for mTBI using S100B (0.899 [95% confidence interval (CI): 0.78-0.92]) was similar to that using apoA-I (0.902 [0.87-0.93]), and the sensitivity using S100B (0.252 [0.22-0.28]) was similar to that using apoA-I (0.249 [0.22-0.28]). The area under the receiver operating characteristic curve (AUC) for the combination of S100B and apoA-I (0.738, 95% CI: 0.71, 0.77), however, was significantly higher than the AUC for S100B alone (0.709, 95% CI: 0.68, 0.74, p=0.001) and higher than the AUC for apoA-I alone (0.645, 95% CI: 0.61, 0.68, p<0.0001). The AUC for prediction of abnormal initial head CT scan using S100B was 0.694 (95%CI: 0.62, 0.77) and not significant for apoA-I. At a S100B cutoff of <0.060 μg/L, the sensitivity for abnormal head CT was 98%, and 22.9% of CT scans could have been avoided. There was significant age and race-related variation in the accuracy of S100B for the diagnosis of mTBI. The combined use of serum S100B and apoA-I maximizes classification accuracy for mTBI, but only S100B is needed to classify abnormal head CT scan. Because of significant subgroup variation in classification accuracy, age and race need to be considered when using S100B to classify subjects for mTBI.

Time course of induction of oxytocin messenger ribonucleic acid levels in the hypothalamic paraventricular nucleus of ovariectomized rats following gonadal steroid administration.

The nonapeptide oxytocin (OT) is important for uterine contractility at parturition, milk ejection during lactation, and the induction of maternal behavior. OT messenger ribonucleic acid (mRNA) levels increase in the paraventricular and supraoptic nuclei (PVN and SON) of late pregnant and lactating rats and are modulated by the steroid milieu that accompanies these states. Specifically, sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal 48 hrs prior to sacrifice increases PVN, and to a lesser but significant degree, SON OT mRNA. To better define the time course of induction of OT mRNA levels following P withdrawal, ovariectomized Sprague-Dawley rats were treated with empty or steroid-filled capsules. On day 1, animals received an E2-filled or empty capsule, followed by P-filled or empty capsules on day 3. On day 14, P-filled or empty capsules were removed and animals were sacrificed 24, 36, or 48 hrs later. The hypothalamic PVN were analyzed for OT mRNA by in situ hybridization histochemistry. Significant differences in PVN OT mRNA were found among the groups (P<0.0001, Kruskal-Wallis). Animals in the 48 hr (P=0.007) and 36 hr (P=0.005), but not the 24 hr, steroid-treated groups had significantly increased OT mRNA relative to their respective sham-treated cohorts (Mann-Whitney U test). The relative abundance of PVN OT mRNA differed among the steroid-treated groups (Kruskal-Wallis, P<0.0003), with highest levels at 48 hr. We conclude that increases in PVN OT mRNA occur by 36 hrs, and are highest at 48 hrs, after P withdrawal in the E2-primed rat. Future studies will determine if OT-mediated changes in behavior or physiology that surround parturition are related to these changes in OT mRNA.