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

Abstract

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.

Keywords: brain metabolites; concussion; magnetic resonance spectroscopy; multi-site; multi-vendor; orthopedic injury control; pediatric mTBI.

FIGURE 1

Representative spectrum from a single participant. The black line indicates the raw data, and the red line indicates the overall fit from LCModel after processing. The inset shows the voxel location in the left dorsolateral prefrontal cortex.

FIGURE 2

Concentrations of the five metabolites of interest in mmol/L separated by group (concussion in yellow and Orthopedic Injury (OI) in teal). The black lines in the boxes represent the median and the box represents the interquartile range, with the 1.5 times the interquartile range values represented by the whiskers. The circles represent outliers (at least greater than 1.5 times the interquartile range from the median). No statistically significant group differences were found between concussion and OI for any metabolite. See Table 2 for full statistical results.

FIGURE 3

(a) Absolute and (b) tCr‐referenced concentrations of all metabolites separated by the vendor and injury group. The black lines in the boxes represent the median and the box represents the interquartile range, with the 1.5 times the interquartile range values represented by the whiskers. The circles represent outliers (at least greater than 1.5 times the interquartile range from the median) and the asterisks represent statistically significant outliers (at least three times the interquartile range from the median); however, all data met quality control requirements and visual inspection did not suggest the data should be excluded. For all metabolites, there were no statistically significant differences between concussion and OI; however, for all metabolites there were statistically significant differences between vendors.

FIGURE 4

Metabolite levels referenced to tCr separated by group. The black lines in the boxes represent the median and the box represents the interquartile range, with the maximum and minimum values represented by the whiskers on either end of the box plot. The circles represent outliers (at least 1.5 times the interquartile range from the median) outside the maximum and minimum and the asterisk represent statistically significant outliers (at least three times the interquartile range from the median). All outliers passed quality control. No statistically significant group differences between concussion and OI were found for any Cr‐referenced metabolite.