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Description
Concussion, a subset of mild traumatic brain injury (mTBI), has recently been brought to the forefront of the media due to a large lawsuit filed against the National Football League. Concussion resulting from injury varies in severity, duration, and type, based on many characteristics about the individual that research does not presently understand. Chronic fatigue, poor working memory, impaired self-awareness, and lack of attention to task are symptoms commonly present post-concussion. Currently, there is not a standard method of assessing concussion, nor is there a way to track an individual's recovery, resulting in misguided treatment for better prognosis. The aim of the following study was to determine patient specific higher-order cognitive processing deficits for clinical diagnosis and prognosis of concussion. Six individuals (N=6) were seen during the acute phase of concussion, two of whom were seen subsequently when their symptoms were deemed clinically resolved. Subjective information was collected from both the patient and from neurology testing. Each individual completed a task, in which they were presented with degraded speech, taxing their higher-order cognitive processing. Patient specific behavioral patterns are noted, creating a unique paradigm for mapping subjective and objective data for each patient's strategy to compensate for deficits and understand speech in a difficult listening situation. Keywords: concussion, cognitive processing
ContributorsBerg, Dena (Author) / Liss, Julie M (Committee member) / Azuma, Tamiko (Committee member) / Caviness, John (Committee member) / Arizona State University (Publisher)
Created2013
Description
The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.
ContributorsHoffman, Ann (Author) / Conrad, Cheryl D. (Thesis advisor) / Olive, M. Foster (Committee member) / Hammer, Jr., Ronald P. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
Description
The recent spotlight on concussion has illuminated deficits in the current standard of care with regard to addressing acute and persistent cognitive signs and symptoms of mild brain injury. This stems, in part, from the diffuse nature of the injury, which tends not to produce focal cognitive or behavioral deficits that are easily identified or tracked. Indeed it has been shown that patients with enduring symptoms have difficulty describing their problems; therefore, there is an urgent need for a sensitive measure of brain activity that corresponds with higher order cognitive processing. The development of a neurophysiological metric that maps to clinical resolution would inform decisions about diagnosis and prognosis, including the need for clinical intervention to address cognitive deficits. The literature suggests the need for assessment of concussion under cognitively demanding tasks. Here, a joint behavioral- high-density electroencephalography (EEG) paradigm was employed. This allows for the examination of cortical activity patterns during speech comprehension at various levels of degradation in a sentence verification task, imposing the need for higher-order cognitive processes. Eight participants with concussion listened to true-false sentences produced with either moderately to highly intelligible noise-vocoders. Behavioral data were simultaneously collected. The analysis of cortical activation patterns included 1) the examination of event-related potentials, including latency and source localization, and 2) measures of frequency spectra and associated power. Individual performance patterns were assessed during acute injury and a return visit several months following injury. Results demonstrate a combination of task-related electrophysiology measures correspond to changes in task performance during the course of recovery. Further, a discriminant function analysis suggests EEG measures are more sensitive than behavioral measures in distinguishing between individuals with concussion and healthy controls at both injury and recovery, suggesting the robustness of neurophysiological measures during a cognitively demanding task to both injury and persisting pathophysiology.
ContributorsUtianski, Rene (Author) / Liss, Julie M (Thesis advisor) / Berisha, Visar (Committee member) / Caviness, John N (Committee member) / Dorman, Michael (Committee member) / Arizona State University (Publisher)
Created2014
Description
The objective of this small animal pre-clinical research project was to study quantitatively the long-term micro- and macro- structural brain changes employing multiparametric MRI (Magnetic Resonance Imaging) techniques. Two separate projects make up the basis of this thesis. The first part focuses on obtaining prognostic information at early stages in the case of Traumatic Brain Injury (TBI) in rat animal model using imaging data acquired at 24-hours and 7-days post injury. The obtained parametric T2 and diffusion values from DTI (Diffusion Tensor Imaging) showed significant deviations in the signal intensities from the control and were potentially useful as an early indicator of the severity of post-traumatic injury damage. DTI was especially critical in distinguishing between the cytotoxic and vasogenic edema and in identification of injury regions resolving to normal control values by day-7. These results indicate the potential of quantitative MRI as a clinical marker in predicting prognosis following TBI. The second part of this thesis focuses on studying the effect of novel therapeutic strategies employing dendritic cell (DC) based vaccinations in mice glioma model. The treatment cohorts included comparing a single dose of Azacytidine drug vs. mice getting three doses of drug per week. Another cohort was used as an untreated control group. The MRI results did not show any significant changes in between the two treated cohorts with no reduction in tumor volumes compared to the control group. The future studies would be focused on issues regarding the optimal dose for the application of DC vaccine. Together, the quantitative MRI plays an important role in the prognosis and diagnosis of the above mentioned pathologies, providing essential information about the anatomical location, micro-structural tissue environment, lesion volume and treatment response.
ContributorsAnnaldas, Bharat (Author) / Kodibagkar, Vikram (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Bhardwaj, Ratan (Committee member) / Arizona State University (Publisher)
Created2014
Description
Patients with malignant brain tumors have a median survival of approximately 15 months following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. It has been shown that this metabolic therapy enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood.
The current study reports that KetoCal® (KC; 4:1 fat:protein/carbohydrates), fed ad libitum, alters hypoxia, angiogenic, and inflammatory pathways in a mouse model of glioma. Tumors from animals maintained on KC showed reduced expression of the hypoxia marker carbonic anhydrase 9 (CA IX), a reduction in hypoxia inducible factor 1-alpha (HIF-1α) and decreased activation of nuclear factor kappa B (NF-κB). Animals maintained on KC also showed a reduction in expression of vascular endothelial growth factor receptor 2 (VEGFR2) and decreased microvasculature in their tumors. Further, peritumoral edema was significantly reduced in animals fed the KC and protein analysis showed significantly altered expression of the tight junction protein zona occludens-1 (ZO-1) and the water channeling protein aquaporin-4 (AQP4), both of which have been implicated in malignant processes in glioma, including the formation of peritumoral edema in patients. Taken together the data suggests that KC alters multiple processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
The current study reports that KetoCal® (KC; 4:1 fat:protein/carbohydrates), fed ad libitum, alters hypoxia, angiogenic, and inflammatory pathways in a mouse model of glioma. Tumors from animals maintained on KC showed reduced expression of the hypoxia marker carbonic anhydrase 9 (CA IX), a reduction in hypoxia inducible factor 1-alpha (HIF-1α) and decreased activation of nuclear factor kappa B (NF-κB). Animals maintained on KC also showed a reduction in expression of vascular endothelial growth factor receptor 2 (VEGFR2) and decreased microvasculature in their tumors. Further, peritumoral edema was significantly reduced in animals fed the KC and protein analysis showed significantly altered expression of the tight junction protein zona occludens-1 (ZO-1) and the water channeling protein aquaporin-4 (AQP4), both of which have been implicated in malignant processes in glioma, including the formation of peritumoral edema in patients. Taken together the data suggests that KC alters multiple processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
ContributorsWoolf, Eric C (Author) / Scheck, Adrienne C (Thesis advisor) / Lake, Douglas F (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2014
Description
The ability to monitor electrophysiological signals from the sentient brain is requisite to decipher its enormously complex workings and initiate remedial solutions for the vast amount of neurologically-based disorders. Despite immense advancements in creating a variety of instruments to record signals from the brain, the translation of such neurorecording instrumentation to real clinical domains places heavy demands on their safety and reliability, both of which are not entirely portrayed by presently existing implantable recording solutions. In an attempt to lower these barriers, alternative wireless radar backscattering techniques are proposed to render the technical burdens of the implant chip to entirely passive neurorecording processes that transpire in the absence of formal integrated power sources or powering schemes along with any active circuitry. These radar-like wireless backscattering mechanisms are used to conceive of fully passive neurorecording operations of an implantable microsystem. The fully passive device potentially manifests inherent advantages over current wireless implantable and wired recording systems: negligible heat dissipation to reduce risks of brain tissue damage and minimal circuitry for long term reliability as a chronic implant. Fully passive neurorecording operations are realized via intrinsic nonlinear mixing properties of the varactor diode. These mixing and recording operations are directly activated by wirelessly interrogating the fully passive device with a microwave carrier signal. This fundamental carrier signal, acquired by the implant antenna, mixes through the varactor diode along with the internal targeted neuropotential brain signals to produce higher frequency harmonics containing the targeted neuropotential signals. These harmonics are backscattered wirelessly to the external interrogator that retrieves and recovers the original neuropotential brain signal. The passive approach removes the need for internal power sources and may alleviate heat trauma and reliability issues that limit practical implementation of existing implantable neurorecorders.
ContributorsSchwerdt, Helen N (Author) / Chae, Junseok (Thesis advisor) / Miranda, Félix A. (Committee member) / Phillips, Stephen (Committee member) / Towe, Bruce C (Committee member) / Balanis, Constantine A (Committee member) / Frakes, David (Committee member) / Arizona State University (Publisher)
Created2014
Description
ABSTRACT Post-Traumatic Stress Disorder (PTSD), depression, and insomnia are prevalent among United States (US) military veterans. This study investigates whether Brain Boosters, a new cognitive enhancement group therapy, improves symptoms of PTSD, depression, and insomnia among veterans completing the groups. The study population includes 64 US military veterans treated in the setting of the Veterans Affairs (VA) Health Care System in Phoenix, AZ. Group members were US military veterans, age 22 to 87 (mean age=53.47), who had served in or after World War II (WWII), who sought mental health care at the Phoenix VA from 2007 through 2011. Participants were treated with Brain Boosters therapy. They completed measures of mental-health related symptoms before and after this therapy. Participants were assessed pre and post group with the PTSD Checklist for military personnel (PCL-M), the Patient Health Questionnaire (PHQ-9; a measure of depression symptoms), and the Insomnia Severity Index (ISI). Statistical analyses were done with paired samples t-tests and McNemar's tests, using SPSS. The hypotheses were that symptoms of PTSD, depression, and insomnia would show statistically significant improvement with Brain Boosters therapy. Results supported the hypotheses that symptoms of PTSD and depression would improve significantly. Insomnia did not show significant improvement. The results showed the mean PCL-M score was 54.84 before Brain Boosters therapy and 51.35 after (p= 0.008). The mean PHQ-9 score was 15.21 before Brain Boosters therapy and 13.05 after (p= 0.002). The mean ISI score was 15.98 before Brain Boosters Therapy and 14.46 after (p= 0.056). Although this is a nonrandom, uncontrolled trial, findings nevertheless suggest that Brain Boosters may be an effective therapy to reduce PTSD symptom severity and depression symptom severity. This may be especially important for veterans seeking alternatives to pharmacological intervention or traditional therapeutic interventions.
ContributorsWalter, Christina M (Author) / Roberts, Nicole A. (Thesis advisor) / Burleson, Mary H. (Committee member) / Miller, Paul (Committee member) / Arizona State University (Publisher)
Created2012
Description
Though for most of the twentieth century, dogma held that the adult brain was post-mitotic, it is now known that adult neurogenesis is widespread among vertebrates, from fish, amphibians, reptiles and birds to mammals including humans. Seasonal changes in adult neurogenesis are well characterized in the song control system of song birds, and have been found in seasonally breeding mammals as well. In contrast to more derived vertebrates, such as mammals, where adult neurogenesis is restricted primarily to the olfactory bulb and the dentate gyrus of the hippocampus, neurogenesis is widespread along the ventricles of adult amphibians. I hypothesized that seasonal changes in adult amphibian brain cell proliferation and survival are a potential regulator of reproductive neuroendocrine function. Adult, male American bullfrogs (Rana catesbeiana; aka Lithobates catesbeianus), were maintained in captivity for up to a year under season-appropriate photoperiod. Analysis of hormone levels indicated seasonal changes in plasma testosterone concentration consistent with field studies. Using the thymidine analogue 5-bromo-2-deoxyuridine (BrdU) as a marker for newly generated cells, two differentially regulated aspects of brain cell neogenesis were tracked; that is, proliferation and survival. Seasonal differences were found in BrdU labeling in several brain areas, including the olfactory bulb, medial pallium, nucleus accumbens and the infundibular hypothalamus. Clear seasonal differences were also found in the pars distalis region of the pituitary gland, an important component of neuroendocrine pathways. BrdU labeling was also examined in relation to two neuropeptides important for amphibian reproduction: arginine vasotocin and gonadotropin releasing hormone. No cells co-localized with BrdU and either neuropeptide, but new born cells were found in close proximity to neuropeptide-containing neurons. These data suggest that seasonal differences in brain and pituitary gland cell neogenesis are a potential neuroendocrine regulatory mechanism.
ContributorsMumaw, Luke (Author) / Orchinik, Miles (Thesis advisor) / Deviche, Pierre (Committee member) / Chandler, Douglas (Committee member) / Arizona State University (Publisher)
Created2012
Description
Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how experiences throughout an individual's life influence such interactions. The core question of this thesis is how individuals’ experience contributes to within-caste behavioral variation in a social group. I investigate the effects of individual history, including physical injury and food-related experience, on individuals' social food sharing behavior, responses to food-related stimuli, and the associated neural biogenic amine signaling pathways. I use the eusocial honey bee (Apis mellifera) system, one in which individuals exhibit a high degree of plasticity in responses to environmental stimuli and there is a richness of communicatory pathways for food-related information. Foraging exposes honey bees to aversive experiences such as predation, con-specific competition, and environmental toxins. I show that foraging experience changes individuals' response thresholds to sucrose, a main component of adults’ diets, depending on whether foraging conditions are benign or aversive. Bodily injury is demonstrated to reduce individuals' appetitive responses to new, potentially food-predictive odors. Aversive conditions also impact an individual's social food sharing behavior; mouth-to-mouse trophallaxis with particular groupmates is modulated by aversive foraging conditions both for foragers who directly experienced these conditions and non-foragers who were influenced via social contact with foragers. Although the mechanisms underlying these behavioral changes have yet to be resolved, my results implicate biogenic amine signaling pathways as a potential component. Serotonin and octopamine concentrations are shown to undergo long-term change due to distinct foraging experiences. My work serves to highlight the malleability of a social individual's food-related behavior, suggesting that environmental conditions shape how individuals respond to food and share information with group-mates. This thesis contributes to a deeper understanding of inter-individual variation in animal behavior.
ContributorsFinkelstein, Abigail (Author) / Amdam, Gro V (Thesis advisor) / Conrad, Cheryl (Committee member) / Smith, Brian (Committee member) / Neisewander, Janet (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2017
Description
Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
ContributorsHarrison, Jordan L (Author) / Lifshitz, Jonathan (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Willyerd, Frederick A (Committee member) / Pirrotte, Patrick (Committee member) / Arizona State University (Publisher)
Created2017