Quantitative multivoxel proton MR spectroscopy for the identification of white matter abnormalities in mild traumatic brain injury: Comparison between regional and global analysis

Abstract

Background 3D brain proton MR spectroscopic imaging (1H MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub‐1 cm3, spatial resolution than single‐voxel 1H MRS with the ability to separate tissue‐type partial volume contribution(s). Purpose To determine if: 1) white matter (WM) damage in mild traumatic brain injury (mTBI) is homogeneously diffuse, or if specific regions are more affected; 2) partial‐volume‐corrected, structure‐specific 1H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. Study Type Retrospective cross‐sectional cohort study. Population Twenty‐seven subjects: 15 symptomatic mTBI patients, 12 matched controls. Field Strength/Sequence 3T using 3D 1H MRSI over a 360‐cm3 volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm3. Assessment N‐acetyl‐aspartate (NAA), creatine, choline, and myo‐inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. Statistical Tests Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. Results Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations < controls') within a narrow range: 0.3 ≤ Cohen's d ≤ 0.6. Data Conclusion Since the patient group was symptomatic and exhibiting global WM NAA deficits, these findings suggest: 1) diffuse axonal mTBI damage; that is 2) below the 1H MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single‐voxel 1H MRS, placed anywhere in WM regions, may be well suited for mTBI 1H MRS studies, given that these results are confirmed in other cohorts. Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1424–1432.

Global decrease in brain sodium concentration after mild traumatic brain injury

“…Linear regression, however, revealed global WM decreases of the neuronal marker N -acetyl-aspartate. 52 Our results were consistent with previous 1 H MRSI literature 53–56 demonstrating widespread, rather than focal, metabolic injury in TBI. While the current 23 Na MRI results are yet to be replicated, the similarities with 1 H MRSI are noteworthy, since they suggest that compared to the macro-(anatomical MRI) and micro-(diffusional) structural phenotype of injury, physiological sequelae (metabolic and ionic) may have a more diffuse distribution.…”

The Clinical Utility of Magnetic Resonance Spectroscopy in Traumatic Brain Injury: Recommendations from the ENIGMA MRS Working Group

“…The data analysis methods used in most SVS and MRSI TBI studies have been based on sampling preselected brain regions known to be susceptible to injury, with comparison to results from the same region in normal control subjects. For MRSI studies, multiple individual voxel results can be averaged over a region of interest (ROI) to improve SNR (Davitz et al, 2019;Kirov et al, 2007;Sours, George, Zhuo, Roys, & Gullapalli, 2015), and ROI analysis methods can be automated using spatial normalization that matches each metabolite image to a brain atlas (Maudsley et al, 2009;Spurny et al, 2019). Also widely used in TBI studies are global MRSI approaches, which obtain average concentrations over large 2D or 3D volumes (Cohen et al, 2007;Gasparovic et al, 2009;Govind et al, 2010;Mayer et al, 2015;Yeo et al, 2006).…”

“…Since it is well-known that TBI injury is multi-focal (Biasca & Maxwell, 2007;Bigler, 2013;Browne, Chen, Meaney, & Smith, 2011;Johnson, Stewart, & Smith, 2013), averaging over a large area of diffuse injury would be expected to yield better sensitivity to injury compared to examining a smaller region (due to the higher SNR in a larger volume). Indeed, it was recently shown that when studying NAA decreases in white matter, global linear regression had better sensitivity for discriminating patients from controls when compared with regional voxel averaging (Davitz et al, 2019). Such global approaches also eliminate bias in choosing what particular (smaller) region(s) should be interrogated.…”

“…Three-dimensional volumes are usually centered around the corpus callosum to cover these regions and the deep gray matter (George et al, 2014;Kirov et al, 2007;Holshouser et al, 2019;Sours et al, 2015), while whole-brain coverage techniques by default cover most of the supratentorial brain (Govind et al, 2010;Maudsley et al, 2015;Widerström-Noga, Govind, Adcock, Levin, & Maudsley, 2016;Maudsley et al, 2017;Babikian et al, 2018;Dennis et al, 2018). While there is no literature consensus on which exact brain region(s) to study with either SVS or MRSI, recent evidence suggests that for maximum sensitivity to white matter injury, location is less important than the sensitivity of the method (Davitz et al, 2019).…”

“…Specifically, it was found that NAA deficits in patients would have been detected in white matter regions, as long as the MRS technique yielded coefficients of variation of less than 8%, a feat achievable with large single-voxels, or global MRSI approaches, such as linear regression over 2D or 3D volumes (Davitz et al, 2019).…”