The clinical utility of proton magnetic resonance spectroscopy in traumatic brain injury: recommendations from the ENIGMA MRS working group

Abstract

Proton (¹H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo ¹H magnetic resonance spectroscopy and review ¹H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic ¹H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of ¹H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Keywords: Brain injury; Concussion; Magnetic resonance spectroscopy; Trauma.

Fig. 1

Single voxel spectroscopy (SVS PRESS; TR/TE = 3000/30 ms; 3.0 T) collected from a 20 × 20 × 20 mm³ voxel the right frontal white matter of a 10 month old showing commonly observed neurometabolites. NAA (N-acetylaspartate), Glx (overlapping glutamate and glutamine), Cr (creatine), Cho (choline), and mI (myo-inositol)

Fig. 2

Sagittal (a), T1-weighted MRI of a patient’s head showing the location and geometry of the spectroscopy volume of interest (VOI; white frame) and the six 0.75 cm thick individual spectroscopic slices within the VOI. The yellow arrow indicates the slice shown in (b). A metabolite map overlaid on the T1-weighted image shows each voxel’s NAA concentration as a gradient from black (lowest) to red (highest) (c). Similarly each voxel’s tissue gray matter (d) and white matter (e) fractions are shown as gradient from black to red overlaid on the tissue segmentation maps. The spectral map from the VOI is shown in (f). The four spectra bound by the rectangular box are shown in detail in (g). Note the two outer spectra have no metabolite signal, because they correspond to voxels within the lateral ventricles (b). The two inner spectra originate from the splenium and correspondingly contain no gray matter (d). While they contain equal white matter fraction of about ~100% (e), the NAA signal (g) and concentration (c) are lower in one of the voxels. This patient had postconcussive symptoms and was part of a group-level analysis, which found lower global white matter NAA levels in patients compared to controls (Kirov et al., 2013a, b)

Fig. 3

Percent differences of the group mean metabolite measures relative to control values for a group with moderate TBI (mean GCS 12.9, range 6 to 15). Regions with significant differences, for p < 0.05, are shown as a color overlay superimposed on the spatial reference magnetic resonance imaging. Results are shown for N-acetyl-aspartate/creatine (a), creatine (b), and choline (c), with the corresponding color scales indicated for each. Data was acquired at 3 T using a volumetric MRSI sequence with spatial sampling of 50×50×18 points over 280×280×180 mm³ and TE = 70 ms (modified from Maudsley et al. 2015)

Fig. 4:

MRSI volume of interest (VOI) overlaid onto a T2 weighted MR image of a 3 month old NAT patient who presented with an initial GCS score of 3, retinal hemorrhages and diffuse hypoxic-ischemic injury (a). MRSI (PRESS; TR/TE = 3000/144 ms; 1.5 T) was acquired 1 day after injury. (b). Spectral map shows a diffuse decrease of NAA and large inverted Lac peaks (doublet at 1.33 ppm; B). The Lac peaks are inverted as a result of the intermediate echo time. Spectrum from the right parieto-occipital white matter shows markedly decreased NAA and presence of Lac (c)

Fig. 5

a. MRS is predictive of outcome in severe TBI (Mountford et al., 2010). Representative spectra acquired in healthy controls (top) and patients with severe traumatic brain injury based on outcome. The second from the top shows spectra with good outcome. Third from the top shows a patient in a persistent vegetative state (PVS) and the bottom spectrum shows a patient who died. Note the decrease in NAA, increase in lactate and glutamate/glutamine with greater severity of outcome. All spectra were acquired at 1.5 T using STEAM (TE = 30 ms) in the posterior cingulate. b. MRS is sensitive to subconcussive brain trauma (Koerte et al. 2015). Retired professional soccer players with no history of concussion, with the only exposure to repetitive head impacts due to heading of the soccer ball, and athletes with no exposure to head impacts were scanned using PRESS (TE = 30 ms) in the posterior cingulate area at 3 T. In heavy blue is the averaged spectrum of all controls and in red are the individual soccer players. There was a significant increase in choline and myo-inositol found in the soccer players showing spectroscopic changes due to subconcussive impacts

Fig. 6

Recommended frontal white matter MRS voxel location. The recommended location, angulation and dimensions of a frontal white in matter MRS voxel is shown in red highlight, overlaid on grayscale sections through a T1-weighted 3-dimensional MR volume image. Displays of the voxel on four representative sagittal, axial and coronal sections of the T1-weighted volume image are provided. The voxel’s dimensions are 2.0 × 2.5 × 1.5 cm = 7.5 cm³. Angulation and dimensions, which are expected to depend on subject’s anatomy and head position, were adjusted for this particular subject to achieve maximal white matter content and a volume as close to 8.0 cm³ as possible