Toward a High-Resolution Neuroimaging Biomarker for Mild Traumatic Brain Injury: From Bench to Bedside

Mild traumatic brain injury (mTBI) continues to be a major public health issue among our active military, veterans, and society at large. The Centers for Disease Control and Prevention (CDC) estimates that ~1.5 million people annually survive a TBI and ~230,000 require in-patient treatment. To fully gauge the efficacy of emerging therapeutic drug candidates for the treatment of mTBI, reliable biomarkers have to be identified for early detection of brain injury and subsequent prediction of the outcome. Guidelines about the use of high-resolution neuroimaging techniques in the treatment and management of mTBI recognized the substantial contribution of magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), and 2-photon imaging for their sensitivity in visualizing white matter (WM) tracts and sensorimotor circuits (1–3). MRI imaging, with its increased sensitivity to visualize WM tracts and sensorimotor circuits, the cerebellum, and extra-motor pathology and pathways, thus, is a favored approach in the search for biomarkers. The power of cutting edge imaging methodologies, in combination with collaboration and data sharing among numerous centers, is recognized in neurodegenerative research. Such a multicenter, collaborative approach for the study of neuroimaging biomarkers for mTBI has the prospect to generate data sets large enough to judge the feasibility of MRI as an outcome measure for different treatment strategies. A comparison of spatiotemporal resolution and penetration depth of various neuroimaging methods compared to MRI is shown in Figure ​Figure11. Figure 1 Comparison of spatial and temporal resolution and penetration depth of different neuroimaging techniques used in clinical and laboratory setting to investigate mild TBI, moderate/severe TBI, and blast injury. Illustration of functional neuroimaging and ... The main goal is to formulate guidelines on MRI imaging protocols for studies of mTBI focused on four broader research goals. Optimize matching of patients to available therapies for personalized mTBI treatments. Develop effective mTBI patients outcome measures for drug treatments. Design one-to-one personalized novel therapeutic strategies on individual basis. Identify promising intervention strategies and execute it for armed forces patients and civilians. Diffusion tensor imaging Diffusion tensor imaging (DTI) is a MRI method that is susceptible to the direction of water movement. It has the most sensitive and predictive MRI metric in TBI and can be used to detect pathology within neuronal WM tracts (1, 9). In mTBI, this technique effectively differentiates patients with mTBI from control patients, regardless of severity and time frame following injury, and reveals neuropathological patterns that were previously only observed in histological studies post-mortem. Specific to mTBI, the fractional anisotropy component of DTI has yielded the most reliable results. In a study examining 30 war veterans with a history of mTBI, with a subgroup of 13 showing impaired neuropsychological performance, evaluated as executive function (EF) measure, DTI detected WM differences that correlated with reduced EF performance (10). Damage to tracts of WM causes freer movement of water molecules in these areas, resulting in a decrease in the fractional anisotropy value which can function as a measure for the extent of injury. DTI biomarker findings provide novel information about brain-behavior relations that could never be gleaned from just the neuropsychological data, since group averaging neuropsychological test findings may obscure those with mTBI. However, DTI has so far proved inconsistent in the diagnosis of soldiers with blast-related mTBI and there is no consensus on the ideal method because of the small numbers of patients studied. Human study conducted on 63 US military personnel within 90 days of blast-related mTBI, all had normal CT, but 18 patients had abnormalities on DTI consistent with diffuse axonal injury (11). A new mode of MRI, called super-resolution track diffusion imaging, produces high-resolution fiber tracking and might have application in the detection of subtle abnormalities after mTBI (12). While showing great potential as a clinical biomarker or for predicting mTBI outcomes, further long-term studies are needed to understand the true value of DTI in this field.