Doctor of Philosophy, The Ohio State University, 2023, Neuroscience Graduate Studies Program

Traumatic brain injury (TBI) is the leading cause of injury-induced disabilities that decrease quality of life. Neuroinflammation propagated by immune cells like microglia causes or worsens post-TBI maladies and is impacted by environmental factors after injury. Stress is a significant post-TBI factor that profoundly influences inflammation and provides a gateway to dysfunctional neuroimmune responses and behavioral decline following TBI. Mounting preclinical and clinical evidence finds TBI suppresses hypothalamic-pituitary-adrenal (HPA)-axis activity in response to stressors. Even though the HPA-axis is a key mediator of stress-immune bidirectional communication, little is known about the consequences of aberrant stress responses after injury. Sleep disturbances are a clinically relevant post-TBI stressor that could better elucidate the relationship between HPA-axis dysfunction and maladaptive inflammation after TBI. Indeed, acute sleep disruption engages the dysfunctional HPA-axis after lateral fluid percussion (lFPI) with suppressed production of stress hormone, corticosterone (CORT) (Chapter 2). Sleep disruption further exacerbates TBI-induced glial-mediated inflammation and causes lasting anxiety-like behavior. Prevalence of HPA-axis dysfunction in preclinical and clinical TBI populations is better reported, however mechanisms of how TBI alters HPA-axis regulation remain unknown. To determine how TBI influences stress-responsive circuitry and long-term inflammatory and behavioral consequences of sleep disturbances, transient sleep fragmentation (SF) was used as a transient, daily stressor chronically after lFPI (Chapter 3). SF engages the intact HPA-axis of uninjured sham mice, eliciting robust neuronal activity of the first step in the HPA-axis, the paraventricular nucleus (PVN). TBI enhances glucocorticoid receptor (GR) sensitivity in the hippocampus, a major regulator of HPA-axis reactivity that could confer TBI-induced suppression, associated with suppresse (open full item for complete abstract)

Committee: Olga Kokiko-Cochran (Advisor); Leah Pyter (Committee Member); John Sheridan (Committee Member); Jonathan Godbout (Advisor) Subjects: Neurosciences

MS, University of Cincinnati, 2020, Medicine: Clinical and Translational Research

Objective: Seizures and abnormal periodic or rhythmic patterns are observed on continuous electroencephalography (cEEG) in up to half of patients hospitalized with moderate-to-severe traumatic brain injury (TBI). We aimed to determine the impact of seizures and abnormal periodic or rhythmic patterns on cognitive outcome 3 months following moderate-to-severe TBI. Design: Post-hoc analysis of a multicenter randomized, controlled phase 2 clinical trial conducted from 2010-2016 across 20 US Level I trauma centers. Patients with non-penetrating TBI and post-resuscitation Glasgow Coma Scale (GCS) 4–12 were included. Bedside cEEG was initiated per protocol upon admission to intensive care and the burden of ictal-interictal continuum (IIC) patterns including seizures was quantified. A summary global cognition score at 3 months following injury was used as the primary outcome. Measures and Main Results: 142 patients (age mean+/-SD 32+/-13 years; 131 [92%] male) survived with a mean global cognition score of 81+/-15; nearly one-third were considered to have poor functional outcome. 89/142 (63%) patients underwent cEEG, of whom 13/89 (15%) had severe IIC patterns. The quantitative burden of IIC patterns correlated inversely with the global cognition score (r=-0.57; p=0.04). In multiple variable analysis, the burden of IIC patterns was independently associated with the global cognition score after controlling for demographics, pre-morbid estimated intelligence, injury severity, sedatives and antiseizure drugs. Conclusions: The burden of seizures and abnormal periodic or rhythmic patterns was independently associated with worse cognition at 3 months following TBI. Their impact on longer-term cognitive endpoints and the potential benefits of seizure detection and treatment in this population warrant prospective study.

Committee: Scott Langevin Ph.D. (Committee Chair); Daniel Woo M.D. (Committee Member); Nanhua Zhang Ph.D. (Committee Member) Subjects: Surgery

Doctor of Philosophy, The Ohio State University, 2020, Neuroscience Graduate Studies Program

The autonomic nervous system (ANS) is a complex network responsible for coordinating the involuntary functions of the body. The sympathetic branch of the ANS innervates organs and blood vessels via spinal pathways that are severely disrupted by high level spinal cord injury (SCI). Potentially fatal autonomic dysfunction develops in individuals following a spinal cord injury (SCI) occurring above the major spinal sympathetic outflow (spinal level T6). This `dysautonomia' can manifest in a number of ways, ranging from acute bouts of hypertensive autonomic dysreflexia (AD) to chronic immune suppression, and contributes to morbidity and mortality in the population living with SCI. Due to the large number of vital functions the autonomic nervous system regulates, maintenance of the normal functioning of this network is especially important to the SCI community. Recent work has identified and characterized intraspinal anatomical changes that lead to autonomic dysfunction, but the underlying drivers of post-injury plasticity remain poorly understood. After SCI, intraspinal circuitry above and below the level of injury undergoes a slow and protracted period of structural and molecular “plasticity”; “sprouts” emerge from intact and injured axons and new synapses form on spinal neurons creating new circuitry. In this thesis, experiments were designed to further understand and quantify the anatomical changes that take place in autonomic circuitry following a severe high-level SCI. Additionally, we set out to identify the underlying causes of this maladaptive plasticity and test clinically relevant interventions to prevent the development of this aberrant network and the resulting post-SCI dysautonomia. Herein, plasticity within autonomic neural networks was evaluated after SCI and compared to those same measures in uninjured controls as well as SCI mice with various interventions. We demonstrated that after SCI, there is an increase in the number of excitatory synapses presen (open full item for complete abstract)

Committee: Phillip Popovich PhD (Advisor); Anthony Brown PhD (Committee Member); Jan Schwab MD/PhD (Committee Member); John Sheridan PhD (Committee Member) Subjects: Immunology; Neurobiology; Neurology; Neurosciences

Doctor of Philosophy, The Ohio State University, 2019, Neuroscience Graduate Studies Program

Spinal cord injury (SCI) is a devastating condition causing severe loss of motor, sensory, and autonomic function below where the injury occurs. injury the cord causes severe damage to cell components, blood-spinal cord barrier, and axon tracts. However, SCI also causes hemorrhage and the release of cell content that initiate a secondary wave of inflammation and additional tissue damage. Therefore, targeting the immune system acutely after injury may prevent further damage to the cord. However, components of the neuroinflammatory response are also beneficial for spinal cord repair long-term. A deeper understanding of these divergent aspects of post-SCI inflammation and immune function could aid in the development of therapies that modulate immune responses to be less damaging while promoting their reparative properties. Translating promising therapeutics from bench to bedside has been historically grim in the context of central nervous system (CNS) injury and disease. Within the context of neuroimmunology, there are many differences in the immune systems of rodents and humans that may preclude the translation of therapeutic strategies, warranting a further understanding of the human immune response to SCI. However, studies involving human or large animal models are prohibitively expensive, difficult to perform, and preclude in vivo mechanistic studies. Novel models of human immune function within the context of CNS injury and disease are warranted. Humanized mice are immunocompromised mice engrafted with human immune systems, creating an in vivo model of human immune function. The premise of humanized mice originally came from a need to model HIV infection. Humanized mice have since allowed for the investigation of human immunobiology in the context of hematopoiesis, immunotherapy, immune-oncology, and infectious disease. Humanized mice represent a promising tool to model human immune responses to CNS injury and disease, including SCI. The first section of thi (open full item for complete abstract)

Committee: Phillip Popovich Ph.D. (Advisor); Jonathan Godbout Ph.D. (Committee Member); Andrea Tedeschi Ph.D. (Committee Member); Adrienne Dorrance Ph.D. (Committee Member); Stefan Niewiesk Ph.D., D.V.M. (Committee Member) Subjects: Biomedical Research; Immunology; Neurobiology; Neurosciences

Doctor of Philosophy, The Ohio State University, 2006, Interdisciplinary Programs

The role of the inflammatory response following spinal cord injury (SCI) remains debatable. The inflammatory response is necessary for clearance of dead/necrotic cells and tissue, as well as clearance of apoptotic cells from the lesion site. In addition, phagocytosis of inhibitory myelin debris is an important function of post-SCI inflammation. However, this inflammatory response may contribute to the ongoing intraspinal degeneration. Neutrophils release myeloperoxidase and reactive oxygen species which may cause cell death at the injury site. CNS macrophages can produce NO, glutamate, and proinflammatory cytokines which can be toxic to neurons. Recent data indicate that survival of traumatized neurons is strain-dependent and influenced by polygenic loci that control resistance/susceptibility to experimental autoimmune encephalomyelitis (EAE). Here, we describe patterns of neurodegeneration and intraparenchymal inflammation after traumatic SCI in mice known to exhibit varying degrees of EAE susceptibility. In general, genetic predisposition to EAE predicted the magnitude of intraparenchymal inflammation but not lesion size or locomotor recovery. Thus, strain-dependent neuroinflammation was observed after SCI but without a consistent relationship to EAE susceptibility or lesion progression. Activation of macrophages via Toll-like receptors (TLRs) is important for inflammation and host defense against pathogens. Recent data suggest that non-pathogenic molecules released by trauma (i.e. HMGB1, HSP70) also can trigger TLRs. Here, we tested whether TLRs are regulated after SCI and examined their effects on functional and anatomical recovery. We show that various TLR mRNA are increased after SCI as are molecules involved in TLR signaling. TLR2 and TLR4 deficient mice sustained locomotor deficits relative to SCI wild-type mice which were associated with unique patterns of demyelination, astrogliosis, and macrophage activation. These data indicate that in the absence of pat (open full item for complete abstract)

Committee: Phillip Popovich (Advisor) Subjects: