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

Abstract

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.

Keywords: concussion; magnetic resonance spectroscopy; metabolites; repetitive head impacts; subconcussive hits; traumatic brain injury.

FIG. 1.

An overview of study selection and reasons for exclusion.

FIG. 2.

Metabolite effect sizes (Hedge's g) and 95% confidence intervals (CI) stratified by brain region studied for (A) NAA, (B) Cr, (C) Cho, (D) Glx and (E) mI. Total number of brain-injured participants (n_TBI) and non-brain-injured controls (n_Cont) included in each brain region analysis are presented. The overall n represents the total number of participants included in each metabolite meta-analysis (participants from studies that measured metabolites in multiple regions of interest were only counted once).

FIG. 3.

Schematic of the regional metabolite meta-analyses (nine regions defined: frontal [pink], frontoparietal, parietal [light blue], parieto-occipital, occipital [violet], temporal, subcortical [yellow], corpus callosum [green], and cerebellar regions [dark blue]). Brain regions were defined by the description provided in the original research articles. If no description was explicitly provided, brain regions were categorized by visually inspecting figures depicting voxel placement and comparison with similar voxel placements from other articles. Regional delineations can be seen for the frontal, parietal, occipital, subcortical, corpus callosum, and cerebellar regions. The frontoparietal cortex (not explicitly shown in the figure) was defined as a region transecting the central sulcus that was composed of both the frontal and parietal lobes. Similarly, the parieto-occipital cortex was defined as a region transecting the parieto-occipital sulcus, and was composed of both the parietal and occipital lobes. Although not shown here, the temporal lobe was delineated by the Sylvian fissure and the pre-occipital notch. Metabolites that were found to be significantly altered in brain-injured subjects relative to controls are indicated. ↑ = Metabolite significantly increased in brain-injured subjects. ↓ = Metabolite significantly decreased in brain-injured subjects. * = Metabolite alterations that approached statistical significance.