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.

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.

Mild traumatic brain injury (mTBI) is the most common neurological disorder and is typically characterized by temporally limited cognitive impairment and emotional symptoms. Previous examinations of intrinsic resting state networks in mTBI have primarily focused on abnormalities in static functional connectivity, and deficits in dynamic functional connectivity have yet to be explored in this population. Resting-state data was collected on 48 semi-acute (mean = 14 days post-injury) mTBI patients and 48 matched healthy controls. A high-dimensional independent component analysis (N = 100) was utilized to parcellate intrinsic connectivity networks (ICN), with a priori hypotheses focusing on the default-mode network (DMN) and sub-cortical structures. Dynamic connectivity was characterized using a sliding window approach over 126 temporal epochs, with standard deviation serving as the primary outcome measure. Finally, distribution-corrected z-scores (DisCo-Z) were calculated to investigate changes in connectivity in a spatially invariant manner on a per-subject basis. Following appropriate correction for multiple comparisons, no significant group differences were evident on measures of static or dynamic connectivity within a priori ICN. Reduced (HC > mTBI patients) static connectivity was observed in the DMN at uncorrected (p < 0.005) thresholds. Finally, a trend (p = 0.07) for decreased dynamic connectivity in patients across all ICN was observed during spatially invariant analyses (DisCo-Z). In the semi-acute phase of recovery, mTBI was not reliably associated with abnormalities in static or dynamic functional connectivity within the DMN or sub-cortical structures.

Objective: To examine the underlying pathophysiology of mild traumatic brain injury through changes in gray matter diffusion and atrophy during the semiacute stage.Methods: Fifty patients and 50 sex-, age-, and education-matched controls were evaluated with a clinical and neuroimaging battery approximately 14 days postinjury, with 26 patients returning for follow-up 4 months postinjury. Clinical measures included tests of attention, processing speed, executive function, working memory, memory, and self-reported postconcussive symptoms. Measures of diffusion (fractional anisotropy [FA], mean diffusivity) and atrophy were obtained for cortical and subcortical structures to characterize effects of injury as a function of time.Results: Patients reported more cognitive, somatic, and emotional complaints during the semiacute injury phase, which were significantly reduced 4 months postinjury. Patients showed evidence of increased FA in the bilateral superior frontal cortex during the semiacute phase, with the left superior frontal cortex remaining elevated 4 months postinjury. There were no significant differences between patients and matched controls on neuropsychological testing or measures of gray matter atrophy/mean diffusivity at either time point.Conclusions: Increased cortical FA is largely consistent with an emerging animal literature of gray matter abnormalities after neuronal injury. Potential mechanistic explanations for increased FA include cytotoxic edema or reactive gliosis. In contrast, there was no evidence of cortical or subcortical atrophy in the current study, suggesting that frank neuronal or neuropil loss does not occur early in the chronic disease course for patients with typical mild traumatic brain injury. Although numerous diffusion tensor imaging studies have explored axonal integrity after mild traumatic brain injury (mTBI), 1,2 the effects of mTBI on gray matter are more poorly characterized. Previous studies reported nonsignificant trends 3 and reduced 4 anisotropic diffusion after mTBI. However, both studies were conducted with chronically symptomatic and/or mixed patient populations. Both variables contribute to neurobehavioral sequelae 5 and white matter integrity, 1 indicating the need for a well-powered study of gray matter diffusion metrics in patients with more typical mTBI. Additionally, recent animal models indicate increased anisotropy within the thalamus and hippocampus during acute and more chronic injury phases. 6,7 Although evidence of atrophy has been found as early as 1 to 3 weeks postinjury in moderate to severe TBI,8,9 it becomes more prevalent at 6 to 12 months, 10-13 even in the absence of macroscopically detectable lesions.14,15 Studies of patients with complicated 16 and symptomatic mild to moderate 17 TBI indicate atrophy as a function of disease progression approximately 6 months 16 or 1 year 17 postinjury. To our knowledge, no studies have directly assessed cortical thickness changes prospectively after mTBI.