Browsing by Subject "Brain"
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Item Computational issues in using Bayesian hierarchical methods for the spatial modeling of fMRI data.(2010-08) Lee, Kuo-JungOne of the major objectives of fMRI (functional magnetic resonance imaging) studies is to determine which areas of the brain are activated in response to a stimulus or task. To make inferences about task-specific changes in underlying neuronal activity, various statistical models are used such as general linear models (GLMs). Frequentist methods assessing human brain activity using data from fMRI experiments rely on results from the theory of Gaussian random fields. Such methods have several limitations. The Bayesian paradigm provides an attractive framework for making inference using complex models and bypassing the multiple comparison problems. We propose a Bayesian model which not only takes into account the complex spatio-temporal relationships in the data while still being computationally feasible, but gives a framework for addressing other interesting questions related to how the human brain works. We study the properties of this approach and demonstrate its performance on simulated and real examples.Item Evaluation of Visual Attention to Images by Adults with Traumatic Brain Injury(2017-05) Swanson, SarahAbstract The most common persistent symptoms following traumatic brain injury (TBI) include deficits in vision, cognition, and communication. The combination of cognitive-communication and visual impairments experienced by those with brain injury have detrimental effects on rehabilitation and recovery, affecting an individual’s ability to interpret the physical and social world and even engage in basic self-care tasks. Considering the widespread effects of these deficits on an individual’s daily life, healthcare professionals need information on implementation of visual supports in the rehabilitation process. Therefore, the purpose of this study was to determine how individuals with and without TBI exhibit differences in the decision-making process, organizational search, processing time, and accuracy when engaging in a visual processing task comparing explicit and implicit information conditions. Participants included 15 adults with histories of mild to severe TBI and 15 age-, gender-, and education-matched controls. Participants completed a decision-making task where they matched picture to sentence for three conditions: (a) a condition targeting the main action, (b) a condition targeting a background detail, and (c) a condition targeting a physical or mental inference. The researchers utilized eye-tracking hardware and software to track participant eye movements and analyze various eye-movement metrics. Results of this study demonstrated that participants with and without TBI demonstrated significantly more regressions to the sentence, a higher number of fixations, and longer average fixation duration for the inference condition. Furthermore, participants with TBI displayed significantly longer fixations for the inference condition compared to controls, all of which suggest that the inference condition was more challenging or engaging than the explicit conditions. Additionally, all participants allocated nearly the same percentage of time fixating on the target image as they did to viewing all three foil images collectively. This information provides insight into how individuals with and without TBI make decisions. Rehabilitation professionals need information regarding the use of visual supports for individuals with TBI. The knowledge gained from this research provides important information visual processing following TBI and the use of images in rehabilitation to support cognition and language comprehension.Item HDL-Mimetic Peptides as Potential Therapeutics for Alzheimer's Disease(2018-08) Chernick, DustinAlzheimer’s disease (AD) is the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. A number of large scale human clinical studies have confirmed a robust connection between high density lipoprotein (HDL) – known as the ‘good cholesterol’ levels and AD. Low levels of HDL are associated with increased risk and severity of AD. The role of HDL in the brain is not fully established, however, the anti-inflammatory and anti-oxidative properties of HDL are thought to be critical for its beneficial effects. Apolipoprotein E (apoE) is a key constituent of HDL-like particles in the interstitial fluid (ISF) and cerebral spinal fluid (CSF) in the brain. ApoE exists in 3 common variants in the human population (apoE2, E3, and E4), and the apoE4 isoform is the strongest genetic risk factor for AD, accounting for 40-60% of cases. This risk allele is known to increase neuroinflammation and to promote the aggregation and deposition of amyloid beta (Aβ) in the brain, effects which are influenced by the poor lipidation status of apoE4 (incomplete or improper composition of HDL-like particles) in the brain. Previous studies in the laboratory of Dr. Ling Li have shown that overexpression of human apoA-I, the primary apolipoprotein associated with HDL in the periphery, mitigated amyloid pathology and rescued memory deficits in AD mice. However, a full-length, glycosylated protein is extremely difficult and costly to synthesize and to administer. Therefore, the goal of my research was to test the therapeutic potential of small HDL-mimetic peptides, designed to mimic the beneficial function of their parent apolipoproteins, in AD. My studies focused on 4F, an 18 amino acid HDL-mimetic peptide that has been shown to be safe and well tolerated in human clinical trials for cardiovascular disease. I have demonstrated that the lipidation state of apoE is negatively impacted by the addition of aggregated Aβ to astrocytes from mice and humans, in vitro, an effect that is reversed by the addition of 4F. In addition, I confirmed that apoE4 is less lipidated than apoE2 and E3 at baseline, and demonstrated that apoE4 is more susceptible to the detrimental effects of Aβ on lipidation than apoE2. Intriguingly, 4F was able to completely rescue this effect, bringing apoE4 lipidation levels on par with those of apoE2, even in the presence of Aβ. Preliminary in vivo studies in mice expressing the human apoE isoforms and in a mouse model of AD indicate that 4F reduces soluble amyloid levels in the brain and attenuates memory deficits. As chronic neuroinflammation is a key hallmark of AD pathology, another line of my research focused on a small molecule, called Minnelide. Minnelide is a water soluble, pro-drug of triptolide, which is an anti-inflammatory agent that has been shown in Dr. Li’s lab and in other labs to mitigate AD pathology and rescue memory deficits in animal models. Poor solubility hinders this agent’s prospects in the clinic, and so we sought to test the efficacy of Minnelide in AD. My studies show that Minnelide attenuated age-related cognitive decline in AD mice, independent of Aβ levels in the brains of these animals. These data, taken together, indicate that HDL mimetic peptides, and targeting of inflammatory pathways in the periphery and in the brain are promising avenues for continued efforts to find an effective treatment for AD.Item Human auditory source discrimination.(2011-07) Gardeen, Stephen J.The aim of this study is to examine the auditory system's ability to process low energy frequency transpositions of complex sounds. The auditory processing of complex sounds such as musical instruments, voice, or environmental events is currently an active area of research. Some propose that auditory "objects" are represented by neurons which encode the `invariant' spectro-temporal acoustic properties (Griffiths & Warren,2004). These sound features tend to be heavily damped and very transient and, therefore, frequency rich. This study shows the auditory's sensitivity to detect these adjustments by detecting the pre-attentive magnetic mismatch response (MMNm) from 8 subjects passively listening to complex audio stimulations. Responses were detected from most subjects even though participants could not attentively discriminate the sounds. This result is somewhat controversial in that current views suggests that a mismatch response indicates processing that is available for higher processing i.e. should be attentively discriminable (Näätänen et al., 2010). Localization results suggest the mismatch processing is performed in the auditory associations regions (superior temporal sulcus, insula) of the auditory cortex. These results suggest that transient sounds might be essential to auditory object identification, and that the auditory system is able to distinguish at a sensory level, shifts in the heavily damped spectral structure of complex sounds even though some cannot do so attentively. This could be due to the greater analysis given by the human brain to determining the pitch center rather then the sound timbre, yet some trained musicians have the ability to distinguish these subtle differences (i.e. differences between manufacturers of the same kinds of instruments).Item Identifying Parameters to Excite or Suppress Peripheral and Central Neurons Using Ultrasound for a New Noninvasive Neuromodulation Approach(2019-06) Guo, HongsunUltrasound (US) has shown to activate brain circuits, making it a promising noninvasive neuromodulation technique. However, little is known about the underlying mechanisms and neuromodulatory effects across different stimulus parameters. Here, we present research in which we applied transcranial US to different cortical regions and performed brain mapping studies in guinea pigs using extracellular electrophysiology. We observed that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminated the US-induced activity, revealing an indirect auditory mechanism for US neural activation. This finding indicates that US stimulation of the brain predominantly activates the ascending auditory system through a cochlear pathway, which can activate other nonauditory regions through cross-modal projections. We then used similar approaches to study US modulatory effects on brain circuits in deafened animals. We observed that US induces localized suppression of somatosensory and visual evoked activity, which is associated with temperature rises in the brain tissue caused by US stimulation. This finding challenges the idea that US non-thermal effects are the only mechanism accounting for suppression of cortical activity by US stimulation. Whereas US activation of brain has been widely reported, activation of peripheral nerves by US have been reported with inconsistent results. Here, we show that US did not directly activate a mammalian sciatic nerve isolated from the surrounding tissue even at high pressures (1.3 to 5 MPa for different transducers) and various pulse patterns, but it could activate sensory structures (e.g., receptors in the skin or surrounding tissue) during stimulation of a non-isolated sciatic nerve, which could be mistakenly interpreted as direct activation of nerves (i.e., activation of the sensory structures leads to activation of peripheral nerves). We further demonstrated that US could reliably suppress nerve activity in vivo, depending on specific pulse durations (PDs), pressures, and center frequencies of US, with the observation that rises in tissue temperature caused by US stimulation drives greater suppressive effects. Maintaining the nerve temperature at a constant level prevents the suppression of nerve activity. These overall findings reveal that US can stimulate sensory structures rather than nerve fibers and that the US thermal effect is a major mechanism for suppression of nerve activity. Further improving our understanding of how US interacts with and modulates receptors, nerve fibers and cells within the brain will facilitate the development of new ultrasound-based neuromodulation therapies for various neurological and psychiatric disorders.Item Immunological benefits of a novel polycaprolactone-polyorthoester-based therapeutic vaccine in a mouse model of glioma(2014-08) Grinnen, Karen LynnCancer immunotherapy has led to significant improvement in the survival of patients with previously untreatable malignancies. The use of therapeutic vaccines is a promising form of immunotherapy, but their efficacy remains ambiguous. Much of the difficulty in identifying the optimal formulation and delivery is related to the complicated nature of the immune response, where it is uncertain which aspects would be most effective in destroying cancer cells. In this thesis, a novel polymeric delivery system, involving poly (caprolactone)-co-poly (ortho ester) [PCL-POE], was used to deliver tumor antigens and adjuvants in a controlled manner. We hypothesized that persistent release of tumor antigens from the biodegradable polymer would result in an increase in the number and persistence of anti-tumor lymphocytes in the effector state. To test this hypothesis, vaccines were administered to mice and the time dependent immunological response was evaluated. The polymeric delivery system resulted in an in vitro release profile characterized by a burst release of both antigen and adjuvant followed, in both cases, by a much slower phase of release. We also observed that the slow release provided by the PCL-POE polymer stimulated prolonged maturation of dendritic cells, activation and persistence of anti-OVA antibodies and antigen-specific T cells following a single vaccination. The vaccine system was also tested in a mouse model of glioblastoma multiforme (GBM). We observed a significant, potentially translatable increase in overall survival.Item Measuring Brain Endothelial Cell Bioenergetics Via Extracellular Flux Analysis(2019-07) McDonald, CadeThe neurovascular unit (NVU) is an important structural component in the central nervous system (CNS). The NVU consists of multiple cell types that include endothelial cells, pericytes, astrocytes, and others, working collectively as a restrictive interface between blood and neural tissue within the CNS. The NVU functions to transport nutrients, ions, and other substances to and from the blood to maintain homeostasis within the neural cell microenvironment. The NVU is responsible for the regulation of nutrient and ion transport from the blood as neurons require a fastidious supply of nutrients and ions in order to function properly. It is also important to regulate the neural cell microenvironment as many molecules and substrates in blood serum can be detrimental to neural function. This neural dysfunction may, in turn, lead to CNS complications. A dysfunctional NVU is associated with many disease states, including Alzheimer’s, ALS, strokes, multiple sclerosis, epilepsy, and glioblastomas. These disease states are linked to, but not limited to, deregulation of nutrient transport, NVU inflammation and leakage of blood constituents into the neural environment, downregulation of the basal lamina, reduced efficacy and downregulation of ATP-binding cassette (ABC) transporters, and downregulation of tight junction proteins. Therefore, it is important that the NVU possesses mechanisms for which it can restrict passage of detrimental substances into the CNS. The endothelial cell is a principal barrier-forming cell of the NVU because of its direct contact with the blood, its intercellular tight junctions, biotransforming enzymes, and asymmetric distribution of active and carrier-mediated transporters. These properties are important in the separation of blood from neural tissue and regulation of nutrients and ions within the neural environment. Maintaining and regulating these properties requires an abundant supply of energy, in the form of adenosine triphosphate (ATP). Therefore, endothelial cell energy metabolism is a critically important area of study. Cellular energy metabolism is considered the process of exploiting various metabolic substrates to produce ATP. Cells typically utilize glycolysis and oxidative phosphorylation (OXPHOS) as energy producing pathways to maintain cellular ATP demand. OXPHOS is considered the major contributor in ATP production as it produces ~ 33 molecules of ATP per glucose molecule, whereas glycolysis produces only two molecules of ATP per glucose molecule. Glycolysis is often overlooked due to this imbalance of ATP production. However, it is becoming more evident that glycolysis may be a primary energy producing pathway due to its rapid turnover rate and production of molecules that are able to be utilized as building blocks for cellular compartments. Cellular bioenergetics using extracellular flux analysis has been extensively used to study many different cell types such as tumor, immune, and stem cells, but little is known about the energy producing pathways of brain endothelial cells. Here, we characterize the bioenergetics of human brain microvascular endothelial cells by using human brain microvascular endothelial hCMEC/D3 cells as a model. hCMEC/D3 cell bioenergetic properties were characterized by investigating metabolite preference and the effects of various metabolic inhibitors on extracellular acidification and OXPHOS rates. Glycolysis and OXPHOS can be quantitatively measured by using extracellular flux analysis. Using sensitive probes, extracellular flux analysis can measure extracellular acidification and oxygen consumption to quantify glycolytic and OXPHOS rates, respectively. In this study, we show that these cells utilize glycolysis as a primary metabolic pathway and glucose as the preferred metabolite. Although glucose is the primary metabolite hCMEC/D3 cells utilize, they are able to maintain ATP production by utilizing pyruvate and glutamine as well via OXPHOS. Using monocarboxylate transporter 1 (MCT1), mitochondrial pyruvate carrier (MPC), glutaminase (GLS), and glucose transporter 1 (GLUT1) inhibitors, we were able to explore the metabolic flexibility of hCMEC/D3 cells. Nutrient transport inhibition significantly altered glycolytic and oxidative properties of hCMEC/D3 cells. These findings reveal a basic understanding of brain endothelial cell energy production and metabolism. This data may also contribute to our understanding of altered brain endothelial cell function in disease or under conditions of active angiogenesis during development or tumorigenesis. Further understanding of altered brain endothelial cell energy metabolism in a diseased state can allow for the development of therapeutics that target these altered pathways.Item Micronutrient interactions affecting the developing rat brain(2013-06) Bastian, Thomas WilliamMicronutrient deficiencies affect billions of people worldwide and often coexist in developing countries due to consumption of diets lacking nutrient diversity. Thus, it is important to consider how micronutrients such as copper (Cu), iron (Fe), and iodine interact physiologically. Cu, Fe, and iodine/thyroid hormone (TH) deficiencies lead to similar brain development deficits, suggesting these micronutrient deficiencies share a common mechanism contributing to the observed derangements. Previous studies in rodents and humans indicate that Cu and Fe deficiencies during adolescence or adulthood lead to impaired TH status. However, prior to this thesis research, relationships between Fe or Cu deficiencies and thyroidal status had not been assessed in the most vulnerable population, the developing fetus/neonate. My first two studies showed that Fe deficiency lowers newborn rat circulating and brain TH concentrations and alters TH-regulated brain gene expression. In a third study, Fe deficiency exacerbated the effect of mild TH insufficiency on neonatal thyroidal status and brain TH-responsive gene expression. Together, these novel findings suggest that impaired neonatal thyroidal status may contribute to some of the brain developmental abnormalities associated with fetal/neonatal Fe deficiency. Fe deficiency also has significant impacts on the developing brain independent of effects on thyroid function. In humans, Fe deficiency often results in anemia, reduced blood oxygen carrying capacity. Decreased oxygen delivery to the brain can induce a compensatory increase in blood vessel outgrowth. My final study demonstrated, for the first time, that Fe deficiency anemia increases blood vessel growth in the neonatal rat brain. The functional contribution of increased vasculature to the developing Fe-deficient brain is unknown but could be adaptive, maladaptive, or both. In summary, my thesis research exploring micronutrient interactions during brain development has identified two novel potential contributors to the brain developmental derangements associated with Fe deficiency: impaired neonatal thyroid function and increased neonatal brain vasculature.Item Molecular therapy for mucopolysaccharidosis Type I(2010-11) Wolf, Daniel AdamMucopolysaccharidosis type I (MPS I) is caused by deficiency of the lysosomal hydrolase alpha-L-iduronidase (IDUA). IDUA is a required component of the step-wise degradative pathway responsible for the catabolism of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. As a result, these GAGs accumulate within lysosomes causing the development of multisystemic disease. Patients with MPS I present with clinical manifestations of disease within the first two years of life including corneal clouding, hepatoslenomegaly, skeletal dysplasias, cardiopulmonary disease, and obstructive airway disease. Additionally, patients with severe MPS I, also known as Hurler syndrome, develop hydrocephalus and severe neurocognitive decline. The current standard of care for Hurler patients included intravenous administration of recombinant enzyme upon diagnosis followed by hematopoeitic stem cell transplantation (HSCT) once a proper donor cell source is identified. Following HSCT, many patients exhibit a reduced rate of neurological deterioration. However, the potential of HSCT to ameliorate central nervous system manifestations of disease is limited by the inability of IDUA to efficiently cross the blood brain barrier. The results of my experiments demonstrate that GAG storage materials were partially reduced in the brains of MPS I mice following bone marrow transplantation with wild-type donor marrow (Chapter 2). However, pathogenic accumulation of GM3 ganglioside, not normally expressed in the brain, remained present in treated animals. This highlights the necessity to achieve more efficient delivery of IDUA to the central nervous system in order to normalize brain biochemistry. Thus, I propose the application of intracerebroventricular (ICV) infusion of adeno-associated viral vectors in order to mediate gene transfer and expression of IDUA in the brain. Infusion of an AAV serotype 8 vector into neonatal MPS I mice resulted in widespread long-term expression of high levels of IDUA throughout the brain consistent with normalization of GAG storage material and complete prevention of a neurocognitive deficit in a Morris water maze test (Chapter 3). Infusion of the same vector into adult MPS I animals resulted in low levels of IDUA expression and partial reduction of storage material in the brain consistent with partial improvement in the Morris water maze test (Chapter 4). The results of these experiments support the adoption of ICV infusion of AAV vectors as a supplement to enzyme replacement therapy and HSCT for the treatment of Hurler syndrome.Item Optical and electrophysiological technologies for monitoring cortex-wide brain activity(2023-06) Hu, JiaRecording cortex-wide brain activity and decoding the brain’s neural computations are required to mediate behaviors. Such an understanding will help formulate better treatments for neurological disorders and improve the quality of life. Technologies for sensing neural activities have been continuously developed over the past century. These technologies have gradually improved to recording from larger brain regions at high temporal and spatial resolution. Miniaturized devices have been developed for performing such imaging in freely-behaving animals. Along these lines, this thesis first aimed to develop a high-accessibility neural activity sensing technology and developed a fully desktop-fabricated flexible Graphene electrocorticography (ECoG) arrays that can be completely built using commonly used laboratory tools without the need for specialized cleanroom facilities. The ECoG arrays could be implanted chronically for up to 180 days allowing high-quality measurement surface field potentials. Building on this work, I developed a 3D-printed transparent ECoG array that simultaneously performs ECoG recordings and mesoscale Calcium (Ca2+) imaging from multiple sites. This device allowed the combination of high temporal resolution electrophysiological measurements with high spatial resolution optical readout of neural activities. In in vivo recording, the 3D-printed ECoG recorded stimuli-evoked and anesthesia drug-induced brain activity in mice and showed strong correlations between the optical and electrical signals with a cross-correlation factor > 75%. In the third aim, I developed a miniaturized micro-camera array microscope (mini-MCAM) for cortex-wide Calcium imaging at single-cell resolution in head-fixed or freely behaving mice. Mini-MCAM is an array of 4 microcameras generating a large computationally stitched FOV of 30-40 mm2 with a central resolution of 9.9 µm. The mini-MCAM recorded spontaneous brain activities at head-fixed and freely behaving states where distinctive neurons’ activities were recorded and identified. In this thesis, all three neural activity sensing technologies share a common goal to improve the existing neural activity sensing technologies and accelerate fundamental neuroscience research, which will bring new insights into the brain.Item Role of the median preoptic nucleus in chronic blood pressure regulation by angiotensin II(2008-12) Ployngam, TrasidaThe median preoptic nucleus (MnPO) receives dense reciprocal inputs from both the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), the circumventricular organs known to be important as central neural sensors of circulating angiotensin II (ANG II). This thesis proposes to establish the role of the MnPO in chronic regulation of blood pressure based on the central hypothesis that the MnPO is a crucial component of the central sympathoexcitatory circuitry necessary for chronic blood pressure control following ANG II activation of the SFO and OVLT. Throughout the studies, cardiovascular responses to either pharmacological or physiological changes of circulating ANG II activity were compared between MnPO lesioned rats and sham lesioned controls. The first specific aim was designed to test the hypothesis that the intact MnPO is necessary for the full hypertensive response to chronic intravenous ANG II administration. In this specific aim, rats with electrolytic lesion of the MnPO displayed significantly attenuated hypertensive responses by day 7 through day 10 of ANG II infusion compared to sham lesioned rats. Therefore, we concluded that the MnPO is a crucial component of the central neuronal circuitry mediating chronic ANG II-induced hypertension. Sub-aim 1A was designed to determine the specific role of the MnPO neurons versus fibers of passage in the attenuated hypertensive responses to ANG II observed in the MnPO lesioned rats. In line with the findings of specific aim 1, rats with ibotenic acid lesion of the MnPO demonstrated attenuated responses to the hypertensive effect of chronic ANG II administration. However, the attenuated responses were less extensive relative to those seen in the electrolytic lesioned rats. Therefore, it was concluded that neuronal cell bodies in the MnPO are necessary for the full hypertensive response to chronic ANG II administration; however, damage of the fibers of passage partly contributes to the attenuated hypertensive responses observed in the electrolytic lesioned rats. The second specific aim was to determine the role of the MnPO in mediating the chronic hypotensive effect of the AT1 receptor antagonist, losartan. In this specific aim, rats with ibotenic acid lesion of the MnPO showed exaggerated hypotensive responses to chronic losartan administration. These findings were accompanied with a greater decline in total peripheral resistance in the MnPO lesioned rats. Therefore, we concluded that MnPO neurons do not mediate the chronic hypotensive effect of losartan and that the MnPO is not necessary for basal blood pressure control by endogenous ANG II. However, the findings suggested that the MnPO neurons likely participate in baroreflex mechanisms buffering against losartan-induced hypotension. The last specific aim was to establish the role of the MnPO in normal blood pressure control during chronic high dietary salt intake. Although plasma sodium concentration and osmolality were raised significantly in rats with electrolytic lesion of the MnPO during high salt intake, their mean arterial pressure and heart rate were comparable with those of sham lesioned rats throughout the study. Therefore, we concluded that the MnPO is not necessary to maintain normal blood pressure during high dietary salt intake. However, MnPO lesioned rats displayed less renal sodium retention during high salt intake compared to sham lesioned rats suggesting the role of the MnPO in the central neurohumoral control of sympathetic outflow, in particular, renal sympathetic activity, during chronic high salt intake. In conclusion, overall, the findings in this dissertation provide important insights into the role of the MnPO in the chronic hypertension induced by ANG II. Furthermore, they provide additional evidence of the integrative role of the MnPO in chronic normal blood pressure control by circulating ANG II, plasma osmolality, and the baroreflex.