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. 2012 Apr;135(Pt 4):1281-92.
doi: 10.1093/brain/aws073.

Biomarkers of Increased Diffusion Anisotropy in Semi-Acute Mild Traumatic Brain Injury: A Longitudinal Perspective

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Free PMC article

Biomarkers of Increased Diffusion Anisotropy in Semi-Acute Mild Traumatic Brain Injury: A Longitudinal Perspective

Josef M Ling et al. Brain. .
Free PMC article

Abstract

Mild traumatic brain injury is the most prevalent neurological insult and frequently results in neurobehavioural sequelae. However, little is known about the pathophysiology underlying the injury and how these injuries change as a function of time. Although diffusion tensor imaging holds promise for in vivo characterization of white matter pathology, both the direction and magnitude of anisotropic water diffusion abnormalities in axonal tracts are actively debated. The current study therefore represents both an independent replication effort (n = 28) of our previous findings (n = 22) of increased fractional anisotropy during semi-acute injury, as well as a prospective study (n = 26) on the putative recovery of diffusion abnormalities. Moreover, new analytical strategies were applied to capture spatially heterogeneous white matter injuries, which minimize implicit assumptions of uniform injury across diverse clinical presentations. Results indicate that whereas a general pattern of high anisotropic diffusion/low radial diffusivity was present in various white matter tracts in both the replication and original cohorts, this pattern was only consistently observed in the genu of the corpus callosum across both samples. Evidence for a greater number of localized clusters with increased anisotropic diffusion was identified across both cohorts at trend levels, confirming heterogeneity in white matter injury. Pooled analyses (50 patients; 50 controls) suggested that measures of diffusion within the genu were predictive of patient classification, albeit at very modest levels (71% accuracy). Finally, we observed evidence of recovery in lesion load in returning patients across a 4-month interval, which was correlated with a reduction in self-reported post-concussive symptomatology. In summary, the corpus callosum may serve as a common point of injury in mild traumatic brain injury secondary to anatomical (high frequency of long unmyelinated fibres) and biomechanics factors. A spatially heterogeneous pattern of increased anisotropic diffusion exists in various other white matter tracts, and these white matter anomalies appear to diminish with recovery. This macroscopic pattern of diffusion abnormalities may be associated with cytotoxic oedema following mechanical forces, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water. Animal models more specific to the types of mild traumatic brain injury typically incurred by humans are needed to confirm the histological correlates of these macroscopic markers of white matter pathology.

Figures

Figure 1
Figure 1
Fractional anisotropy (FA) values from all regions of interest. This figure presents the mean FA values from the replication cohort during their first visit. Fractional anisotropy values are corrected for differences in premorbid intelligence, patients with mild TBI (mTBI) represented by black bars and healthy controls (HC) by grey bars. Error bars represent the standard deviation of the sample. (A) Regions of interest include (A) the genu (GNU), body (BDY) and splenium (SPL) of the corpus callosum (CC), as well as the superior corona radiata (SCR), the superior longitudinal fasciculus (SLF), the uncinate fasciculus (UF), the corona radiata (CR), and the internal capsule (IC) from the left (B) and right (C) hemispheres. Significant effects are denoted with double asterisks, statistical trends with a single asterisk.
Figure 2
Figure 2
Cluster analysis. This figure shows the mean square root of the number of clusters and their associated volumes for which individual subject z-scores exhibited low (z ≤ −2 SD below the pooled healthy controls mean) or high (z ≥ 2 SD above the healthy controls mean) anisotropy. All values are corrected for differences in premorbid intelligence, with mild traumatic brain injury patients (mild TBI) represented by black bars and healthy controls (HC) by grey bars (error bar = SD). (A) Results for the original cohort of patients and controls, whereas (B) represents the replication cohort. Significant effects are denoted with double asterisks, statistical trends with a single asterisk.
Figure 3
Figure 3
Cluster results as a function of voxel threshold. The y-axis represents the square root of the mean number (top) and mean volume (bottom panel) for clusters exhibiting high anisotropy (z ≥ 2.0) in patients with mild traumatic brain injury (mild TBI; black bars) and healthy controls (HC; grey bars). The x-axis represents different minimal cluster volume thresholds, ranging between 32 and 320 µl. Error bars represent the standard deviation. A full range of voxel thresholds (16–1008 µl) are shown in Supplementary Fig. 1.
Figure 4
Figure 4
Longitudinal measures of high anisotropy. This figure presents longitudinal changes in anisotropy measures for patients with mild traumatic brain injury (mild TBI; black bars) and healthy controls (HC; grey bars). Solid bars indicate data from Visit 1 whereas bars with diagonals show Visit 2 data, with all error bars equivalent to the standard deviation. (A) Mean fractional anisotropy (FA) of the genu of the corpus callosum, whereas the number of clusters with high anisotropic diffusion (z ≥ 2.0) and their respective volumes are presented in (B) and (C), respectively. Significant effects are denoted with double asterisks.

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