Matching Items (8)
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- All Subjects: Traumatic Brain Injury
- All Subjects: Brain--Wounds and injuries.
- Creators: Newbern, Jason
Description
Following a traumatic brain injury (TBI) 5-50% of patients will develop post traumatic epilepsy (PTE). Pediatric patients are most susceptible with the highest incidence of PTE. Currently, we cannot prevent the development of PTE and knowledge of basic mechanisms are unknown. This has led to several shortcomings to the treatment of PTE, one of which is the use of anticonvulsant medication to the population of TBI patients that are not likely to develop PTE. The complication of identifying the two populations has been hindered by the ability to find a marker to the pathogenesis of PTE. The central hypothesis of this dissertation is that following TBI, the cortex undergoes distinct cellular and synaptic reorganization that facilitates cortical excitability and promotes seizure development. Chapter 2 of this dissertation details excitatory and inhibitory changes in the rat cortex after severe TBI. This dissertation aims to identify cortical changes to a single cell level after severe TBI using whole cell patch clamp and electroencephalogram electrophysiology. The work of this dissertation concluded that excitatory and inhibitory synaptic activity in cortical controlled impact (CCI) animals showed the development of distinct burst discharges that were not present in control animals. The results suggest that CCI induces early "silent" seizures that are detectable on EEG and correlate with changes to the synaptic excitability in the cortex. The synaptic changes and development of burst discharges may play an important role in synchronizing the network and promoting the development of PTE.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2014
Neuroinflammation Following Experimental Diffuse Brain Injury in Pre-pubertal and Peri-pubertal Rats
Description
Traumatic brain injury is the leading cause of mortality and morbidity in children and adolescents. Adolescence is a critical time in development where the body and brain undergoes puberty, which not only includes reproductive maturation, but also adult social and cognitive development. Brain-injury-induced disruptions can cause secondary inflammation processes and as a result, pediatric TBI can lead to significant life-long and debilitating morbidities that continue long after initial injury. In this study, neuroinflammation following diffuse brain injury was explored in prepubertal and peripubertal rats using an adapted method of midline fluid percussion injury (mFPI) for juvenile rats to further understand the relationship between pediatric TBI and puberty disruption due to endocrine dysfunction. We expect the adapted mFPI model to be effective in producing diffuse, moderate brain injury in juvenile rats and hypothesize that pre-pubertal rats (PND35) will have increased neuroinflammation compared to peri-pubertal rats (PND17) and shams because of the potential neuroprotective nature of sex steroids. Male Sprague-Dawley rats (n=90) were subjected to either a diffuse midline fluid percussion injury (mFPI) or sham injury at post-natal day (PND) 17 (pre-puberty) or PND35 (peri-puberty). Animals were sacrificed at different time points defined as days post injury (DPI) including 1DPI, 7DPI and 25DPI to represent both acute and chronic time points, allowing for comparisons within groups (injury vs. sham) and across groups (PND17 vs PND35). Body weight of the rats was measured postoperatively at various time points throughout the study to follow recovery. Tissue was collected and subjected to Heamatoxylin and Eosin (H&E) stain to visualize histology and evaluate the application of diffuse mFPI to juvenile rats. In addition, tissue underwent immunohistochemical analysis using 3,3'-diaminobenzidine (DAB) to stain for ionized calcium binding proteins (Iba1) in order to assess injury-related neuroinflammation in the form of microglia activation. Diffuse brain injury using the mFPI model did not affect rat body weight or cause overt cell death, suggesting adaption of the adult mFPI model for juvenile rats is representative of moderate diffuse brain injury. In addition, diffuse TBI lead to morphological changes in microglia suggesting there is an increased inflammatory response following initial insult, which may directly contribute to improper activation of pubertal timing and progression in adolescent children affected. Since there is little literature on the full effects of puberty dysfunction following TBI in the pediatric population, there is a significant need to further assess this area in order to develop improved interventions and potential therapies for this affected population.
ContributorsNewbold, Kelsey Bevier (Author) / Newbern, Jason (Thesis director) / Rowe, Rachel (Committee member) / Ortiz, J. Bryce (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Neuroinflammation is an important secondary injury response occurring after traumatic brain injury (TBI). Anxiety-like disorders are commonly exacerbated after TBI and are mediated through the amygdala; however, the amygdala remains understudied despite its important contribution in processing emotional and stressful stimuli. Therefore, we wanted to study neuroinflammation after experimental TBI using midline fluid percussion in rodent models. We assessed microglia morphology over time post-injury in two circuit related nuclei of the amygdala, the basolateral amygdala (BLA) and central amygdala of the nucleus (CeA), using skeletal analysis. We also looked at silver staining and glial fibrillary acidic protein (GFAP) to evaluate the role of neuropathology and astrocytosis to evaluate for neuroinflammation in the amygdala. We hypothesized that experimental diffuse TBI leads to microglial activation in the BLA-CeA circuitry over time post-injury due to changes in microglial morphology and increased astrocytosis in the absence of neuropathology. Microglial cell count was found to decrease in the BLA at 1 DPI before returning to sham levels by 28 DPI. No change was found in the CeA. Microglial ramification (process length/cell and endpoints/cell) was found to decrease at 1DPI compared to sham in the CeA, but not in the BLA. Silver staining and GFAP immunoreactivity did not find any evidence of neurodegeneration or activated astrocytes in the respectively. Together, these data indicate that diffuse TBI does not necessarily lead to the same microglial response in the amygdala nuclei, although an alternative mechanism for a neuroinflammatory response in the CeA likely contributes to the widespread neuronal and circuit dysfunction that occurs after TBI.
ContributorsHur, Yerin (Author) / Newbern, Jason (Thesis director) / Thomas, Theresa Currier (Committee member) / Beitchman, Joshua (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Annually, approximately 1.7 million people suffer a traumatic brain injury (TBI) in the United States. After initial insult, a TBI persists as a series of molecular and cellular events that lead to cognitive and motor deficits which have no treatment. In addition, the injured brain activates the regenerative niches of the adult brain presumably to reduce damage. The subventricular zone (SVZ) niche contains neural progenitor cells (NPCs) that generate astrocytes, oligodendrocyte, and neuroblasts. Following TBI, the injury microenvironment secretes signaling molecules like stromal cell derived factor-1a (SDF-1a). SDF-1a gradients from the injury contribute to the redirection of neuroblasts from the SVZ towards the lesion which may differentiate into neurons and integrate into existing circuitry. This repair mechanism is transient and does not lead to complete recovery of damaged tissue. Further, the mechanism by which SDF-1a gradients reach SVZ cells is not fully understood. To prolong NPC recruitment to the injured brain, exogenous SDF-1a delivery strategies have been employed. Increases in cell recruitment following stroke, spinal cord injury, and TBI have been demonstrated following SDF-1a delivery. Exogenous delivery of SDF-1a is limited by its 28-minute half-life and clearance from the injury microenvironment. Biomaterials-based delivery improves stability of molecules like SDF-1a and offer control of its release.
This dissertation investigates SDF-1a delivery strategies for neural regeneration in three ways: 1) elucidating the mechanisms of spatiotemporal SDF-1a signaling across the brain, 2) developing a tunable biomaterials system for SDF-1a delivery to the brain, 3) investigating SDF-1a delivery on SVZ-derived cell migration following TBI. Using in vitro, in vivo, and in silico analyses, autocrine/paracrine signaling was necessary to produce SDF-1a gradients in the brain. Native cell types engaged in autocrine/paracrine signaling. A microfluidics device generated injectable hyaluronic-based microgels that released SDF-1a peptide via enzymatic cleavage. Microgels (±SDF-1a peptide) were injected 7 days post-TBI in a mouse model and evaluated for NPC migration 7 days later using immunohistochemistry. Initial staining suggested complex presence of astrocytes, NPCs, and neuroblasts throughout the frontoparietal cortex.
Advancement of chemokine delivery was demonstrated by uncovering endogenous chemokine propagation in the brain, generating new approaches to maximize chemokine-based neural regeneration.
ContributorsHickey, Kassondra (Author) / Stabenfeldt, Sarah E (Thesis advisor) / Holloway, Julianne (Committee member) / Caplan, Michael (Committee member) / Brafman, David (Committee member) / Newbern, Jason (Committee member) / Arizona State University (Publisher)
Created2021
Description
Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. When TBI occurs in children it often results in severe cognitive and behavioral deficits. Post-injury, the pediatric brain may be sensitive to the effects of TBI while undergoing a number of age-dependent physiological and neurobiological changes. Due to the nature of the developing cortex, it is important to understand how a pediatric brain recovers from a severe TBI (sTBI) compared to an adult. Investigating major cortical and cellular changes after sTBI in a pediatric model can elucidate why pediatrics go on to suffer more neurological damage than an adult after head trauma. To model pediatric sTBI, I use controlled cortical impact (CCI) in juvenile mice (P22). First, I show that by 14 days after injury, animals begin to show recurrent, non-injury induced, electrographic seizures. Also, using whole-cell patch clamp, layer V pyramidal neurons in the peri-injury area show no changes except single-cell excitatory and inhibitory synaptic bursts. These results demonstrate that CCI induces epileptiform activity and distinct synaptic bursting within 14 days of injury without altering the intrinsic properties of layer V pyramidal neurons. Second, I characterized changes to the cortical inhibitory network and how fast-spiking (FS) interneurons in the peri-injury region function after CCI. I found that there is no loss of interneurons in the injury zone, but a 70% loss of parvalbumin immunoreactivity (PV-IR). FS neurons received less inhibitory input and greater excitatory input. Finally, I show that the cortical interneuron network is also affected in the contralateral motor cortex. The contralateral motor cortex shows a loss of interneurons and loss of PV-IR. Contralateral FS neurons in the motor cortex synaptically showed greater excitatory input and less inhibitory input 14 days after injury. In summary, this work demonstrates that by 14 days after injury, the pediatric cortex develops epileptiform activity likely due to cortical inhibitory network dysfunction. These findings provide novel insight into how pediatric cortical networks function in the injured brain and suggest potential circuit level mechanisms that may contribute to neurological disorders as a result of TBI.
ContributorsNichols, Joshua (Author) / Anderson, Trent (Thesis advisor) / Newbern, Jason (Thesis advisor) / Neisewander, Janet (Committee member) / Qiu, Shenfeng (Committee member) / Stabenfeldt, Sarah (Committee member) / Arizona State University (Publisher)
Created2015
Description
Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases, yet its neuropathophysiology is still poorly understood. While a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (post-natal day 20) to repeat weight drop impact. Animals were anesthetized and subjected to sham or rmTBI once per day for 5 days. At 14 days post injury (PID), magnetic resonance imaging (MRI) revealed that rmTBI animals displayed marked cortical atrophy and ventriculomegaly. Specifically, the thickness of the cortex was reduced up to 46% beneath and the ventricles increased up to 970% beneath the impact zone. Immunostaining with the neuron specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker, 4-Aminophyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents.
ContributorsGoddeyne, Corey (Author) / Anderson, Trent (Thesis advisor) / Smith, Brian (Committee member) / Kleim, Jeffrey (Committee member) / Arizona State University (Publisher)
Created2014
Description
Traumatic brain injury (TBI) consists of the primary mechanical forces to the head followed by secondary inflammatory cascades. This inflammatory cascade consists of neuroinflammation characterized by microglial activation as the first line of defense. Another component of secondary inflammation comprises of activation of peripheral immune cells that can infiltrate the compromised blood brain barrier and susceptible organs such as the lungs. Acute inflammatory processes in the lungs include a disruption of the epithelial barriers allowing infiltration of neutrophils, and edema build up in the alveoli. This is known as acute lung injury (ALI) and it dampens respiratory function in approximately 20-25% of TBI patients necessitating an intervention. Remote ischemic conditioning (RIC) is an intervention consisting of repeated intervals of cessation and reperfusion of blood flow to a distal limb and has treated ALI, myocardial infarction, and neurological injury. TBI was hypothesized to induce ALI through degradation of alveolar-capillary membrane and infiltration of peripheral leukocytes. Furthermore, RIC was hypothesized to protect the integrity of the alveolar-capillary membrane, reduce infiltration of peripheral immune cells, and reduce microglial activation in the brain through myokine recruitment. Male CD1 mice were subject to either midline fluid percussion or sham injury and further randomized into 4 groups: sham, sham RIC, TBI, TBI RIC. RIC was administered on proximal thigh for 4x5 minutes, with 5-minute reperfusion one hour prior to TBI. One-hour post-injury, brain, lung, BAL fluid, and blood were collected. Lung histopathology showed RIC reduced hydrostatic edema in the alveoli by protecting the alveolar capillary membrane. BAL findings revealed TBI mice had increased neutrophil counts, RIC lowered neutrophil counts. In the brain, RIC increased cortex microglial endpoints were observed with no other significant differences in microglial morphology as well as plasma myokine levels across all sham, sham RIC, TBI, and TBI RIC animals. While underlying mechanisms still have to be further studied, this current study provides evidence that RIC can be used as a therapeutic intervention to ameliorate TBI-induce ALI.
ContributorsChristie, Immaculate (Author) / Newbern, Jason (Thesis director) / Lifshitz, Jonathan (Committee member) / Saber, Maha (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Traumatic brain injury (TBI) is a major cause of disability, with approximately 1.7 million incidents reported annually. Following a TBI, patients are likely to sustain sensorimotor and cognitive impairments and are at an increased risk of developing neurodegenerative diseases later in life. Despite this, robust therapies that treat TBI neuropathology are not available in the clinic. One emerging therapeutic approach is to target epigenetic mediators that modulate a variety of molecular regulatory events acutely following injury. Specifically, previous studies demonstrated that histone deacetylase inhibitor (HDACi) administration following TBI reduced inflammation, enhanced functional outcomes, and was neuroprotective. Here, we evaluated a novel quisinostat-loaded PLA-PEG nanoparticle (QNP) therapy in treating TBI as modeled by a controlled cortical impact. We evaluated initial pharmacodynamics within the injured cortex via histone acetylation levels following QNP treatment. We observed that QNP administration acutely following injury increased histone acetylation specifically within the injury penumbra, as detected by Western blot analysis. Given this effect, we evaluated QNP therapeutic efficacy. We observed that QNP treatment dampened motor deficits as measured by increased rotarod latency to fall relative to blank nanoparticle- and saline-treated controls. Additionally, open field results show that QNP treatment altered locomotion following injury. These results suggest that HDACi therapies are a beneficial therapeutic strategy following neural injury and demonstrate the utility for nanoparticle formulations as a mode for HDACi delivery following TBI.
ContributorsMousa, Gergey (Author) / Stabenfeldt, Sarah (Thesis director) / Newbern, Jason (Committee member) / Sirianni, Rachael (Committee member) / School of Life Sciences (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05