Although the vast majority of all head injuries are classified as mild to moderate, many patients report persistent neuropsychiatric symptoms, despite normal clinical neuroimaging. Generally, traumatic brain injury (TBI) is difficult to detect and diagnose, and the scope of the problem is compounded significantly given that we know very little about the neuropathology and sequelae of neurotrauma. Historically, the brainstem has been implicated as a particularly vulnerable structure in the context of TBI. However, unfortunately, to our knowledge, there are no existing data relating injury severity variables (e.g., loss of consciousness [LOC]~ post-traumatic amnesia [PTA]~ number and frequency of blasts) as well as commonly experienced post-concussive symptoms (PCS~ e.g., sleep difficulties, balance/coordination problems, dizziness, tinnitus) to actual pathology in the human brain, and this could be directly related to the inability to visualize small, critical white matter tracts within the brainstem, a vital structure that is critically important for respiratory function, cardiovascular regulation, and sleep and alertness. Although it is thought that diffusion tensor imaging (DTI) can help address the shortcomings of conventional imaging techniques in the evaluation of patients with TBI, there is a lack of comprehensive, multidisciplinary TBI studies focusing on brainstem white matter integrity and injury severity markers, and research examining this population has been extremely limited. For example, to date, whole-brain DTI data in humans have been collected using multislice acquisition techniques that have limited imaging resolution to perform measurements with very thin slices, prohibiting the study of small white matter tracts and deep intracranial structures (i.e., brainstem). Indeed, there are very few brainstem DTI studies in TBI, and none have assessed associations to important injury severity variables and enduring neuropsychiatric symptoms comprising the posttraumatic syndrome. Despite a paucity of DTI studies in TBI, promising findings from animal and clinical studies-as well as our own pilot data in support of this proposal-provide preliminary support for the potential use of DTI as a biomarker of TBI-related white matter injury. We thus propose to use a newly developed methodology (HARDI~ described in the Methods section of the proposal) coupled with high spatial-resolution anatomic images in order to help identify and visualize important brainstem tracts that may represent the anatomical substrates of TBI. Using this approach, millimetric slices and probabilistic tractography allow thinner brainstem tracts to be identified, especially within low anisotropic areas. Thus, in 190 veterans and combat controls (mild to moderate TBI: 120~ combat and non-combat exposed NC: 70), we will employ DTI tractography in the context of a novel, cutting edge imaging sequence and analytic approach in order to fully segment and properly visualize critical brainstem white matter tracts and relate white matter integrity to important injury severity variables and PCS symptoms across mechanism of injury (blast versus blunt force TBI). Primary aims will also examine whether and how other important injury variables (e.g., number and proximity of blasts) modify the relationship between white matter integrity and PCS symptoms in this vulnerable population. To our knowledge, our proposal represents the first to fully segment and properly visualize critical brainstem white matter tracts, examine brainstem white matter integrity by mechanism of neurotrauma, and relate DTI indices to important injury severity and PCS variables. We expect that findings will advance our knowledge of the clinical utility of DTI in identifying specific brainstem white matter changes in mild to moderate TBI, and they will provide novel information about the effects of differing mechanisms of injury on brain regions that have been shown in tissue studies to be particularly vulnerable to the effects of TBI. Clearly, linkages of injury severity characteristics and enduring PCS symptoms typically associated with vegetative signs of psychiatric origin to a neuroanatomic substrate would have very important implications for this relatively new field.
The proposed state-of-the-art, multidisciplinary study will use advanced neuroimaging methods (quantitative DTI tractography) in order to relate important injury severity variables (e.g., LOC, PTA) and highly prevalent neurobehavioral symptoms that comprise the post-concussive syndrome (e.g, sleep disturbance, balance/coordination difficulties, dizziness) to white matter changes in the brainstem, a vulnerable structure that, to date, has been especially difficult to properly visualize upon neuroimaging. Across each aim, we will examine whether brainstem DTI indices are uniquely associated with mechanism of injury. Exploratory analyses will assess whether brainstem DTI indices are associated with cognitive and psychosocial outcome, and whether diffusion metrics (axial diffusivity [AD] and radial diffusivity [RD]) assist in understandng changes that might be seen with increasing chronicity from time of injury.