Applications of CT Perfusion-Based Triaging and Prognostication in Acute Ischemic Stroke

CT Perfusion (CTP) is a minimally invasive imaging technique that aids acute ischemic stroke (AIS) triage and prognostication by determining tissue viability based on hemodynamic parameters. The goals of this research are to determine: 1) CTP thresholds for estimation of infarct and penumbra volume, 2) how CTP scan duration impacts infarct and penumbra volume estimates, and 3) reliability of CTP for predicting functional outcomes following intra-arterial therapy (IAT). Chapter 2 introduced an experimental study for determining ischemia-time dependent thresholds for brain infarction using multimodal imaging in a porcine stroke model that is easier to implement than previous large animal stroke models. CTP determined an absolute cerebral blood flow (CBF) threshold of 12.6±2.8mL∙min-1∙100g-1 for brain infarction after 3h of ischemia, which was close to that derived using hydrogen clearance in a previous study by Jones et al (Journal of Neurosurgery, 1981;54(6):773-782). Chapter 3 retrospectively investigated the impact of CTP scan duration on cerebral blood volume (CBV), CBF, and time-to-maximum (Tmax) and found optimal scan durations that minimized radiation dose while not under- or over-estimating infarct volumes measured using two previously derived CBF thresholds for infarction. We found that CBV and Tmax decreased at shorter scan durations, whereas CBF was independent of scan duration, consequently, infarct volume estimated by both CBF thresholds was independent of scan duration. Chapter 4 compared reperfusion seen on follow-up CTP to reperfusion predicted by post-IAT digital subtraction angiography (DSA) and the ability of the two modalities to predict good 90-day functional outcome in a retrospective study. We found that patients with ‘complete reperfusion’ grades on DSA often had ischemic tissue on follow-up CTP and that follow-up CTP had superior specificity and accuracy for predicting functional outcome compared to DSA. In summary, this research has shown that CBF thresholds can reliably detect infarct in AIS and are independent of scan duration, allowing radiation dose to be minimized by limiting scans to 40s without compromising accuracy of infarct volume estimates. Finally, CTP is a more specific and accurate predictor of functional outcome than the commonly used post-procedural DSA, this could help select patients for neuroprotective therapy

Targeting Cerebral Oedema and Elevated Intracranial Pressure in a Preclinical Model of Ischaemic Stroke

Stroke is a devastating condition, affecting over 17 million people worldwide annually. Interruption of cerebral arterial blood flow in ischaemic stroke initiates a cascade of deleterious events, leading to irreversible cell damage and secondary injury. Specifically, the development of cerebral oedema, whereby disruption to the blood–brain barrier (BBB) precipitates abnormal fluid accumulation within the brain parenchyma, leads to a consequent rise in intracranial pressure (ICP). Persistently elevated ICP results in loss of cerebral autoregulation and brain herniation, making it a leading cause of death and disability poststroke. Despite this, current treatments fail to prevent the pathophysiological development of oedema, rather targeting the symptoms once established. As such, understanding the mechanisms underlying cerebral oedema and elevated ICP is essential in order to develop more targeted and effective treatments to prevent oedema genesis and improve patient outcomes. Neurogenic inflammation, mediated by substance P (SP), has been linked to profound BBB disruption, oedema development and poor functional outcome post-stroke. SP binds to the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral oedema following stroke in rodent models. However, more clinically-relevant animal models are required to validate efficacy of novel stroke therapeutics to improve clinical translation. Thus, this thesis sought to determine the efficacy of NK1-R antagonist treatment in reducing cerebral oedema and ICP in a clinically-relevant ovine stroke model. Merino sheep (Ovis aries; n=125) were used across the five thesis studies. For Aim 1 (n=34F), a non-survival permanent middle cerebral artery occlusion (MCAo) model was used to determine the efficacy of various NK1-R receptor antagonist regimens or decompressive craniectomy in reducing ICP post-stroke. Once an optimum dosage was determined, Aims 2 and 3 (n=23F;24M) involved development of a transient MCAo survival model and characterisation of the temporal profile of oedema and ICP. Finally, Aim 4 and 5 (n=9F;9M), sought to determine the ideal time-course of treatment, and investigate the efficacy of the NK1-R antagonist following transient stroke via assessment of neurological and functional outcomes. ICP was assessed via invasive monitoring, with arterial blood pressure, temperature and blood gases also measured. Magnetic resonance imaging (MRI) and immunohistochemistry (IHC) was also performed. Motion capture and a modified neuroscore was used to assess changes in motor function and demeanour. This thesis identified that two doses of the NK1-R antagonist were efficacious in reducing ICP following permanent MCAo. A transient stroke model was successfully developed and characterised, with ICP peaking at 5-6 days post-stroke. NK1-R antagonist treatment, both acutely (1-3 days), and in a delayed fashion (5-day), significantly reduced ICP post-stroke. Finally, a motion capture tool was successfully established and validated as a quantitative method to assess motor function following transient ovine stroke, with animal gait significantly impaired post-stroke. The work presented in this thesis encompasses a comprehensive evaluation of the efficacy of NK1-R antagonist treatment in a clinically-relevant ovine model, providing strong preclinical evidence for further investigation. Accordingly, Phase II trials are currently underway in Australia, the United Kingdom and the United States of America.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Image-Guided Abdominal Surgery and Therapy Delivery

ABSTRACT Image-Guided Surgery has become the standard of care in intracranial neurosurgery providing more exact resections while minimizing damage to healthy tissue. Moving that process to abdominal organs presents additional challenges in the form of image segmentation, image to physical space registration, organ motion and deformation. In this paper, we present methodologies and results for addressing these challenges in two specific organs: the liver and the kidney

Recent Advances in the Therapeutic and Diagnostic Use of Liposomes and Carbon Nanomaterials in Ischemic Stroke

The complexity of the central nervous system (CNS), its limited self-repairing capacity and the ineffective delivery of most CNS drugs to the brain contribute to the irreversible and progressive nature of many neurological diseases and also the severity of the outcome. Therefore, neurological disorders belong to the group of pathologies with the greatest need of new technologies for diagnostics and therapeutics. In this scenario, nanotechnology has emerged with innovative and promising biomaterials and tools. This review focuses on ischemic stroke, being one of the major causes of death and serious long-term disabilities worldwide, and the recent advances in the study of liposomes and carbon nanomaterials for therapeutic and diagnostic purposes. Ischemic stroke occurs when blood flow to the brain is insufficient to meet metabolic demand, leading to a cascade of physiopathological events in the CNS including local blood brain barrier (BBB) disruption. However, to date, the only treatment approved by the FDA for this pathology is based on the potentially toxic tissue plasminogen activator. The techniques currently available for diagnosis of stroke also lack sensitivity. Liposomes and carbon nanomaterials were selected for comparison in this review, because of their very distinct characteristics and ranges of applications. Liposomes represent a biomimetic system, with composition, structural organization and properties very similar to biological membranes. On the other hand, carbon nanomaterials, which are not naturally encountered in the human body, exhibit new modes of interaction with biological molecules and systems, resulting in unique pharmacological properties. In the last years, several neuroprotective agents have been evaluated under the encapsulated form in liposomes, in experimental models of stroke. Effective drug delivery to the brain and neuroprotection were achieved using stealth liposomes bearing targeting ligands onto their surface for brain endothelial cells and ischemic tissues receptors. Carbon nanomaterials including nanotubes, fullerenes and graphene, started to be investigated and potential applications for therapy, biosensing and imaging have been identified based on their antioxidant action, their intrinsic photoluminescence, their ability to cross the BBB, transitorily decrease the BBB paracellular tightness, carry oligonucleotides and cells and induce cell differentiation. The potential future developments in the field are finally discussed

PRELIMINARY FINDINGS OF A POTENZIATED PIEZOSURGERGICAL DEVICE AT THE RABBIT SKULL

The number of available ultrasonic osteotomes has remarkably increased. In vitro and in vivo studies have revealed differences between conventional osteotomes, such as rotating or sawing devices, and ultrasound-supported osteotomes (Piezosurgery®) regarding the micromorphology and roughness values of osteotomized bone surfaces. Objective: the present study compares the micro-morphologies and roughness values of osteotomized bone surfaces after the application of rotating and sawing devices, Piezosurgery Medical® and Piezosurgery Medical New Generation Powerful Handpiece. Methods: Fresh, standard-sized bony samples were taken from a rabbit skull using the following osteotomes: rotating and sawing devices, Piezosurgery Medical® and a Piezosurgery Medical New Generation Powerful Handpiece. The required duration of time for each osteotomy was recorded. Micromorphologies and roughness values to characterize the bone surfaces following the different osteotomy methods were described. The prepared surfaces were examined via light microscopy, environmental surface electron microscopy (ESEM), transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM) and atomic force microscopy. The selective cutting of mineralized tissues while preserving adjacent soft tissue (dura mater and nervous tissue) was studied. Bone necrosis of the osteotomy sites and the vitality of the osteocytes near the sectional plane were investigated, as well as the proportion of apoptosis or cell degeneration. Results and Conclusions: The potential positive effects on bone healing and reossification associated with different devices were evaluated and the comparative analysis among the different devices used was performed, in order to determine the best osteotomes to be employed during cranio-facial surgery

The Pathophysiologic Significance of Endothelins in the Cerebral Circulation

This thesis examined the pathophysiologic role of the endothelins in the cerebral circulation. Endothelin receptors were characterised in the rabbit basilar artery in vitro and in feline cerebral resistance arterioles in situ. Investigations in the feline cerebral resistance arterioles were designed to examine the cerebrovascular effects and blood-brain barrier penetration of non-peptide and peptide endothelin receptor antagonists. The pathophysiologic role of the endothelins were examined, using validated doses of endothelin receptor antagonists (primarily Bosentan), in experimental models of focal cerebral ischaemia in the cat, transient global cerebral ischaemia in the rat and subdural haematoma in the rat. In the rabbit basilar artery in vitro, pre-incubation with either the combined ETA/ETB endothelin receptor antagonist Bosentan (4-tert-Butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene sulphonamide) or the endothelin ETA receptor antagonist BQ-123 (cyclo D-Aspartate-D-Tryptophan-L-Leucine-D-Valine-L-Proline) had minimal effect on the resting tone of arterial segments. The ETB receptor agonist BQ-3020 (N-Acetyl [11 Ala,15 Ala] ET-1 (6-21)) elicited a small constriction of the arterial segments. Bosentan (10 muM) elicited a rightward shift of the ET-1 concentration response curve (pA2 = 5.1). BQ-123 (0.1 - 10 muM) elicited a concentration dependent rightward shift of the ET-1 concentration response curve (pA2 = 5.3). BQ-123 (1 muM) elicited a substantial rightward shift of the ET-3 concentration response curve (pA2 = 7.2). The observations suggested the presence of an 'atypical' endothelin ETA receptor mediating vasoconstriction in the rabbit basilar artery. The receptors mediating the cerebrovascular actions of endothelins were examined in feline cerebral resistance arterioles in vivo. The adventitial microapplication of the endothelin ETA receptor antagonist BQ-123 (0.1 - 10 muM) per se had minimal effect on cerebral resistance arterioles examined. The adventitial microapplication of endothelin-1 (10 nM) elicited a marked vasoconstriction of cerebral resistance arterioles (-29.1 +/- 1.9 % from pre-injection baseline). The endothelin-1 induced vasoconstriction was attenuated, in a dose dependent manner, by the adventitial co-application of BQ-123 and endothelin-1 (estimated IC50 0.7 muM). The adventitial microapplication of the endothelin ETB receptor agonist BQ-3020 (0.001 - 1 muM) effected a dose dependent vasodilatation (EC50 30 nM, maximum response 25 +/- 5 % from pre-injection baseline). The magnitude of the vasodilatation elicited by BQ-3020 (100 nM and 1 muM) was dependent on the pre-injection calibre of the arterioles examined. The intracarotid infusion (via the lingual artery) of BQ- 3020 (0.5-500 pmol/min) had no significant effect on the calibre of cerebral resistance arterioles. These results suggest that the peptide endothelin ETB receptor agonist fails to gain access to the cerebrovascular endothelin ETB receptors following its intraluminal administration. These investigations indicate that endothelin ETA receptors mediate vasoconstriction and endothelin ETB receptors mediate vasodilatation in feline cerebral resistance arterioles in vivo. The cerebrovascular actions of Bosentan, a novel endothelin antagonist with effects at ET

An electronically steered, wearable transcranial doppler ultrasound system

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 137-144).This thesis details the design of a transcranial Doppler (TCD) ultrasound system to measure cerebral blood flow velocity (CBFV) at the middle cerebral artery (MCA). TCD sonography has been clinically indicated in a variety of neurovascular diagnostic applications. Acceptance of conventional TCD methods, however, has been primarily impeded by several constraints, including restrictive system form factors, measurement reliability concerns, and the need for a highly-skilled operator. The goal of this work is to reduce the effects of such limitations through the development of a highly-compact, wearable TCD ultrasound system for autonomous CBFV measurement. A first-generation, eight channel printed circuit board prototype system has been designed, fabricated, and experimentally tested. Characterization of the prototype system using a Doppler flow phantom resulted in a normalized root-mean-square error of < 3.5% over the range of expected in vivo MCA flow velocities. Extension of the initial prototype to higher channel count systems and the development of phased array beamformation and algorithmic vessel location are also examined in this work. The emergence of simple, robust, and non-invasive neurovascular diagnostic methods presents an enormous opportunity for the advancement of neurovascular monitoring, particularly in applications where - due to restrictions in current diagnostic modalities - standard monitoring procedures have not yet been established.by Sabino Joseph Pietrangelo.S.M