Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

The Association of Saliva Cytokines and Pediatric Sports-Related Concussion Outcomes.

OBJECTIVES: This study aimed to explore cytokine alterations following pediatric sports-related concussion (SRC) and whether a specific cytokine profile could predict symptom burden and time to return to sports (RTS). SETTING: Sports Medicine Clinic. PARTICIPANTS: Youth ice hockey participants (aged 12-17 years) were recruited prior to the 2013-2016 hockey season. DESIGN: Prospective exploratory cohort study. MAIN MEASURE: Following SRC, saliva samples were collected and a Sport Concussion Assessment Tool version 3 (SCAT3) was administered within 72 hours of injury and analyzed for cytokines. Additive regression of decision stumps was used to model symptom burden and length to RTS based on cytokine and clinical features. RRelieFF feature selection was used to determine the predictive value of each cytokine and clinical feature, as well as to identify the optimal cytokine profile for the symptom burden and RTS. RESULTS: Thirty-six participants provided samples post-SRC (81% male; age 14.4 ± 1.3 years). Of these, 10 features, sex, number of previous concussions, and 8 cytokines, were identified to lead to the best prediction of symptom severity (r = 0.505, P = .002), while 12 cytokines, age, and history of previous concussions predicted the number of symptoms best (r = 0.637, P < .001). The prediction of RTS led to the worst results, requiring 21 cytokines, age, sex, and number of previous concussions as features (r = -0.320, P = .076). CONCLUSIONS: In pediatric ice hockey participants following SRC, there is evidence of saliva cytokine profiles that are associated with increased symptom burden. However, further studies are needed.

Longitudinal changes in brain metabolites following pediatric concussion.

Concussion is commonly characterized by a cascade of neurometabolic changes following injury. Magnetic Resonance Spectroscopy (MRS) can be used to quantify neurometabolites non-invasively. Longitudinal changes in neurometabolites have rarely been studied in pediatric concussion, and fewer studies consider symptoms. This study examines longitudinal changes of neurometabolites in pediatric concussion and associations between neurometabolites and symptom burden. Participants who presented with concussion or orthopedic injury (OI, comparison group) were recruited. The first timepoint for MRS data collection was at a mean of 12 days post-injury (n = 545). Participants were then randomized to 3 (n = 243) or 6 (n = 215) months for MRS follow-up. Parents completed symptom questionnaires to quantify somatic and cognitive symptoms at multiple timepoints following injury. There were no significant changes in neurometabolites over time in the concussion group and neurometabolite trajectories did not differ between asymptomatic concussion, symptomatic concussion, and OI groups. Cross-sectionally, Choline was significantly lower in those with persistent somatic symptoms compared to OI controls at 3 months post-injury. Lower Choline was also significantly associated with higher somatic symptoms. Although overall neurometabolites do not change over time, choline differences that appear at 3 months and is related to somatic symptoms.

Saliva Cortisol as a Biomarker of Injury in Youth Sport-Related Concussion.

Increasing rates of sport-related concussion (SRC) in youth impose a significant burden on public health systems and the lives of young athletes. Accurate prediction for those likely to develop persistent post-concussion symptomology (PPCS) using a fluid biomarker, reflecting both acute injury and recovery processes, would provide the opportunity for early intervention. Cortisol, a stress hormone released through the hypothalamic-pituitary-adrenal (HPA) axis following injury, may provide a missing physiological link to clinical recovery. This cohort study investigated the change in saliva cortisol following SRC and the association between cortisol and symptom burden in pediatric ice hockey players. Further, the association between cortisol levels and medical clearance to return to play was explored. In total, cortisol samples from 233 players were included; 165 athletes (23.6% female) provided pre-injury saliva and 68 athletes (19.1% female) provided post-SRC saliva samples for cortisol analysis. Quantile (median) regressions were used to compare cortisol between pre-injury and post-SRC groups, and the association between total symptoms (/22) and symptom severity scores (/132) reported on the Sport Concussion Assessment Tool (SCAT)3/SCAT5 and post-SRC cortisol (adjusting for age, sex, history of concussion, and time from injury to sample collection). Results demonstrated significantly lower saliva cortisol in post-SRC athletes compared with the pre-injury group (ß = -0.62, 95% confidence interval [CI; -1.08, -0.16], p = 0.009). Post-SRC cortisol was not significantly associated with the SCAT3/SCAT5 symptom totals or symptom severity scores; however, females were found to report more symptoms (ß = 6.95, 95% CI [0.35, 13.55], p = 0.040) and greater symptom severity (ß = 23.87, 95% CI [9.58, 38.15], p = 0.002) compared with males. Exploratory time-to-event analysis revealed a point estimate suggesting a potential association between low cortisol levels and days to medical clearance to return to play. Although preliminary, these findings suggest that the HPA axis may be dysregulated post-SRC. Further, our exploratory analysis and case presentation of post-injury outliers highlight the need to further research cortisol as a prognostic biomarker to inform individualized sex-specific care after SRC.

Comparison of different approaches to manage multi-site magnetic resonance spectroscopy clinical data analysis.

Introduction: The effects caused by differences in data acquisition can be substantial and may impact data interpretation in multi-site/scanner studies using magnetic resonance spectroscopy (MRS). Given the increasing use of multi-site studies, a better understanding of how to account for different scanners is needed. Using data from a concussion population, we compare ComBat harmonization with different statistical methods in controlling for site, vendor, and scanner as covariates to determine how to best control for multi-site data. Methods: The data for the current study included 545 MRS datasets to measure tNAA, tCr, tCho, Glx, and mI to study the pediatric concussion acquired across five sites, six scanners, and two different MRI vendors. For each metabolite, the site and vendor were accounted for in seven different models of general linear models (GLM) or mixed-effects models while testing for group differences between the concussion and orthopedic injury. Models 1 and 2 controlled for vendor and site. Models 3 and 4 controlled for scanner. Models 5 and 6 controlled for site applied to data harmonized by vendor using ComBat. Model 7 controlled for scanner applied to data harmonized by scanner using ComBat. All the models controlled for age and sex as covariates. Results: Models 1 and 2, controlling for site and vendor, showed no significant group effect in any metabolites, but the vendor and site were significant factors in the GLM. Model 3, which included a scanner, showed a significant group effect for tNAA and tCho, and the scanner was a significant factor. Model 4, controlling for the scanner, did not show a group effect in the mixed model. The data harmonized by the vendor using ComBat (Models 5 and 6) had no significant group effect in both the GLM and mixed models. Lastly, the data harmonized by the scanner using ComBat (Model 7) showed no significant group effect. The individual site data suggest there were no group differences. Conclusion: Using data from a large clinical concussion population, different analysis techniques to control for site, vendor, and scanner in MRS data yielded different results. The findings support the use of ComBat harmonization for clinical MRS data, as it removes the site and vendor effects.

Magnetic Resonance Spectroscopy of Traumatic Brain Injury and Subconcussive Hits: A Systematic Review and Meta-Analysis.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique used to study metabolites in the brain. MRS findings in traumatic brain injury (TBI) and subconcussive hit literature have been mixed. The most common observation is a decrease in N-acetyl-aspartate (NAA), traditionally considered a marker of neuronal integrity. Other metabolites, however, such as creatine (Cr), choline (Cho), glutamate+glutamine (Glx) and myo-inositol (mI) have shown inconsistent changes in these populations. The objective of this systematic review and meta-analysis was to synthesize MRS literature in brain injury and explore factors (biological factors such as brain region, injury severity, time since injury, demographics and technical methodological factors such as field strength, acquisition parameters, analysis approach) that may contribute to differential findings. One hundred and thirty-eight studies met inclusion criteria for the systematic review and of those, 62 NAA, 24 Cr, 49 Cho, 18 Glx, and 21 mI studies met inclusion criteria for meta-analysis. A random effects model was used for meta-analyses with brain region as a subgroup for each of the five metabolites studied. Meta-regression was used to examine the influence of potential moderators including injury severity, time since injury, age, sex, tissue composition, and methodological factors. In this analysis of 1428 unique brain-injured subjects and 1132 controls, the corpus callosum was identified as a brain region highly susceptible to metabolite alteration. NAA was consistently decreased in TBI of all severities, but not in subconcussive hits. Cho and mI were found to be increased in moderate-to-severe TBI but not in mild TBI. Glx and Cr were largely unaffected, but did show alterations in certain conditions.

Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms.

Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism.