Aysha Allard Brown
Doctor of Philosophy in Neuroscience (PhD)
Research Topic
Investigating the effect of hemodynamic management and anticoagulation therapy on intraparenchymal hemorrhage after traumatic spinal cord injury
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
One of the only available treatment options to potentially improve neurologic recovery after acute spinal cord injury (SCI) is to augment the mean arterial blood pressure (MAP) to promote blood flow and oxygen delivery to the injured spinal cord. However, to optimize such hemodynamic management, clinicians would require a method to monitor the physiological effects of these MAP alterations within the injured cord. To address this need, I developed a technique using an implantable optical sensor based on near-infrared spectroscopy (NIRS) to monitor real-time spinal cord tissue oxygenation and hemodynamics after acute SCI. NIRS is an optical technology that uses light in the near-infrared spectrum to monitor changes in the concentrations of oxygenated and deoxygenated hemoglobin, from which changes in tissue oxygenation and perfusion can be inferred.In Chapter 1, I provide an overview of acute SCI and hemodynamic management and discuss the background of NIRS and its application on the spinal cord.In Chapter 2, I use a porcine model of thoracic SCI to study the effect of early vasopressor administration on oxygenation and hemodynamic responses within the spinal cord using intraparenchymal sensors.In Chapter 3, I investigate the feasibility and effectiveness of using an implantable NIRS sensor to monitor real-time spinal cord tissue oxygenation and hemodynamics during the first 7 days post- injury in the porcine model.In Chapter 4, I use the experimental protocol and analytical processes developed in Chapter 3 to evaluate refined and improved versions of the NIRS system for clinical application.In Chapter 5, I assess the accuracy of the clinical NIRS system to gold-standard intraparenchymal sensors and reference NIRS systems in both skeletal muscle and a porcine model.Through these pre-clinical studies, I have established a technique to monitor the oxygenation and hemodynamic status of the injured spinal cord to optimize clinical care. This work lays the foundation for direct monitoring of the spinal cord prior to its clinical translation and provides a broad landscape of oxygenation and hemodynamic responses in the spinal cord as reference for future work, as well as a resource for future studies developing and evaluating such technologies.
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Spinal cord injury is a devastating condition with variability in injury mechanisms and neurologic recovery. Spinal cord impairment is measured and classified by a widely accepted standard neurologic examination, however this examination is extremely challenging to conduct due to the fact that patients are often sedated, unconscious, or have multiple injuries. The lack of objective diagnostic or prognostic tools is a barrier for clinical trials. Biological markers (biomarkers) are promising as they represent an unbiased approach to classify injury severity and predict neurologic outcome. MicroRNAs are attractive biomarker candidates in neurological disorders due to their stability in biological fluids, conservation between humans and model mammals, and tissue specificity. These features of microRNAs motivated my research to identify the changes in expression of microRNAs following different injury severities in human patients with spinal cord injury, as well as in a large animal model of spinal cord injury using pigs. In Chapter 1, I provide background on the diagnosis and prognosis of spinal cord injury and discuss the current status of biomarkers for spinal cord injury. In Chapter 2, I provide the historical context for the use of animal models for studying spinal cord injury and review the current status of such animal models and injury paradigms in spinal cord injury research. In Chapter 3, I used a porcine model of thoracic spinal cord injury to study the effects of injury severity on microRNA expression. I identified a set of microRNAs that are diagnostic for injury severity and prognostic for behavioural and histological outcome. In Chapter 4, I identified changes in microRNA expression following acute spinal cord injury in a cohort of 44 human patients. I identified a set of microRNAs that are diagnostic for baseline injury severity and prognostic for neurologic outcome. These data describe the alterations in the microRNA profiles following acute spinal cord injury and identify a common set of microRNAs that can be used as diagnostic and prognostic tools. Furthermore, the data obtained and analyzed in pigs and humans with spinal cord injury provides a reference data set for future work as well as for correlative pig-human investigations.
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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Currently, hemodynamic management is one of the only treatment options to improve neurologic recovery in patients with acute spinal cord injury (SCI). Our team has developed a novel implantable sensor based on near-infrared spectroscopy (NIRS) that is able to monitor spinal cord hemodynamics and oxygenation in real-time following acute SCI. In order to collect data, the NIRS sensor should be in direct contact with the spinal cord and emit near-infrared light into the tissue. As a safety assessment measure, I aimed to study the potential heat generation and contact compression effects of a series of custom implantable NIRS sensors developed in our research laboratory on the spinal cord tissue, as it is important prior to its clinical translation. In Chapter 1, I describe acute SCI and clinical treatment options such as hemodynamic management, as well as using NIRS to monitor spinal cord hemodynamics and improve the management of acute SCI. I also provide a background of NIRS technology, its clinical transcutaneous and novel implantable applications, and its risk factors and safety aspects. In Chapter 2, I investigate the potential heating effect of our spinal cord NIRS sensor using an in vitro setup. In this chapter, I have compiled information for a review article titled "Thermal Threshold for Tissue Damage from Near-Infrared Spectroscopy Sensors," which I plan to submit to a peer-reviewed journal. In Chapter 3, I focus on the potential impact of NIRS sensor compression on the spinal cord tissue in a porcine model of acute SCI. In Chapter 4, I provide a summary, conclusions, and future directions. In the appendix, I provide a summary of the regulatory process for the application of the NIRS sensor (version 5) in the NIRS clinical trial. With these pre-clinical experiments, I have assessed the safety of the first series of the spinal cord NIRS sensors, which will ultimately lead to the design of the newest version of the sensor to be placed on the spinal cord of human SCI patients in a clinical trial. This study could help future studies in evaluating the safety of implantable NIRS sensors.
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Neurogenic lower urinary tract dysfunction after spinal cord injury results in severe morbidity and mortality. Consequences of neurogenic lower urinary tract dysfunction include urinary tract infections, incontinence, upper urinary tract deterioration, and reduced quality of life. Urodynamic studies are the current gold standard for characterizing neurogenic lower urinary tract dysfunction. Currently, there is a need for a large animal model of neurogenic lower urinary tract dysfunction for evaluation of the utility and safety of novel human-sized devices or treatments. In this thesis, the functional and morphologic changes of the bladder were characterized in a porcine model of spinal cord injury. In Chapter 1, I provide background on spinal cord injury and the pathophysiology of neurogenic lower urinary tract dysfunction. I also discuss about the use of animal models for evaluation of human lower urinary tract diseases.In Chapter 2, I pioneered a protocol to perform clinically relevant urodynamic studies in a porcine model of thoracic spinal cord injury. I identified that the pig’s lower urinary tract function is very similar to human bladder function before and after spinal cord injury. In Chapter 3, I describe a protocol to implant radio telemetric devices into a porcine model to characterize physiologic bladder function and to evaluate the practicality of the system. I identified comparable detrusor pressure and external urethral sphincter activity recordings between the urodynamics and telemetry systems before and after spinal cord injury. In Chapter 4, I evaluated the effects of chronic bladder drainage on the functional and histologic features of the bladder. I found high-risk urodynamic features in pigs that received chronic bladder drainage.I have established a protocol to perform urodynamic studies in a porcine model of spinal cord injury to characterize neurogenic lower urinary tract dysfunction. The potential to perform repeated urodynamic studies in a single animal allows for investigation into the efficacy of treatment of therapies and devices over time. This scientific contribution will help bridge the gap between animal experimentation and human application for neurogenic lower urinary tract dysfunction after spinal cord injury.
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Spinal cord injuries (SCI) are one of the most physically and psychologically devastating injuries one can survive. Despite decades of intense research effort, robust therapeutic treatment for this catastrophic condition remains elusive. The nature of the sequelae of SCI is characterized by progressive cell death in the injury penumbra, resulting in further neurological impairments. The intricate relationship between the vascular and nervous systems has become increasingly evident in many aspects of both normal physiology, and various pathological conditions, including SCI. Vascular abnormalities play a central role in the propagation of secondary damage after SCI. The aim of this thesis is to further the understanding of the vascular changes that occur after acute SCI. The endogenous expression of three angiogenic proteins: Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and Angiogenin will be examined after acute traumatic SCI. In the first study, the concentration of these proteins will be measured in a temporal series of cerebrospinal fluid (CSF) samples after human SCI. In the second study, the relative protein expression of Ang1 and Ang2 will be characterized in rat spinal cord after SCI. In human, Ang1 in CSF is not significantly different from non-SCI values after the initial spike at 24 hours post-SCI. Ang2 in CSF shows a delayed but persistent increase through the first 5 days post-SCI. In contrast, Ang1 in rat spinal cord decreases as early as 2 hours post-SCI, while low molecular weight Ang2 increases dramatically after SCI, from 2 hours to 3 days post-injury, peaking with a 13-fold elevation at 24 hours post-injury. These findings represent the first description of these proteins in the acute SCI setting in human CSF and rat spinal cord. The sustained elevation of Ang2 illustrates a possible mechanism by which reported vascular dysfunction and increases in blood-spinal cord-barrier (BSCB) permeability occurs after SCI. The patterns of change reported between the two studies may allude to the feasibility of using CSF as a biological proxy to future investigations into the biochemical events which occur in the spinal cord after SCI, and guide the development of pharmacologic treatments for this devastating condition.
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Spinal cord injury (SCI) is a devastating condition that causes paralysis below the level of the injury. To date, there is no convincingly effective treatment. An enormous preclinical and clinical effort is underway to find a treatment, and one approach is to search for pharmacological agents that are already in clinical use (albeit for different indications), but that may also have neuroprotective properties. Examples of such drugs are magnesium, Riluzole (sodium channel blocker), minocycline and statins. While the majority of human SCI occur in the cervical spinal cord, the vast majority of laboratory SCI research employs animal models of thoracic SCI. An important step, therefore, in the preclinical evaluation of novel treatments is to assess their efficacy in a model of cervical SCI. First, I describe the development of a novel unilateral contusive model of cervical SCI with refined biomechanical, functional, and histological parameters using the Infinite Horizon spinal cord injury device. I conducted a series of experiments in which the spinal cord was injured using various impact forces, impact trajectories, and impact locations off the midline. Behavioral deficits were assessed using a variety of forelimb function tests, after which the cords were evaluated histologically. From these series of experiments, I established a new cervical unilateral spinal cord injury contusion model. Next, I evaluated the neuroprotective effects of minocycline and simvastatin in the clinically relevant unilateral cervical contusion model. Minocycline is a commonly prescribed tetracycline antibiotic that is prescribed for acne. Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors that lower cholesterol. As both drugs have translational potential and have been reported to have neuroprotective properties in various neurological diseases, I assessed the neuroprotective effects of these drugs using a host of functional and histological assessments. In the end, there were no neurological improvements with minocycline or simvastatin treatment after a cervical contusion injury.
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