A Tmu/Nih Integrated Research Project (4-3)─ Establishment of Image Diagnosis of Mild Traumatic Brain Injury by Functional Neuroimaging

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 investigate the neuroimage method to detect functional and structure changes in brain of mTBI animals. It utilizes an array of advanced neuroimaging methods to better understand the underlying neuropathology associated with mild and moderate TBI, and to develop improved methods for the assessment of such patients in clinical settings. The traumatic brain injury (TBI) produces a broad range of short- and long-term physical, cognitive, behavioral and emotional impairments that depend on the severity of the injury. While it is relatively easy to diagnose severe TBI victims who suffer direct damage to the brain tissue or to the blood brain barrier who or develop post injury edema, the diagnosis of those suffering from moderate or mild TBI is less evident. Routine and extended laboratory and clinical evaluation of mTBI patients fails to show any clear morphological brain defects, but the patients frequently suffer lasting cognitive and emotional difficulties, including various degrees of amnesia, difficulty in concentration and executive functions, depression, apathy and anxiety. Although clinical signs and symptoms of mTBI usually resolve within the first year after injury, many patients continue to manifest prolonged or even permanent neurocognitive dysfunction, which has been termed “the post-concussive syndrome”. 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. More recently, Blast-Induced Traumatic Brain Injury (BI-TBI) has become one of the most prevalent injuries occurring in US military operations in Southwest Asia. A recent study by the RAND Corporation, which has since been endorsed by the military, found that 19% of all individuals involved in combat in Southwest Asia have suffered some degree of traumatic brain injury. While there are many injured war fighters who have sustained moderate and severe TBI, the overwhelming vast majority of the individuals suffer mTBI. There are signs in the on-going clinical observations that underscore the urgency of this need. In addition to hearing loss and complaints of reduced cognitive function, mTBI effects appear to include an increased prevalence and severity of prominent signs of mTBI such as headaches, constant unsteadiness (poor balance) and true vertigo. Recently, it has been estimated that at least 15% of those who serve in Iraq suffer a clinically significant degree of mTBI. 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 of balance disorders, anxiety disorders and migraine. An important component of the development of animal models of mTBI is to determine the degree to which damage incurred in these animal models can be detected and extended to clinical diagnosis in mTBI personnel. Conventional clinical neurimaging, using routine CT or MRI often fails to show signs of abnormality on initial examination. To overcome these limitations, we propose to use serial MRIs over a 6-month period from mTBI animals. We expect that the pathological phenomenon characterized initially will provide objective endpoints for assessing outcomes of pharmaceutical interventions for mTBI. Innovative MRI, and DTI analysis methods will be used. Hence, we will use state-of-the-art structural and functional neuroimaging methodologies to identify the pathophysiological effects of mTBI injury exposure in a subset of animals subjected to mTBI and after new drug treatment. In this project, we are to (1) characterize the abnormalities in spontaneous and evoked brain activity (electrophysiological studies) in mTBI and use source modeling to identify the cortical regions implicated in the generation of this activity; (2) determine whether metrics of task-related functional connectivity (inter-areal electrophysiological coherence) are associated with water maze task performance metrics in treated mTBI animals and controls; (3) determine whether a reduction in task-related coherent activity can be predicted by DTI-based measures of diffuse axonal injury in the same animal and (4) quantify the volumes of regional neuroanatomical structures that are known to be affected by atrophic processes consequent to TBI.