Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes

Abstract

Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated to the clinic. Increased importance on the progressive, long-term consequences of TBI have been emphasized, both in the experimental and clinical literature. Thus, there is a need for a better understanding of the chronic consequences of TBI, with the ultimate goal of developing novel therapeutic interventions to treat the devastating consequences of brain injury. In models of mild, moderate, and severe TBI, histopathological and behavioral studies have emphasized the progressive nature of the initial traumatic insult and the involvement of multiple pathophysiological mechanisms, including sustained injury cascades leading to prolonged motor and cognitive deficits. Recently, the increased incidence in age-dependent neurodegenerative diseases in this patient population has also been emphasized. Pathomechanisms felt to be active in the acute and long-term consequences of TBI include excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, as well as decreased neurogenesis. The current article will review many of these pathophysiological mechanisms that may be important targets for limiting the chronic consequences of TBI.

Keywords: TBI; atrophy; inflammation; neurogenesis; progressive damage; white matter.

FIG. 1.

Double-stained hematoxylin-eosin and Luxol-fast blue sections 1 year after traumatic brain injury (TBI) or sham procedure. (A) TBI animal showing gross atrophy with marked expansion of the ipsilateral lateral ventricle. (B) Sham-operated animal appearing unremarkable. (C) Higher magnification of external capsule thinning (arrows) after TBI. Reprinted from Bramlett and Dietrich (2002), with kind permission of Springer Science and Business Media.

FIG. 2.

(A) Postmortem from a patient who survived 7 years after severe TBI. Note the dilated ventricles, focal areas of white matter (WM) degeneration (arrows), atrophic corpus callosum, and prominence of the interhemispheric and Sylvian fissures reflective of generalized cortical atrophy. (B) Similar-level T1 MRI coronal section depicting comparable ventricular dilation, and also note the prominence of the cortical sulci and Sylvian fissure as well. (C) Axial fluid-attenuated inversion recovery (FLAIR) sequence depicting bilateral WM signal abnormality. (D) Resliced from the axial acquisition of the FLAIR sequence, this coronal FLAIR image shows extensive WM changes in the periventricular and deep WM of the frontal lobes, in association with the dilated ventricles. The focal areas of WM degeneration that can be seen in (A) will display as signal abnormality in the WM as shown in (D). Reprinted from Bigler and Maxwell (2011), with kind permission of IOS Press.

FIG. 3.

Continuum of biomarkers for TBI pathophysiology and its manifestation over time. Reprinted from Wang and colleagues (2013), with kind permission of the Society of Photo-Optical Instrumentation Engineers (SPIE).

FIG. 4.

Coronal brain magnetic resonance images and histopathology from rats at 1 year after controlled cortical impact (CCI; A, B, C, and D) and 1 year after sham surgery (E, F, G, and H). In the CCI example shown, a large cystic lesion was observed encompassing both the cortex and hippocampus ipsilateral to the impact at 1 year after injury. That lesion is identified as a region of hyperintensity on both the T2-weighted image (A) and the T1obs map (B) and as a region lacking perfusion (C). The corresponding histopathology (cresyl-violet–stained section through the imaging plane) confirms the location of the cystic cavity after CCI (D), but not after sham surgery (H). For figure presentation purposes, pixels outside the brain were assigned to zero intensity. Although the perfusion slice shown for injured rat (C) represents the best example of average for the overall effect of injury on CBF, it does not necessarily reflect the mean CBF for each individual region of interest. Reprinted from Kochanek and colleagues (2002), with kind permission of Mary Ann Liebert, Inc. CBF, cerebral blood flow.