Two Coarse Spatial Patterns of Altered Brain Microstructure Predict Post-traumatic Amnesia in the Subacute Stage of Severe Traumatic Brain Injury

Abstract

Introduction: Diffuse traumatic axonal injury (TAI) is one of the key mechanisms leading to impaired consciousness after severe traumatic brain injury (TBI). In addition, preferential regional expression of TAI in the brain may also influence clinical outcome. Aim: We addressed the question whether the regional expression of microstructural changes as revealed by whole-brain diffusion tensor imaging (DTI) in the subacute stage after severe TBI may predict the duration of post-traumatic amnesia (PTA). Method: Fourteen patients underwent whole-brain DTI in the subacute stage after severe TBI. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for five bilateral brain regions: fronto-temporal, parieto-occipital, and midsagittal hemispheric white matter, as well as brainstem and basal ganglia. Region-specific calculation of mean FA and MD only considered voxels that showed no tissue damage, using an exclusive mask with all voxels that belonged to local brain lesions or microbleeds. Mean FA or MD of the five brain regions were entered in separate partial least squares (PLS) regression analyses to identify patterns of regional microstructural changes that account for inter-individual variations in PTA. Results: For FA, PLS analysis revealed two spatial patterns that significantly correlated with individual PTA. The lower the mean FA values in all five brain regions, the longer that PTA lasted. A pattern characterized by lower FA values in the deeper brain regions relative to the FA values in the hemispheric regions also correlated with longer PTA. Similar trends were found for MD, but opposite in sign. The spatial FA changes as revealed by PLS components predicted the duration of PTA. Individual PTA duration, as predicted by a leave-one-out cross-validation analysis, correlated with true PTA values (Spearman r = 0.68, p _permutation = 0.008). Conclusion: Two coarse spatial patterns of microstructural damage, indexed as reduction in FA, were relevant to recovery of consciousness after TBI. One pattern expressed was consistent with diffuse microstructural damage across the entire brain. A second pattern was indicative of a preferential damage of deep midline brain structures.

Keywords: diffusion tensor imaging; disorders of consciousness; partial least squares analysis; post-traumatic amnesia; prediction; traumatic brain injury.

Figure 1

Image processing. (A) Freesurfer segmentation. (B) Regions of interest (ROIs) segmentation: Fronto-temporal region (blue); parieto-occipital region (white); corpus callosum and parasagittal white matter (red); brainstem (pons, midbrain, and medulla) (dark purple); basal ganglia (caudate, putamen, and pallidum); and thalamus (bright purple). (C) The ROIs are used to extract regional diffusion tensor imaging indices, i.e., fractional anisotropy (FA) and mean diffusion (MD). (D) Normal-appearing white matter. (E) Manual outline of mass lesions and traumatic micro bleeds. (F) Mask of outlined lesions. (G) FA map. (H) MD map.

Figure 2

Component loadings. Component loadings (Comp) for the two partial least squares regression analyses predicting post-traumatic amnesia (PTA) using fractional anisotropy (FA) (first row) and mean diffusion (MD) (second row). Above each plot is noted the percentages in parentheses of FA and MD variation explained by the respective components, Spearman r correlation and p value between the component scores and PTA. Red-colored bars are the deep mesial brain regions, and the blue-colored bars are the hemispheric brain regions. FT, fronto-temporal region; PO, parieto-occipital region; CC, corpus callosum, cingular and subcingular WM; BS, brainstem (pons, midbrain, and medulla); BT, basal ganglia (caudate, putamen, and pallidum) and thalamus.

Figure 3

Correlation between predicted and true post-traumatic amnesia (PTA) scores. This figure shows the correlation between predicted and true z score normalized PTA scores using partial least square regression with leave-one-out cross-validation. The rows represent analyses performed with fractional anisotropy (FA), FA and mean diffusion (MD), FA and micro bleed (MB) volume, and FA and MB count, respectively. The first column shows the correlation between true and predicted PTA scores and lists the Spearman correlation value as well as the permutation test p-value. Columns 2–4 show the component loadings for components 1–3, respectively. Red colored bars are the deep mesial brain regions, and the blue colored bars are the hemispheric brain regions. BS, brainstem (pons, midbrain, and medulla); BT, basal ganglia (caudate, putamen, and pallidum) and thalamus; CC, corpus callosum, cingular and subcingular white matter; FT, fronto-temporal region; PO, parieto-occipital region.