Traumatic brain injury (TBI) is a serious public health problem. Even injuries classified as mild, the most common, can result in persistent neurobehavioural impairment. Diffuse axonal injury is a common finding after TBI, and is presumed to contribute to outcomes, but may not always be apparent using standard neuroimaging. Diffusion tensor imaging (DTI) is a more recent method of assessing axonal integrity in vivo. The primary objective of the current investigation was to characterize white matter integrity utilizing DTI across the spectrum of chronic TBI of all severities. A secondary objective was to examine the relationship between white matter integrity and cognition. Twenty mild, 17 moderate to severe TBI and 18 controls underwent DTI and neuropsychological testing. Fractional anisotropy, axial diffusivity and radial diffusivity were calculated from the DTI data. Fractional anisotropy was the primary measure of white matter integrity. Region of interest analysis included anterior and posterior corona radiata, cortico-spinal tracts, cingulum fibre bundles, external capsule, forceps minor and major, genu, body and splenium of the corpus callosum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus and sagittal stratum. Cognitive domain scores were calculated from executive, attention and memory testing. Decreased fractional anisotropy was found in all 13 regions of interest for the moderate to severe TBI group, but only in the cortico-spinal tract, sagittal stratum and superior longitudinal fasciculus for the mild TBI group. White Matter Load (a measure of the total number of regions with reduced FA) was negatively correlated with all cognitive domains. Analysis of radial and axial diffusivity values suggested that all severities of TBI can result in a degree of axonal damage, while irreversible myelin damage was only apparent for moderate to severe TBI. The present data emphasize that white matter changes exist on a spectrum, including mild TBI. An index of global white matter neuropathology (White Matter Load) was related to cognitive function, such that greater white matter pathology predicted greater cognitive deficits. Mechanistically, mild TBI white matter changes may be primarily due to axonal damage as opposed to myelin damage. The more severe injuries impact both. DTI provides an objective means for determining the relationship of cognitive deficits to TBI, even in cases where the injury was sustained years prior to the evaluation.

Objective: To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury.Methods: High-resolution (voxel size: 0.78 mm ϫ 0.78 mm ϫ 3 mm 3 ) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age-and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei). Results:Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory. Conclusions:The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury results in damage to the thalamic projection fibers and is of clinical relevance to cognition. Neurology ® 2010;74:558 -564 GLOSSARY ACR ϭ anterior corona radiata; AN ϭ anterior thalamic nucleus; bCC ϭ body of the corpus callosum; CST ϭ cortical-spinal tract; DAI ϭ diffuse axonal injury; DM ϭ dorsomedial nucleus; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; fMaj ϭ forceps major; fMin ϭ forceps minor; FOV ϭ field of view; FSE ϭ fast spin echo; gCC ϭ genu of the corpus callosum; IC ϭ internal capsule; IFOF ϭ inferior frontal occipital fasciculus; LOC ϭ loss of consciousness; miTBI ϭ mild TBI; msTBI ϭ moderate to severe TBI; NEX ϭ number of excitations; PCR ϭ posterior corona radiata; PTA ϭ posttraumatic amnesia; PU ϭ pulvinar; ROI ϭ region of interest; sCC ϭ splenium of the corpus callosum; SLF ϭ superior longitudinal fasciculus; SS ϭ sagittal stratum; TBI ϭ traumatic brain injury; TE ϭ echo time; TR ϭ repetition time; VA ϭ ventral anterior thalamic nucleus; VL ϭ ventral lateral thalamic nucleus; VPL ϭ ventral posterior lateral nucleus; VPM ϭ ventral posterior medial nucleus. Traumatic brain injury (TBI) is a serious public health problem with a high incidence 1-3 which can result in structural damage to the cerebrum including contusions, edema, and diffuse axonal injury (DAI).4 DAI has been demonstrated in all stages and severities [5][6][7] and is often the only significant pathology in milder injury...

Following mild traumatic brain injury (TBI), a percentage of individuals report chronic memory and attention difficulties. Traditional neuropsychological assessments often fail to find evidence for such complaints. We hypothesized that mild TBI patients may, in fact, experience subtle cognitive deficits that reflect diminished initial acquisition that can be explained by changes in cerebral white matter microstructure. In the data presented here, a sample of nonlitigating and gainfully employed mild TBI patients demonstrated statistically significant differences from age and education matched control participants in performance on the first trial of a verbal learning task. Performance on this trial was associated with reduced fractional anisotropy in the uncinate fasciculus and the superior longitudinal fasciculus providing an anatomical correlate for the cognitive findings. Mild TBI patients were not impaired relative to control participants on total learning or memory composite variables. Performance on the first learning trial was not related to any psychological variables including mood. We concluded that patients with mild TBI demonstrate diminished verbal learning that is not often interpreted in standard neuropsychological assessment.

This is the first known study to assess amantadine in chronic TBI using PET and the data are consistent with the hypotheses. The conduction of further studies is warranted.