Small animal positron emission tomography (PET) image analysis can be particularly challenging with heavily-lesioned animal disease models with limited tracer uptake such as the 6-hydroxydopamine (OHDA) lesioned rat model of Parkinson's disease. Methodology-related variations in measured values of 10% or 15% can obscure meaningful biological differences, so accurate analysis methods are essential. However, placing regions of interest (ROIs) on these images without additional guidance is unreliable, and can lead to significant errors in results. To address this problem, this work develops a partly atlas-guided method place ROIs on structures that lack specific binding with presynaptic dopaminergic tracers. The method is tested by correlation of PET binding potential (BP) with autoradiographic binding measurements, and with repeated PET scans of the same subjects, both with the presynaptic tracer ¹¹C-dihydrotetrabenazine (DTBZ). The method is found to produce reliable results. When directly comparing PET images of the same subject to detect changes, it is essential to minimize variations due to analysis method. To this end, a masking method for automated image registration (AIR) of PET images with dopaminergic tracer rat images is developed. Coregistration with AIR and separate ROI placement are compared and tested with repeated scans of the same rat with DTBZ, and are found to be equivalent. Kinetic modelling algorithms may also introduce bias or scatter to binding potentials (BP) calculated from TACs or in parametric images. To determine the optimal method for this step, algorithms for dopaminergic tracers are compared for small animal DTBZ, ¹¹C-methylphenidate (MP), and ¹¹C-raclopride (Rac) data. Among the tested methods is a new variant of the Logan graphical kinetic modelling method, developed in this work, that issignificantly less biased by target tissue TAC noise than the standard Logan approach. The modified graphical method is further compared with the Logan graphical algorithms with added-noise simulations. The simplified reference tissue model (SRTM) is found to have the best method for ROI TAC data, while the modified graphical algorithm may be preferred when generating parametric images.

The placebo effect represents a fascinating example of how cognition can influence the physiology of the brain and body. The expectation of therapeutic benefit elicited by a placebo given in the guise of active medication has been proposed to be a form of reward expectation, and is associated with activation of brain reward circuitry. Prominent placebo effects occur in Parkinson’s disease (PD), where the expectation of symptom improvement stimulates dopamine release in the striatum. In the work described in this dissertation, positron emission tomography with [¹¹C] raclopride was used to investigate the relationship between the strength of expectation of benefit and the degree of dopamine release in PD, and how this relationship corresponds to current models of dopamine function in reward. Chapter 3 describes a pilot study conducted in patients who had undergone subthalamic nucleus deep-brain stimulation (STN-DBS) in which we examined how awareness of stimulator status (ON or OFF) affected synaptic dopamine levels compared to when subjects were blind. No difference was detected between conditions; however, it proved to be difficult to maintain blinding due to the profound effects of STN-DBS. Chapter 4 describes the development of the methodology for the analysis of high-resolution PET data, in which we utilized the combined efforts of neuroscience and imaging physics to optimize the analysis of [¹¹C] raclopride PET data. In Chapter 5, I describe the use of verbal instructions to manipulate patients’ expectations in order to investigate how the likelihood of receiving levodopa influenced dopamine release when the patients were in fact given placebo. Placebo-induced dopamine release was differentially modulated by expectation in the dorsal and ventral striatum: dopamine release in the putamen was related monotonically to expected reward value, whereas dopamine released in the ventral striatum reflected the uncertainty of benefit or the salience of the expectation. The placebo effect in PD therefore involves at least two related but separate mechanisms: the expectation of benefit itself, which is scaled to reflect the value of the drug to the patient and is mediated by nigrostriatal dopamine, and the uncertainty or salience of benefit that is mediated by mesolimbic dopamine.

Porphyrins are naturally occurring molecules. Porphysomes are simple multimodal nanoparticles that derive their multifunctionality from porphyrin-based building-blocks. While previous studies have probed their interactions with light, their capacity to stably chelate metal ions has gone largely uninvestigated. Herein are presented and discussed two investigations into metalloporphysomes. First is a method for non-invasively labeling porphysomes with radioactive copper-64. Utilizing exceptionally simple chemistry, this method produces a highly stable radiotracer capable of both PET and fluorescence imaging. Second is a profile of a MRI-detectable, photothermal agent whose photonic properties are serendipitously improved by the incorporation of MRI-active metal ions. By taking advantage of simple chemical substitutions, these studies illustrate methods of accessing new functionalities while maintaining a deeply simple construct, an often overlooked aspect in the development of multimodal nanoparticles.

Laser Transmission Welding (LTW) involves localized heating at the interface of two pieces of plastic (a laser transparent plastic and laser absorbing plastic) to be joined. It produces strong, hermetically sealed welds with minimal thermal and mechanical stress, no particulates and very little flash. An ideal transparent polymer for LTW must have: a low laser absorbance to avoid energy loss, a low level of laser scattering so it can provide a maximum energy flux at the weld interface and also have a high resistance to thermal degradation. The objective of the project was to analyze the effect of blend ratios of polybutylene terephthalate and polyethylene terephthalate (PBT/PET) on these laser welding characteristics. The blends were manufactured by DSM (Netherlands). They were characterized using Differential Scanning Calorimetry (DSC) and Thermal Gravimetry Analysis (TGA). The latter technique was used to estimate the order (n), activation energy (ΔH) and frequency factor (A’) of the degradation reaction of the polymer blends. The normalized power profile of the laser after passing through the transparent polymer was measured using a novel non-contact technique and modeled using a semi-empirical model developed by Dr.Chen. Adding more PET ratio to the blend, did not change beam profile of the transmitted beam significantly. Laser welding experiments were conducted in which joints were made while varying laser power and scanning speed. Measuring the weld strength and width showed that the blends containing PET have higher strength in comparison to pure PBT. The temperature-time profile at the interface during welding was predicted using a commercial FEM code. This information was combined with the degradation rate data to estimate the relative amount of degraded material at the weld interface. It showed that increasing the ratio of PET in the blend makes it more resistant against thermal degradation which can be one of the reasons the PET containing blends reach higher weld strengths when compared to pure PBT. / Thesis (Master, Chemical Engineering) -- Queen's University, 2010-08-31 10:03:42.167

Porphyrins are naturally occurring molecules. Porphysomes are simple multimodal nanoparticles that derive their multifunctionality from porphyrin-based building-blocks. While previous studies have probed their interactions with light, their capacity to stably chelate metal ions has gone largely uninvestigated. Herein are presented and discussed two investigations into metalloporphysomes. First is a method for non-invasively labeling porphysomes with radioactive copper-64. Utilizing exceptionally simple chemistry, this method produces a highly stable radiotracer capable of both PET and fluorescence imaging. Second is a profile of a MRI-detectable, photothermal agent whose photonic properties are serendipitously improved by the incorporation of MRI-active metal ions. By taking advantage of simple chemical substitutions, these studies illustrate methods of accessing new functionalities while maintaining a deeply simple construct, an often overlooked aspect in the development of multimodal nanoparticles.

Listening to music is rated as one of the most pleasurable activities in human life and,in fact, listeners report the emotional impact of music to be one of the main motivatorsas to why they listen to music. This thesis focuses on the positive affective statesexperienced when listening to music and their underlying neural substrates. Despite thefact that research on the neural correlates of music-induced positive affect is arelatively recent undertaking our understanding has significantly improved during thelast decades. The aim of the current thesis is to give an overview of the neuralcorrelates of music-induced positive affect in healthy individuals. As such,psychophysiological, neuroimaging and electrophysiological studies are reviewed.Across studies the consistent involvement of brain regions, such as the orbitofrontalcortex, the striatum and the amygdala and left hemisphere frontal regions in response tomusic-induced positive affect has been found. These structures constitute an importantpart of the mesolimbocortical reward circuitry found to be involved in the processing ofa wide range of pleasures. The thesis also discusses conceptual and methodologicallimitations inherent in the studies reviewed. Understanding the nature and underlyingneural basis of music-induced positive affect is important because of the implications itmay have for psychological and physical wellbeing.

Elevated sympathetic nervous system (SNS) tone contributes to excess cardiac mortality associated with type 2 diabetes mellitus (T2DM). Chronic SNS stimulation has detrimental effects to the heart, in particular, with its cell signaling abilities. (R)-[11C]Rolipram small animal positron emission tomography (PET), an noninvasive nuclear imaging modality, was used to assess phosphodiesterase-4 (PDE4) alterations in a high fat diet (HFD), streptozotocin (STZ) induced model of hyperglycemia in rats. Prior to investigation in the animal model, characterization of (R)-[11C]rolipram small animal PET was completed. (R)-[11C]Rolipram binds specifically to PDE4 in the rat heart demonstrated by competitive blockade with (R)-rolipram with the PDE4 enzyme susceptible to saturation with increasing injected masses of unlabeled rolipram. (R)-[11C]Rolipram cardiac retention was elevated by acute norepinephrine stimulation via desipramine pharmacologic challenge. Quantitative (R)-[11C]rolipram PET was highly reproducible in the heart and presents an ideal avenue to investigate PDE4 alterations. (R)-[11C]rolipram small animal PET did not reveal changes in PDE4 expression and activity in STZ-treated hyperglycemic animals compared to STZ-treated euglycemic and control groups. In vitro measures of PDE4 enzyme expression and activity, with or without desipramine, were also not altered between treatment groups. Although (R)-[11C]rolipram small animal PET does not reveal PDE4 alterations in this animal model of diabetes, its utility to assess PDE4 alterations in other over active SNS pathologies, such as heart failure and obesity, remains.

Ion beam therapy (IBT) is a promising treatment option in radiotherapy. The characteristic physical and biological properties of light ion beams allow for the delivery of highly tumour conformal dose distributions. Related to the sparing of surrounding healthy tissue and nearby organs at risk, it is feasible to escalate the dose in the tumour volume to reach higher tumour control and survival rates. Remarkable clinical outcome was achieved with IBT for radio-resistant, deep-seated, static and well fixated tumour entities. Presumably, more patients could benefit from the advantages of IBT if it would be available for more frequent tumour sites. Those located in the thorax and upper abdominal region are commonly subjected to intra-fractional, respiration related motion. Different motion compensated dose delivery techniques have been developed for active field shaping with scanned pencil beams and are at least available under experimental conditions at the GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany. High standards for quality assurance are required in IBT to ensure a safe and precise dose application. Both underdosage in the tumour and overdosage in the normal tissue might endanger the treatment success. Since minor unexpected anatomical changes e.g. related to patient mispositioning, tumour shrinkage or tissue swelling could already lead to remarkable deviations between planned and delivered dose distribution, a valuable dose monitoring system is desired for IBT. So far, positron emission tomography (PET) is the only in vivo, in situ and non-invasive qualitative dose monitoring method applied under clinical conditions. It makes use of the tissue autoactivation by nuclear fragmentation reactions occurring along the beam path. Among others, β+-emitting nuclides are generated and decay according to their half-life under the emission of a positron. The subsequent positron-electron annihilation creates two 511 keV photons which are emitted in opposite direction and can be detected as coincidence event by a dedicated PET scanner. The induced three-dimensional (3D) β+-activity distribution in the patient can be reconstructed from the measured coincidences. Conclusions about the delivered dose distribution can be drawn indirectly from a comparison between two β+-activity distributions: the measured one and an expected one generated by a Monte-Carlo simulation. This workflow has been proven to be valuable for the dose monitoring in IBT when it was applied for about 440 patients, mainly suffering from deep-seated head and neck tumours that have been treated with 12C ions at GSI. In the presence of intra-fractional target motion, the conventional 3D PET data processing will result in an inaccurate representation of the β+-activity distribution in the patient. Four-dimensional, time-resolved (4D) reconstruction algorithms adapted to the special geometry of in-beam PET scanners allow to compensate for the motion related blurring artefacts. Within this thesis, a 4D maximum likelihood expectation maximization (MLEM) reconstruction algorithm has been implemented for the double-head scanner Bastei installed at GSI. The proper functionality of the algorithm and its superior performance in terms of suppressing motion related blurring artefacts compared to an already applied co-registration approach has been demonstrated by a comparative simulation study and by dedicated measurements with moving radioactive sources and irradiated targets. Dedicated phantoms mainly made up of polymethyl methacrylate (PMMA) and a motion table for regular one-dimensional (1D) motion patterns have been designed and manufactured for the experiments. Furthermore, the general applicability of the 4D MLEM algorithm for more complex motion patterns has been demonstrated by the successful reduction of motion artefacts from a measurement with rotating (two-dimensional moving) radioactive sources. For 1D cos^2 and cos^4 motion, it has been clearly illustrated by systematic point source measurements that the motion influence can be better compensated with the same number of motion phases if amplitude-sorted instead of time-sorted phases are utilized. In any case, with an appropriate parameter selection to obtain a mean residual motion per phase of about half of the size of a PET crystal size, acceptable results have been achieved. Additionally, it has been validated that the 4D MLEM algorithm allows to reliably access the relevant parameters (particle range and lateral field position and gradients) for a dose verification in intra-fractionally moving targets even from the intrinsically low counting statistics of IBT-PET data. To evaluate the measured β+-activity distribution, it should be compared to a simulated one that is expected from the moving target irradiation. Thus, a 4D version of the simulation software is required. It has to emulate the generation of β+-emitters under consideration of the intra-fractional motion, their decay at motion state dependent coordinates and to create listmode data streams from the simulated coincidences. Such a revised and extended version that has been compiled for the special geometry of the Bastei PET scanner is presented within this thesis. The therapy control system provides information about the exact progress of the motion compensated dose delivery. This information and the intra-fractional target motion needs to be taken into account for simulating realistic β+-activity distributions. A dedicated preclinical phantom simulation study has been performed to demonstrate the correct functionality of the 4D simulation program and the necessity of the additional, motion-related input parameters. Different to the data evaluation for static targets, additional effort is required to avoid a potential misleading interpretation of the 4D measured and simulated β+-activity distribu- tions in the presence of deficient motion mitigation or data processing. It is presented that in the presence of treatment errors the results from the simulation might be in accordance to the measurement although the planned and delivered dose distribution are different. In contrast to that, deviations may occur between both distributions which are not related to anatomical changes but to deficient 4D data processing. Recommendations are given in this thesis to optimize the 4D IBT-PET workflow and to prevent the observer from a mis-interpretation of the dose monitoring data. In summary, the thesis contributes on a large scale to a potential future application of the IBT-PET monitoring for intra-fractionally moving target volumes by providing the required reconstruction and simulation algorithms. Systematic examinations with more realistic, multi-directional and irregular motion patterns are required for further improvements. For a final rating of the expectable benefit from a 4D IBT-PET dose monitoring, future investigations should include real treatment plans, breathing curves and 4D patient CT images. / Die Ionenstrahltherapie (englisch: ion beam therapy, IBT) ist eine vielversprechende Behandlungsoption im Bereich der Strahlentherapie. Die charakteristischen physikalischen und biologischen Eigenschaften der Ionenstrahlen werden genutzt, um tumorkonformale Dosisverteilungen zu erzeugen. Die verbesserte Schonung des an den Tumor angrenzenden Normalgewebes und eventuell naheliegender Risikoorgane ermöglicht eine Dosissteigerung im Zielgebiet und somit potentiell höhere Tumorkontroll- und Überlebensraten. Für tiefliegende, gegenüber konventioneller Strahlung resistente, statische und gut fixierte Tumore wurden bereits beachtliche klinische Resultate erzielt. Wahrscheinlich könnten noch mehr Patienten von den Vorteilen der IBT profitieren, wenn diese auch für häufiger auftretende und intrafraktionell bewegliche Tumore uneingeschränkt nutzbar wäre. Verschiedene bewegungskompensierte Bestrahlungsmethoden wurden entwickelt und stehen zumindest unter experimentellen Bedingungen für weitere Untersuchungen am GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt zur Verfügung. Um eine sichere und präzise Dosisapplikation in der IBT zu ermöglichen, werden hohe Anforderungen an die Qualitätssicherung gesetzt. Sowohl auftretende Überdosierungen im Normalgewebe als auch Unterdosierungen im Tumor können den Therapieerfolg gefährden. Da bereits kleine, unerwartete anatomische Veränderungen, zum Beispiel durch Fehlpositionierung des Patienten, Schrumpfung des Tumors oder Schwellungen, zu erheblichen Abweichungen zwischen geplanter und applizierter Dosisverteilung führen können, gibt es Bestrebungen, die applizierte Dosis zumindest qualitativ zu verifizieren. Die Positronen-Emissions-Tomografie (PET) ist derzeit die einzige, bereits klinisch erprobte Methode für ein in vivo, in situ und nicht-invasives qualitatives Dosismonitoring. Diese Methode ist im Stande, die Autoaktivierung des bestrahlten Gewebes zu erfassen, welche aufgrund von Kernfragmentierungsprozessen entlang des Strahlweges erzeugt wird. Unter anderem werden in diesen Reaktionen instabile Nuklide erzeugt, die entsprechend ihrer Halbwertszeit unter Emission eines Positrons zerfallen. Bei der anschließenden Positron-Elektron-Annihilation werden zwei 511keV Photonen in entgegengesetzter Richtung emittiert und können mittels eines geeigneten PET-Scanners als Koinzidenzereignis detektiert werden. Die im Patienten induzierte dreidimensionale (3D) β+-Aktivitätsverteilung kann aus den gemessenen Koinzidenzen rekonstruiert werden. Ein Vergleich der gemessenen mit einer erwarteten, mittels Monte-Carlo Simulation erzeugten β+-Aktivitätsverteilung erlaubt es, Schlussfolgerungen über die tatsächlich im Patienten deponierte 3D Dosisverteilung zu ziehen. Diese Art der Datenauswertung wurde erfolgreich für die qualitative Dosisverifikation von über 440 Patienten eingesetzt, deren Tumore (vorwiegend im Kopf- und Halsbereich) an der GSI mit 12C-Ionen bestrahlt wurden. Bei der konventionellen 3D IBT-PET-Datenverarbeitung wird eine mögliche intrafraktionelle Bewegung des Zielgebietes nicht berücksichtigt und fehlerhaft rekonstruierte β+-Aktivitätsverteilungen sind die Folge. Daher werden vierdimensionale, zeitaufgelöste (4D) Rekonstruktionsalgorithmen benötigt, die für die spezielle Geometrie eines in-beam PET-Scanner adaptiert wurden und eine Kompensation der bewegungsinduzierten Artefakte ermöglichen. Im Rahmen der vorliegenden Arbeit wurde für den an der GSI installierten Doppelkopf-PET-Scanner Bastei ein 4D Maximum-Likelihood-Expectation-Maximization (MLEM) Algorithmus implementiert. Die Funktionsfähigkeit des Algorithmus sowie dessen verbesserte Reduktion von Bewegungsartefakten im Vergleich zu einem bereits vorhandenen Koregistrierungsansatz wurde anhand verschiedener Messungen mit bewegten radioaktiven Quellen und bestrahlten Phantomen sowie einer vergleichenden Simulationsstudie dargelegt. Für die Experimente wurden entsprechende Phantomgeometrien (zumeist aus Polymethylmethacrylat (PMMA)) sowie ein Bewegungstisch für reguläre eindimensionale (1D) Bewegungsmuster entworfen und gefertigt. Zudem wurde durch die erfolgreiche, quasi-statische und nahezu artefaktfreie Rekonstruktion einer rotierenden und sich damit zweidimensional bewegenden Aktivitätsverteilung die prinzipielle Anwendbarkeit des 4D MLEM Algorithmus für komplexere Bewegungsmuster gezeigt. Systematische Punktquellenmessungen mit 1D cos^2- und cos^4-förmigen Bewegungsmustern haben deutlich gemacht, dass der Bewegungseinfluss mit der gleichen Anzahl an Bewegungsphasen besser kompensiert werden kann, wenn die Bewegungsphasen entsprechend der Bewegungsamplitude anstelle der -phase unterteilt sind. In jedem Fall können aber zufriedenstellende Rekonstruktionsergebnisse erzielt werden, wenn durch geeignete Parameterwahl eine mittlere Restbewegung pro Bewegungsphase von maximal etwa der halben Größe eines Detektorkristalls eingestellt wird. Durch weitere Experimente konnte gezeigt werden, dass nach der Rekonstruktion mit dem 4D MLEM Algorithmus die relevanten Parameter für die qualitative Dosisverifikation (Teilchenreichweite, laterale Feldposition und -gradienten) zuverlässig erfasst werden können. Dies ist auch dann der Fall, wenn nur eine verminderte Anzahl an Koinzidenzereignissen, so wie sie unter klinischen Bedingungen zu erwarten ist, für die Auswertung verwendet wird. Um die gemessene β+-Aktivitätsverteilung besser zu beurteilen, sollte sie mit einer simulierten, für die bewegungskompensierte Bestrahlung erwarteten Verteilung verglichen werden und es bedarf deshalb einer 4D Version der Simulationssoftware. Diese muss die Erzeugung sowie den Zerfall der Positronenemitter unter Berücksichtigung der intrafraktionellen Bewegung simulieren und aus den gültigen Koinzidenzereignissen Listmode-Datensätze erstellen. Eine derart überarbeitet Version des Simulationsprogramms wurde für den Bastei PET-Scanner erstellt und wird in dieser Arbeit vorgestellt. Informationen über den exakten Verlauf der bewegungskompensierten Bestrahlung werden durch das Therapiekontrollsystem geliefert. Diese Informationen sowie die intrafraktionelle Bewegung werden in die Simulation realistischer β+-Aktivitätsverteilungen bzw. der zugehörigen Listmode-Datensätze einbezogen. Anhand einer präklinischen Phantom-Simulationsstudie wurde die korrekte Funktionsweise des Simulationsprogramms sowie die Notwendigkeit der zusätzlichen Parameter gezeigt. Im Gegensatz zur Datenauswertung für statische Zielvolumina bedarf es bei intrafraktioneller Bewegung gegebenenfalls zusätzlichen Aufwand, um eine Fehlinterpretation aus dem Vergleich der gemessenen und simulierten β+-Aktivitätsverteilung zu vermeiden. In der vorliegenden Arbeit wird beispielhaft gezeigt, dass sich bei fehlerhafter Bewegungskompensation die gemessene und simulierte β+-Aktivitätsverteilung einander ähneln können, obwohl die applizierte Dosisverteilung deutlich von der geplanten abweicht. Im Gegensatz dazu können auch Abweichungen zwischen Messung und Simulation auftreten, die nicht auf anatomische Veränderungen, sondern auf eine ungenaue 4D Datenverarbeitung zurückzuführen sind. Es werden Vorschläge unterbreitet, um den Prozess der 4D IBT-PET Datenauswertung zu optimieren und somit Fehlinterpretationen zu vermeiden. Die vorliegende Dissertationsschrift enthält durch die Bereitstellung der benötigten 4D Rekonstruktions- und Simulationsprogramme grundlegende Arbeiten für eine mögliche zukünftige Anwendung der 4D IBT-PET als qualitatives Dosismonitoring bei intrafraktionell bewegten Zielvolumina. Für weitere Verbesserungen des Verfahrens sind zusätzliche systematische Betrachtungen mit realistischeren, mehrdimensionalen und unregelmäßigen Bewegungsmustern notwendig. Zukünftige Untersuchungen sollten außerdem echte Bestrahlungspläne, Atemkurven sowie 4D Patienten-CT-Daten einschließen, um den erwartbaren Nutzen eines 4D IBT-PET Dosismonitorings besser abschätzen zu können.

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The effect of orientation and crystallinity of certain polymers, polyethylene, polypropylene, polyethylene terephthalate (PET) and poly (ether ether ketone) (PEEK) , upon the extent and nature of plasma oxidation was studied. It was found that increasing the extent of surface ordering lessened susceptibility to plasma oxidation and reduced the subsequent decay of surface treatment. The surface ageing of plasma oxidised PEEK was extensively studied with regards to the transient increase in hydrophilicity that has been observed after plasma modification. The decay and transient increase in hydrophilicity were found to be dependent upon crystallinity and storage temperature. An estimate of the activation energies for processes leading to the increase in contact angle after plasma modification were calculated and found to suggest that these processes were rotational reorganisations at the surface as opposed to migrational reorganisations. The decay of other plasma modified surfaces revealed that plasma oxidised PET and plasma fluorinated PEEK both underwent transitional reorganisations at the surface, however no such change was observed for ammonia plasma treated PEEK. Plasma modification of carbon fibres was investigated with regards to improving composite performance. Microwave plasma treatments were found to be as good as standard commercial treatments. Graphitic carbon was investigated as a model for carbon fibre surfaces, however, the plasma modified surface was found to age more readily and to be too labile for useful comparison.