Characterization of Thalamocortical Dysrhythmia in Mild Traumatic Brain Injury Using Simultaneous Mri and Eeg Measurements and Pre-Clinical N-Acetylcysteine Treatment Response

The relation between thalamocortical dysrhythmia (TCD) and post-concussive syndrome (PCS) in mild traumatic brain injury (mTBI) patients has recently been recognized in several studies [1-3]; however the potential imaging biomarkers to evaluate neurological functional deficits and to localize TCD, in particular the thalamocortical circuits, have not been established. Based on the current understanding of the mTBI, network dysfunction of thalamocortical circuits is the one of main points of investigation which is characterized by microstructural injuries [4-7], disrupted functional connectivity [1, 8, 9], and the altered interplay between excitatory and inhibitory neurotransmitters [10]. The elevated synaptic glutamate levels after mTBI can further exacerbate the post-traumatic cellular injury [11]. Recent studies have indicated that mTBI patients can benefit from N-acetylcysteine (NAC) treatment by effectively improving the behavioral deficits which had a significant impact on neuropsychological test results [12-14]. Though the cognitive tests outcome after administration of NAC is promising, the neuroimaging evidence of NAC treatment efficacy on mTBI and its prevention of subsequent brain atrophy had not been well explored. The purpose of this study is to propose a TCD model in mTBI by simultaneous measurements of MRI and MR-compatible EEG on human participants followed by a pre-clinical experiment using animal mTBI model to evaluate the therapeutic effect of NAC on mTBI. Through the characterization of the neural network dysfunction from the perspectives of neural electrophysiology, microstructure integrity, and hemodynamic synchrony, we will be able to have a complete vision on the pathophysiological mechanism in mTBI. In addition, this study can help provide the neuroimaging evidence of the NAC efficacy in treating mTBI. The specific aims for this three-year project comprise: 1. Characterize the TCD in patients with mTBI by measuring the theta shift and gamma activity on cortical surface (EEG), microstructural injuries in white matter (MR fractional anisotropy), disrupted thalamocortical connectivity (MR diffusion tensor tractography and fMRI connectivity), and the altered GABA concentrations (MR spectroscopy). 2. Construct a norm of thalamocortical oscillation including the above-mentioned EEG and MRI features from 40 healthy volunteers. 3. Localize TCD at specific cortical regions based on the alterations of structural and functional thalamocortical connectivity compared to the constructed norm. 4. Correlate the impairments of thalamocortical circuits with PCS and the impaired neurocognitive performance by comparing between the sub-categorized mTBI cohorts. 5. Provide neuroimaging evidence of the treatment efficacy of NAC in mTBI and investigate the restoration or reconnection of thalamocortical circuits at follow-up using an animal model. 6. Identify the potential image biomarkers for predicting the cortical regions of brain atrophy 3 months after brain injury.