A Tmu/Nih Integrated Research Project (4-2)─ Establishment of Diagnostic Tools and Treatment Strategies of Mild Traumatic Brain Injury

The prevalence, morbidity and mortality rates and costs associated with mild traumatic brain injury (mTBI) are rising rapidly but no standard preventative measures, diagnosis or treatment exist. This is partly based on the knowledge that closed head injuries far outnumber the penetrative head injuries on which official statistics are based. This proposal is motivated by the recognition that mTBI, particularly late onset mTBI, is a hidden medical problem that may be mitigated by early diagnosis and intervention. For this 4-nation international research integration, the Taipei Medical University(TMU), Wan Fang Hospital (WH) and Shuang He Hospital (SHH) will carry out in both animal model and mTBI patients: 1. transcriptional and translational profiles of mTBI; 2. diagnostic tools and treatment strategies of mTBI; 3. mTBI neuroimaging; and 4. circadian rhythm function after mTBI. The NIH site will carry out in animal models: 1. genomic studies; 2. fMRI measurements; 3. biomedical, histological and behavioral experiments; 4. studies on pineal circadian rhythms; and 5. medication development using medicinal chemistry approaches for anti-apoptotic and anti-inflammatory drugs. The NIH staffs participating are: Barry Hoffer, M.D., Ph.D.-NIDA; Elliot Stein, Ph.D.-NIDA; Amina Woods, Ph.D.-NIDA; Nigel Greig, Ph.D.-NIA and David Klein, Ph.D.-NICHD. The Principle Investigator for Taipei Medical University is Wen-Ta Chiu, M.D., Ph.D., President, Taipei Medical University, Professor, School of Medicine, Taipei Medical University, Taiwan and his staff Drs. Yung-Hsiao Chiang, M.D., Ph.D. –TMUH; Shin-Han Tsai, M.D., Ph.D -SSH; Jia-Wei Lin, M.D., Ph.D. –SSH; Chi-Jen Chen, M.D. –SSH; Jenn-Han Chen, M.D., Ph.D. –WFH; Kuo-Sheng Hung, M.D., Ph.D. –WFH. The Israeli site will carryout open field calibrated blasts of defined over-and underpressure in rats and mice. Test of neurological function, cognitive behaviour and emotional behaviour will then be made at Tel-Aviv University. Tissue will then be sent to other sites for cellular and molecular analysis as described above. The Swedish site will carry out analysis of gene expression using gene chips and in situ hybridization. Gene expression analysis will be confirmed by quantitative PCR, using the genomic data from the Taiwan and NIH sites, as well as their own. This project is designed to establish the diagnosis and treatment strategies of mild traumatic brain injury (mTBI). We conducted an epidemiology study of mTBI in the Taipei city area from July 1, 2001 to June 30, 2002. Totally, 3,243 cases from 22 hospitals were procured. Among these cases, about 10% of them had severe disability and death, and 25% of them developed intracranial hematoma later on. In consistence with our data, the Centers for Disease Control of US have focused considerable attention to short and long-term consequences of blunt trauma and acceleration/deceleration mTBI. This programmatic effort recognizes the significant prevalence, morbidity and mortality rates and costs in civilian and military populations. Since the symptoms are often unrecognized and untreated, they may be manifest at a later time in clinical entitities that include signs and symptoms of post-traumatic migraine and post-traumatic Ménière’s disease. This research plan is a collaborative effort by experienced research teams from United States and Taiwan to use their unique expertise to improve detection, diagnosis, treatment and management of mTBI related symptoms. One of the most common symptoms of TBI is balance disorders. While the incidence of vertigo associated with TBI has been estimated to be 30-40%, the percentage of individuals with any type of balance disorder as a manifestation of TBI is over 80%. The significance of balance disorders goes beyond their frequency. Loss of this sense makes recovery of other (higher brain functions) extremely difficult. Despite the frequency and significance of post-traumatic balance disorders, very little medical research concerning this malady has been published. And, what work has been done focuses largely on post-blunt trauma dizziness with little attention given to mTBI. Balance disorders and cognitive disorders are two of the main core disabilities seen after mTBI. These two disorders may actually be more closely linked than previously appreciate and more accurately studied together. Cognitive function, specifically attention, has been shown to have an influence on balance and postural control. People with balance problems have been shown to have increased requirements of attention in postural control. Patients with vestibular disorders have also been shown to require increased attentional resources to maintain. Yardley, et al. (2001) examined vestibular disorder patients with chronic complaints of ongoing dizziness or unsteadiness, showing that high postural requirements had differentially higher interference on cognitive task performance in patients compared to controls. The project will then focus on developing diagnostic test protocols to better identify this population. Along with standard tests, two new diagnostic techniques will incorporated in a deliverable suite of integrated tests that can be used as far forward as possible in medicine to accurately diagnose both mTBI and mTBI associated balance disorders. This goal is critical because extraneous tests are time consuming, fatiguing, and often confusing both in the clinics and at medial centers. Outcome measures will be analyzed to identify the best prognostic indicators and provide most essential information about functional recovery. The project will then provide the background data necessary for examining the impact of novel treatment strategies (pharmacologic and rehabilitative) fed to this portion of the study by the basic science components of this project. This will allow for the most effective and rapid translation of basic work to clinical product. This proposal is designed to serve goals of Specific aims 1, 2, 3, and 4 so that clinical data inform animal model research and animal model research generates new clinical treatment strategies. Thus patients who receive standard of care treatment to control migraine headache will be randomized into three groups: no additional treatment, versus two groups receiving additional agents that have been shown to be effective in ototoxicity. The effects of these treatments will be evaluated in the patients. A successful outcome of these clinical trials will trigger parallel animal model studies with mTBI to determine mechanisms of action and refine the therapeutic strategies. In this 3-year proposal, we are to study 4 specific aims. They are: (1) Specific aim 1. Determine the prevalence of post-traumatic balance disorders within a population of mTBI patients, (2) Specific aim 2. Determine sub-populations of post-traumatic balance disorders within a mTBI population, (3) Specific aim 3. Determine the most effective diagnostic techniques for identifying the presence of balance disorders in a mTBI population and examine if any of these techniques provide an insight into the whole TBI disorder, (4) Specific aim 4. Determine which outcome measures are the most sensitive indicators of progress in treatment and the most closely related to functional recovery, and (5) Specific aim 5. Determine the effect of two established agents N-acetyl cysteine (NAC) and an Interleukin-1 receptor antagonist (IL-1ra) on outcomes in individuals receiving current standard of care treatment for balance disorders secondary to mTBI and to relate these results to animal models undergoing treatment with the same active agents.