Investigation of TBI in the Ferret Using Advanced MRI and Histopathology Technique

Mild traumatic brain injury (mTBI) is the signature wound of the Iraq and Afghanistan wars and results in a wide variety of symptoms and disabilities. Given the large number of warriors returning with mTBI and their young age, it is extremely important to develop effective therapies that will improve their quality of life and ability to return to work. However, the development and application of effective therapies is challenging because of the diverse locations of injury in the brain, the difficulty in detecting some types of injury (small structural changes resulting from blast), and the assorted symptoms across TBI patients. In order to more successfully treat patients with mTBI, it is important to accurately identify and classify their individual injury. The objective of this proposal is to precisely identify features of brain injury using advanced noninvasive magnetic resonance techniques, which can be used to guide rehabilitation.

mTBI can result in subtle and widespread brain damage that is not detectable with standard magnetic resonance imaging (MRI). Even at times when damage or changes in MRI signal are detected, the underlying physiological source is unknown and could stem from a variety of changes in the brain and be misinterpreted. Therefore, it is essential to identify markers of injury and recovery with MRI and also to identify the underlying physiological cause of these MRI markers. This proposal will establish quantitative advanced MRI methods to distinguish underlying pathology after different models of TBI.

This study will develop a ferret model of mTBI to identify the subtle changes in MRI after injury. While numerous TBI studies are ongoing using mice and rats, the ferret is an important animal for TBI research because its brain has characteristics similar to the human brain in several important aspects. Much of the damage induced by TBI appears to affect the connections in the brain (the white matter). The ferret has a high volume of white matter, with a ratio of white to gray matter that is comparable to humans. In addition, the ferret brain surface is highly folded like human brains (gyrencephalic) whereas rodent brains are smooth (lissencephalic). These features make the ferret brain more likely to react similarly to the human brain than the lissencephalic rodent brain. The Juliano lab has used the ferret for more than 15 years to study brain development; we observed several developmental features of the ferret brain that are more human-like than rodent-like. This makes the ferret a valuable animal model for determining MRI markers that can be used to detect injury and recovery in the human condition.

TBI is a leading cause of morbidity and mortality among injured warfighters. Explosive blast is currently the predominate etiology of this clinical condition among warriors. Sadly, there are no effective specific treatments for clinical practice. The main cause of this therapeutic gap is insufficient knowledge of the mechanistic basis of blast-related TBI. We propose to study in detail how blast affects the gyrencephalic ferret brain. Our project combining the study of TBI in the gyrencephalic ferret with advanced quantitative MRI techniques will evolve the field substantially in our ability to diagnose and treat TBI. The ability to document small structural changes in the brain with non-invasive techniques is essential not only for the initial diagnosis but also to monitor the efficacy of rehabilitation therapies.