Mild Traumatic Brain Injury and Sports-Related Head Impacts Induce Structural, Functional and Neuropathological Changes : Evidence from Experimental Models Guided by a Reverse-Translational Approach
出版項
2020
說明
1 online resource (324 pages)
文字
text
無媒介
computer
成冊
online resource
附註
Source: Dissertations Abstracts International, Volume: 82-03, Section: B
Advisor: Lipton, Michael L;Branch, Craig A
Thesis (Ph.D.)--Albert Einstein College of Medicine, 2020
Includes bibliographical references
While regular exercise has many health benefits, the play of sports is also associated with risk for head injury. It is estimated that nearly 4 million recreational and sports-related concussions occur annually at all ages in the United States. In addition to concussion, athletes can accumulate hundreds, or even thousands, of non-concussive impacts to the head over the course of a single season. These repetitive knocks to the head are "clinically silent" as they do not result in diagnosed concussion or overt acute symptoms and are also known as repetitive subconcussive head impacts (RSHI). Although termed "subconcussive" due to a lack of acute symptoms, subconcussive impacts still apply force to the brain, which may lead to subclinical pathologic changes. There is growing concern about the potential cumulative effects of RSHI on long-term brain health and behavior. Animal models are necessary in translational research, as they contribute valuable preclinical information about injury characteristics and the underlying mechanisms of brain injury. The best characterized and most used traumatic brain injury (TBI) models to date have employed models of relatively severe TBI in that they induce gross brain pathology or significant axonal death using penetrating head impact methods. While these models have significantly contributed to our understanding of more severe TBI, there is a need for effective animal models of less severe TBI. However, such models are scarce and a model specific for RSHI has not been described in the animal literature to date.Diffusion tensor imaging (DTI) has emerged as an MRI method able to detect microstructural damage not visible on standard anatomical images by characterizing the directional coherence of water diffusion in-vivo. DTI has allowed for detection of alterations in white matter microstructure associated with both mild TBI and RSHI. Despite the advancements made in TBI research, research on concussion and RSHI is still in its infancy as many knowledge gaps need to be addressed related to the short- and long-term effects on brain and behavior. Therefore, I sought to investigate the structural, functional and neuropathological characteristics associated with truly mild TBI and RSHI in two rodent models utilizing longitudinal DTI to characterize white matter changes over time, in addition to behavioral assessment and histopathological analysis. A single, very mild TBI resulted in detectable changes by DTI in rats, which peaked at 1-week and returned to baseline values by 2 weeks post-injury demonstrating the evolving nature of the brain's response to injury and recovery. To study the effects of RSHI, I developed a novel animal model, which entails 140 impacts to the head over a 1-week period, far more than in any previously reported animal model of repetitive TBI to date. Importantly, animals were not anesthetized and tolerated the impact protocol with no overt changes in behavior. No overt stigmata of TBI, such as hemorrhage or skull fracture, were caused by the repeated impacts. The novel RSHI model induced attenuated white matter development in female adolescent animals, as well as acute and chronic behavioral changes that recapitulate features of human RSHI. These findings were seen in parallel with widespread and persistent microgliosis and impaired myelination in the developing brain exposed to RSHI.My graduate studies have contributed to the field of TBI by investigating the short- and long-term effects of truly mild TBI and sports-related head impacts. My work describes the first translational animal model of RSHI providing novel insights and quantitative data on white matter microstructure, behavioral outcomes and neuropathology. These studies highlight the evolving nature of the brain's response to injury and recovery, which are distinct from stress, but possibly mediated by age and sex effects. Detection of RSHI-induced developmental brain changes in the adolescent age range do not only provide novel findings, but also represent cause for concern when we consider the health and welfare of our children. Collectively, this body of work provides essential foundations for future research and supports the need for further systematic investigations to better understand the risks and consequences of repeated head impacts in sports
Electronic reproduction. Ann Arbor, Mich. : ProQuest, 2021
