Mild Traumatic Brain Injury with Associated Visual System Dysfunction: Investigating Histopathology, Functional Correlates, and a Novel Therapeutic Immune Modulator

Abstract

Arguably the most important recognitions are due to my parents Michael and Sally, and my siblings Jessica, Lara, and Michael. You helped mold me into the person I am, and have provided unwavering support and assistance through my entire journey. No words can convey my gratitude. Also to my beautiful and intelligent daughter Elowyn, you are too young to read this now but you have brought me joy and grounded me through some of the toughest days. You have also frustrated me to tears, a feat your grandfather would be proud of. To my best friends, Erin Gooch, Jordan Toler, and Dr. Brienne Petcher. You women are beautiful and amazing, and I am honored that you are a part of my life. All of these people have graced my life with so many blessings, it is truly unbelievable to reflect on. Lastly, to my husband, Dr. Patrick Guley, the most analytical and thoroughly skeptical scientist I have ever met. Your incessant love of debate has often challenged my patience, while simultaneously expanding my mind to explore possibilities and topics I would never have previously considered. I cannot thank you enough for the countless hours you've spent discussing my research, giving opinions and suggestions, and critiquing conclusions at every step of the way. When we joined our hands in marriage, we vowed to always pursue the truth, and I could not have asked for a better partner in exploring every inch of this wondrous cosmos. I love you with all of my being. vi ABSTRACT Background. Traumatic brain injury (TBI) is a significant source of morbidity and mortality worldwide. Injuries associated with moderate to severe TBI can be profound, and have historically overshadowed the significant impact mild TBI (mTBI) can have on the lives of affected individuals. Mild TBI can manifest in a number of different ways, but one of the most significant and often debilitating is its impact on the visual system. In order to further investigate the underlying pathology of mTBI and test potential therapeutics, we developed a mouse model of mTBI induced by blast overpressure. In this model, a 50-60 psi blast wave from a highly pressurized bolus of air is directed at a focal region of the left lateral cranium of a mouse, and produces replicable motor, emotional, and visual system deficits with concomitant histopathology. Importantly, this model closely simulates functional visual system damage seen in human cases of mTBI. A major component of the brain's reaction to trauma is an immune response that can cause additional long-term damage above and beyond that of the initial injury. This response was observed in our model as regions of microglial cell activation throughout areas of the brain important for visual processing. A novel therapeutic drug acting at cannabinoid type 2 receptors (CB2), known as SMM-189, had previously shown promise in improving visual outcome after mTBI in our model, but no studies were done to elucidate the cause of this improvement. The purpose of this dissertation was to further characterize visual system dysfunction and histopa...

Long-Term Functional and Structural Consequences of Primary Blast Overpressure to the Eye

“…Several studies have reported thinning of the retina in response to blast injury 53,54 ; yet, other studies have also reported thickening. 55,56 The severity of the blast overpressure conditions employed may contribute to these differences.…”

Post traumatic amnesia as a predictor for development and recovery of visual field defects following mild traumatic brain injury (mTBI)

“…This response was observed in their model as regions of microglial cell activation throughout areas of the brain important for visual processing. 25 Yet another study concluded that TBI of any form can cause cognitive, behavioral and immunologic changes in later life, which underscores the problem of underdiagnosis of mild TBI that can cause long-term neurological deficits. TBI disrupts the blood -brain barrier (BBB) leading to infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration.…”

The onset and recovery timeline of visual photosensitivity following mild traumatic brain injury with special focus on habitual digital device screens users

“…[ 3 4 ] Traumatic brain injury disrupts the blood–brain barrier, leading to the infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration or disruption of neural networks, thus resulting in the manifestation of symptoms. [ 5 6 ]…”

“…[3,4] Traumatic brain injury disrupts the blood-brain barrier, leading to the infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration or disruption of neural networks, thus resulting in the manifestation of symptoms. [5,6] The most common visual deficits associated with mTBI include oculomotor dysfunction (accommodative, version, and vergence) and their associated reading problems, photosensitivity, and visual field defects. [4,7,8] Visual photosensitivity is an abnormal intolerance to light.…”