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.

The relationship between head motion and diffusion values such as fractional anisotropy (FA) and mean diffusivity (MD) is currently not well understood. Simulation studies suggest that head motion may introduce either a positive or negative bias, but this has not been quantified in clinical studies. Moreover, alternative measures for removing bias as result of head motion, such as the removal of problematic gradients, has been suggested but not carefully evaluated. The current study examined the impact of head motion on FA and MD across three common pipelines (tract-based spatial statistics, voxelwise, and region of interest analyses) and determined the impact of removing diffusion weighted images. Our findings from a large cohort of healthy controls indicate that while head motion was associated with a positive bias for both FA and MD, the effect was greater for MD. The positive bias was observed across all three analysis pipelines and was present following established protocols for data processing, suggesting that current techniques (i.e., correction of both image and gradient table) for removing motion bias are likely insufficient. However, the removal of images with gross artifacts did not fundamentally change the relationship between motion and DTI scalar values. In addition, Monte Carlo simulations suggested that the random removal of images increases the bias and reduces the precision of both FA and MD. Finally, we provide an example of how head motion can be quantified across different neuropsychiatric populations, which should be implemented as part of any diffusion tensor imaging quality assurance protocol.

Pediatric mild traumatic brain injury (pmTBI) is the most prevalent neurological insult in children and is associated with both acute and chronic neurobehavioral sequelae. However, little is known about underlying pathophysiology and how injuries change as a function of recovery. Fractional anisotropy, axial diffusivity, and radial diffusivity were examined in 15 semi-acute pmTBI patients and 15 wellmatched controls, with a subset of participants returning for a second visit. A novel analytic strategy was applied to capture spatially heterogeneous white matter injuries (lesions) in addition to standard analyses. Evidence of cognitive dysfunction after pmTBI was observed in the domains of attention (p ϭ 0.02, d ϭ Ϫ0.92) and processing speed (p ϭ 0.05, d ϭ Ϫ0.73) semi-acutely. Region of interest (ROI) and voxelwise analyses indicated increased anisotropic diffusion for pmTBI patients, with an elevated number of clusters with high anisotropy. Metrics of increased anisotropy were able to objectively classify pmTBI from healthy controls at 90% accuracy but were not associated with neuropsychological deficits. Little evidence of recovery in white matter abnormalities was observed over a 4-month interval in returning patients, indicating that physiological recovery may lag behind subjective reports of normality. Increased anisotropic diffusion has been previously linked with cytotoxic edema after TBI, and the magnitude and duration of these abnormalities appear to be greater in pediatric patients. Current findings suggest that developing white matter may be more susceptible to initial mechanical injury forces and that anisotropic diffusion provides an objective biomarker of pmTBI.

Previous work suggests that the ability to selectively attend to and resolve conflicting information may be the most enduring cognitive deficit following mild traumatic brain injury (mTBI). The current study used fMRI to evaluate potential differences in hemodynamic activation in 22 mTBI patients and 22 carefully matched healthy controls (HC) during a multimodal selective attention task (numeric Stroop). Behavioral data indicated faster reaction times for congruent versus incongruent trials and for stimuli presented at 0.66 compared to 0.33 Hz across both groups, with minimal differences in behavioral performance across the groups. Similarly, there were no group-wise differences in functional activation within lateral and medial prefrontal cortex during the execution of cognitive control (incongruent versus congruent trials). In contrast, within-group comparisons indicated robust patterns of attention-related modulations (ARM) within the bilateral dorsolateral prefrontal cortex and bilateral visual streams for HC but not mTBI patients. In addition, mTBI patients failed to exhibit task-induced deactivation within the default-mode network (DMN) under conditions of higher attentional load. In summary, in spite of near normal behavioral performance, current results suggest within-group abnormalities during both the top-down allocation of visual attention and in regulating the DMN during the semi-acute stage of mTBI.

Although several functional magnetic resonance imaging (fMRI) studies have been conducted in human models of mild traumatic brain injury (mTBI), to date no studies have explicitly examined how injury may differentially affect both the positive phase of the hemodynamic response function (HRF) as well as the post-stimulus undershoot (PSU). Animal models suggest that the acute and semi-acute stages of mTBI are associated with significant disruptions in metabolism and to the microvasculature, both of which could impact on the HRF. Therefore, fMRI data were collected on a cohort of 30 semi-acute patients with mTBI (16 males; 27.83 -9.97 years old; 13.00 -2.18 years of education) and 30 carefully matched healthy controls (HC; 16 males; 27.17 -10.08 years old; 13.37 -2.31 years of education) during a simple sensory-motor task. Patients reported increased cognitive, somatic, and emotional symptoms relative to controls, although no group differences were detected on traditional neuropsychological examination. There were also no differences between patients with mTBI and controls on fMRI data using standard analytic techniques, although mTBI exhibited a greater volume of activation during the task qualitatively. A significant Group · Time interaction was observed in the right supramarginal gyrus, bilateral primary and secondary visual cortex, and the right parahippocampal gyrus. The interaction was the result of an earlier time-to-peak and positive magnitude shift throughout the estimated HRF in patients with mTBI relative to HC. This difference in HRF shape combined with the greater volume of activated tissue may be indicative of a potential compensatory mechanism to injury. The current study demonstrates that direct examination and modeling of HRF characteristics beyond magnitude may provide additional information about underlying neuropathology that is not available with more standard fMRI analyses.