Biomarkers of increased diffusion anisotropy in semi-acute mild traumatic brain injury: a longitudinal perspective

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.

Abnormal White Matter Integrity Related to Head Impact Exposure in a Season of High School Varsity Football

“…[43][44][45] It is also well documented that mTBI events in children, as well as adults, have led to changes in DTI scalars, FA in particular. 22,25,26,[46][47][48] Our study shows changes in DTI scalars that are significantly associated with RWE metrics in the absence of a clinical diagnosis of concussion or clinically apparent mTBI.…”

“…23,24 The sensitivity to subtle DTI changes, especially for subconcussive impacts, can be improved by using methods that are not dependent on spatial co-localization of the injury. 25,26 In order to relate changes in imaging data or cognitive function to head impacts, an effective method of measuring the underlying biomechanical response is required. This information can be provided by the Head Impact Telemetry System (HITSÔ).…”

Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

“…The clinical implications of FA change remain controversial, as both increased and decreased FA has been observed in concussion studies. [162][163][164][165][166] These discrepancies may be due, in part, to the considerable spatial heterogeneity in the brain areas examined, 167 as well as differences in the postinjury interval. FA may still have prognostic value, with evidence suggesting that the direction and magnitude of change correlates with clinical outcomes; 166,168 however, this idea awaits validation in both paediatric and adult populations.…”

A Longitudinal Diffusion Tensor Imaging Study Assessing White Matter Fiber Tracts after Sports-Related Concussion

“…Multiple cross-sectional mTBI studies with one or more time points 67,69,71 have broadly discussed the coupled, inverse expression of RD/MD and FA measures in the acute and subacute phases postinjury, that is, increased RD/MD and/or decreased FA or decreased RD/MD and/or increased FA with respect to matched controls. The results of the current study support an earlier hypothesis 24 on the role of focal neurofilament misalignment, as an initializing mechanism leading to decreased FA, increased RD, and reduced AD in human mTBI patients (GCS [13][14][15] imaged approximately 24 h postinjury.…”