<p>Cardiac arrhythmias triggered by both reentrant and focal sources are closely correlated with regions of tissue characterized by significant structural heterogeneity. Experimental and modeling studies of electrical activity in the heart have shown that local microscopic heterogeneities which average out at the macroscale in healthy tissue play a much more important role in diseased and aging cardiac tissue which have low levels of coupling and abnormal or reduced membrane excitability. However, it is still largely unknown how various combinations of microheterogeneity in the intracellular and interstitial spaces affect wavefront propagation in these critical regimes. </p> <p>This thesis uses biophysically realistic 1-D and 2-D computer models to investigate how heterogeneity in the interstitial and intracellular spaces influence both the initiation of ectopic beats and the escape of multiple ectopic beats from a poorly coupled region of tissue into surrounding well-coupled tissue. An approximate discrete monodomain model that incorporates local heterogeneity in both the interstitial and intracellular spaces was developed to represent the tissue domain. </p> <p>The results showed that increasing the effective interstitial resistivity in poorly coupled fibers alters the distribution of electrical load at the microscale and causes propagation to become more like that observed in continuous fibers. In poorly coupled domains, this nearly continuous state is modulated by cell length and is characterized by decreased gap junction delay, sustained conduction velocity, increased sodium current, reduced maximum upstroke velocity, and increased safety factor. In inhomogeneous fibers with adjacent well-coupled and poorly coupled regions, locally increasing the effective interstitial resistivity in the poorly coupled region reduces the size of the focal source needed to generate an ectopic beat, reduces dispersion of repolarization, and delays the onset of conduction block that is caused by source-load mismatch at the boundary between well-coupled and poorly-coupled regions. In 2-D tissue models, local increases in effective interstitial resistivity as well as microstructural variations in cell arrangement at the boundary between poorly coupled and well-coupled regions of tissue modulate the distribution of maximum sodium current which facilitates the unidirectional escape of focal beats. Variations in the distribution of sodium current as a function of cell length and width lead to directional differences in the response to increased effective interstitial resistivity. Propagation in critical regimes such as the ectopic substrate is very sensitive to source-load interactions and local increases in maximum sodium current caused by microheterogeneity in both intracellular and interstitial structure.</p> / Dissertation

<p>Digital tomosynthesis (DTS) is a quasi-three-dimensional (3D) imaging technique which reconstructs images from a limited angle of cone-beam projections with shorter acquisition time, lower imaging dose, and less mechanical constraint than full cone-beam CT (CBCT). However, DTS images reconstructed by the conventional filtered back projection method have low plane-to-plane resolution, and they do not provide full volumetric information for target localization due to the limited angle of the DTS acquisition. </p><p>This dissertation presents the optimization and clinical implementation of image guided radiation therapy using limited-angle projections.</p><p>A hybrid multiresolution rigid-body registration technique was developed to automatically register reference DTS images with on-board DTS images to guide patient positioning in radiation therapy. This hybrid registration technique uses a faster but less accurate static method to achieve an initial registration, followed by a slower but more accurate adaptive method to fine tune the registration. A multiresolution scheme is employed in the registration to further improve the registration accuracy, robustness and efficiency. Normalized mutual information is selected as the criterion for the similarity measure, and the downhill simplex method is used as the search engine. This technique was tested using image data both from an anthropomorphic chest phantom and from head-and-neck cancer patients. The effects of the scan angle and the region-of-interest size on the registration accuracy and robustness were investigated. The average capture ranges in single-axis simulations with a 44° scan angle and a large ROI covering the entire DTS volume were between -31 and +34 deg for rotations and between -89 and +78 mm for translations in the phantom study, and between -38 and +38 deg for rotations and between -58 and +65 mm for translations in the patient study.</p><p>Additionally, a novel limited-angle CBCT estimation method using a deformation field map was developed to optimally estimate volumetric information of organ deformation for soft tissue alignment in image guided radiation therapy. The deformation field map is solved by using prior information, a deformation model, and new projection data. Patients' previous CBCT data are used as the prior information, and the new patient volume to be estimated is considered as a deformation of the prior patient volume. The deformation field is solved by minimizing bending energy and maintaining new projection data fidelity using a nonlinear conjugate gradient method. The new patient CBCT volume is then obtained by deforming the prior patient CBCT volume according to the solution to the deformation field. The method was tested for different scan angles in 2D and 3D cases using simulated and real projections of a Shepp-Logan phantom, liver, prostate and head-and-neck patient data. Hardware acceleration and multiresolution scheme are used to accelerate the 3D estimation process. The accuracy of the estimation was evaluated by comparing organ volume, similarity and pixel value differences between limited-angle CBCT and full-rotation CBCT images. Results showed that the respiratory motion in the liver patient, rectum volume change in the prostate patient, and the weight loss and airway volume change in the head-and-neck patient were accurately estimated in the 60° CBCT images. This new estimation method is able to optimally estimate the volumetric information using 60-degree projection images. It is both technically and clinically feasible for image-guidance in radiation therapy.</p> / Dissertation

La procédure de Ross: Propriétés biomécaniques de l'artère pulmonaire en fonction du phénotype valvulaire aortique Pierre Olivier Dionne, Evan Wener, Alexander Emmott, Raymond Cartier, Rosaire Mongrain, Richard Leask et Ismail El-Hamamsy OBJECTIFS: Le but de cette étude est de déterminer si les propriétés des artères pulmonaires des patients bénéficiant d'une procédure de Ross ayant une valve aortique bicuspide sont différentes que celles des patients ayant une valve aortique tricuspide. MÉTHODOLOGIE: Trente-deux artères pulmonaires et 20 aortes ont été prélevées chez des patients subissant une procédure de Ross au moment de la chirurgie, dans une cohorte de 32 patients. L'analyse histologique et l'étude tensile equi-biaxiale ex-vivo complétées dans les 8 heures suivant le prélèvement furent utilisées afin d'évaluer les différences entre les groupes de patients et entre les artères pulmonaires et les aortes ascendantes. RÉSULTATS: Il n'y avait aucune différence d'épaisseur au niveau des artères pulmonaires lorsque comparées en fonction du phénotype valvulaire aortique (P = 0.94). Il n'y avait aucune différence au niveau des propriétés tensiles parmi les aortes et les artères pulmonaires lorsque comparées en fonction du phénotype valvulaire. Lorsque comparées en fonction de leur indication chirurgicale, les artères pulmonaires de patients ayant une régurgitation aortique pure étaient moins rigides que leur contre-partie (P = 0.002). Il n'y avait aucune différence au niveau du nombre de lamelles élastiques entre les spécimens d'artère pulmonaire en fonction du phénotype valvulaire aortique (Tricuspide, bicuspide ou unicuspide), ni entre les spécimens aortiques. CONCLUSION: Aucune différence significative ne fut observée au niveau des propriétés biomécaniques des artères pulmonaires lorsque comparées selon leur phénotype valvulaire aortique associé. / The Ross procedure: biomechanical properties of the pulmonary artery according to aortic valve phenotype Pierre Olivier Dionne, Evan Wener, Alexander Emmott, Raymond Cartier, Rosaire Mongrain, Richard Leask and Ismail El-Hamamsy OBJECTIVES: The aim of this study is to determine whether patients undergoing the Ross procedure with bicuspid aortic valves have different pulmonary artery biomechanical properties from those with tricuspid valves. METHODS: Thirty-two pulmonary arteries and 20 aortas were obtained from patients undergoing the Ross procedure at the time of surgery, from a cohort of 32 patients. Histological analysis and ex vivo equi-biaxial tensile testing completed within 8 hours of surgery were used to evaluate differences in patient groups and between the pulmonary artery and the ascending aorta. RESULTS: There was no difference in thickness among pulmonary arteries when compared according to aortic valve phenotype (P = 0.94). There was no difference in the tensile tissue properties among aortas and pulmonary arteries when compared according to aortic valve phenotype, in either the circumferential or longitudinal axis. When compared according to the main surgical indication, pulmonary artery walls from patients with pure aortic regurgitation were less stiff than their counterparts (P = 0.002). There was no difference in the number of elastic lamellae in pulmonary artery specimens from the three different aortic valve phenotypes (Tricuspid, bicuspid or unicuspid), as well as in the aortic specimens. CONCLUSION: No significant differences were observed in the biomechanical properties of pulmonary arteries when compared according to aortic valve phenotype.

Superbursts (SBs) are large, seemingly spontaneous activity fluctuations often encountered in high density neural networks in vitro. Little effort has been put forth to define and analyze SBs which are paroxysmal bursting discharges. Through qualitative and quantitative means, I have described specific occurrences of superbursting activity. A complex of paroxysmal bursting has been termed a "superburst episode," and each individual SB is a "superburst event" which is comprises a fine burst structure. Quantitative calculations (employing overall spike summations and coefficient of variation (CV) calculations), reveal three distinct phases. Phase 1 is a "build up" phase of increasingly strong, coordinated bursting with an average of a 17.6% ± 13.7 increase in activity from reference. Phase 2, the "paroxysmal" phase, is comprised of massive coordinated bursting with high frequency spike content. Individual spike activity increases by 52.9% ± 14.6. Phase 3 is a "recovery phase" of lower coordination and an average of a 50.1% ± 35.6 decrease in spike production from reference. SBs can be induced and terminated by physical manipulation of the medium. Using a peristaltic pump with a flow rate of 0.4ml/min, superbursting activity ceases approximately 28.3 min after the introduction of flow. Alternatively, upon cessation of medium flow superbursting activity reemerges after approximately 8.5 min. Additionally, this study explored other methods capable of inducing superbursting activity using osmotic shocks. The induction and termination of SBs demonstrates that the cell culture environment plays a major role in generating this phenomenon. The observations that high density multi-layer neuronal networks in culture are more likely to enter paroxysmal bursting also supports the hypothesis that enrichment and depletion layers of metabolites and ionic species are involved in such unusual activity. The dynamic similarity of the SB phenomenon with epileptiform discharges make further quantification on the spike pattern level pertinent and important.

No description available.

No description available.

<p>The ability to image ventilation and perfusion enables pulmonary researchers to study functional metrics of gas exchange on a regional basis. There is a huge interest in applying imaging methods to study the large number of genetic models of pulmonary diseases available in small animals. Existing techniques to image ventilation and perfusion are often associated with low spatial resolution and ionizing radiation. Magnetic Resonance Imaging (MRI) has been demonstrated successfully for ventilation and perfusion studies in humans. Translating these techniques in small animals remains challenging. This work addresses the ventilation and perfusion imaging in small animals using MRI. </p><p>Qualitative ventilation imaging in rats and mice is possible and has been demonstrated using MRI, however perfusion imaging remains a challenge. In humans and large animals perfusion can be assessed using dynamic contrast-enhanced (DCE) MRI with a single bolus injection of a gadolinium (Gd)-based contrast agent. But the method developed for the clinic cannot be translated directly to image the rat due to the combined requirements of higher spatial and temporal resolution. This work describes a novel image acquisition technique staggered over multiple, repeatable bolus injections of contrast agent using an automated microinjector, synchronized with image acquisition to achieve dynamic first-pass contrast enhancement in the rat lung. This allows dynamic first-pass imaging that can be used to quantify pulmonary perfusion. Further improvements are made in the spatial and temporal resolution by combining the multiple injection acquisition method with Interleaved Radial Imaging and 'Sliding window-keyhole' reconstruction (IRIS). The results demonstrate a simultaneous increase in spatial resolution (<200>um) and temporal resolution (<200>ms) over previous methods, with a limited loss in signal-to-noise-ratio. </p><p>While is it possible to create high resolution images of ventilation in rats using hyperpolarized ³He, extracting meaningful quantitative information indicative of changes in ventilation is difficult. In this work, we also present a signal calibration technique used to normalize the signal of ³He to volume of ³He which can then be used to extract quantitative information of changes in ventilation via normalized difference maps. Combining the techniques for quantitative ventilation and quantitative perfusion we perform studies of change in ventilation/perfusion (V/Q) before and after airway obstruction in rats. The technique is sensitive in detecting statistically significant differences in the heterogeneity of the distribution of V/Q ratio.</p> / Dissertation

<p>Traditional dosimetric devices are inherently point dose dosimeters (PDDs) and can only measure the magnitude of the radiation exposure; hence, they are one-dimensional (1D). To measure the magnitude and spatial location of dose within a volume either several PDDs must be used at one time, or one PDD must be translated from point-to-point. Using PDDs for spatially distributed, two-dimensional (2D), dosimetry is laborious, time consuming, limited in spatial resolution, susceptible to positioning errors, and the currently accepted approach to measuring dose distribution in 2D. This work seeks to expand the current limits of indirectly ionizing radiation dosimetry by using radiochromic film (RCF) for a high-resolution, accurate dosimetry system. Using RCF will extend the current field of radiation dosimetry to spatially quantitative 2D and three-dimensional (3D) measurements. </p> <p>This work was generalized into two aims. The first aim was the development of the RCF dosimetry system; it was accomplished by characterizing the film and the readout devices and developing a method to calibrate film response for absolute dose measurements. The second aim was to apply the RCF dosimetry system to three areas of dosimetry that were inherently volumetric and could benefit from multiple dimensional (2D or 3D) dose analysis. These areas were representative of a broad range of radiation energy levels and were: low-mammography, intermediate-computed tomography (CT), and high-radiobiologcal small animal irradiation and cancer patient treatment verification. The application of a single dosimeter over a broad range of energy levels is currently unavailable for most traditional dosimeters, and thus, was used to demonstrate the robustness and flexibility of the RCF dosimetry system.</p> <p>Two types of RCF were characterized for this work: EBT and XRQA film. Both films were investigated for: radiation interaction with film structure; light interaction with film structure for optimal film readout (densitometry) sensitivity; range of absorbed dose measurements; dependence of film dose measurement response as a function of changing radiation energy; fractionation and dose rate effects on film measurement response; film response sensitivity to ambient factors; and stability of measured film response with time. EBT film was shown to have the following properties: near water equivalent atomic weight (Z_eff); dynamic dose range of (10<super>-1</super>-10<super>2</super>) Gy; 3% change in optical density (OD) response for a single exposure level when exposed to radiation energies from (75-18,000) kV; and best digitized using transmission densitometry. XRQA film was shown to have: a Zeff of ~25; a 12 fold increase in sensitivity at lower photon energies for a dynamic dose range of 10-3-100 Gy, a difference of 25% in OD response when comparing 120 kV to 320 kV, and best digitized using reflective densitometry. Both XRQA and EBT films were shown to have: a temporal stability (&#916;OD) of ~1% for t > 24 hr post film exposure for up to ~20 days; a change in dose response of ~0.03 mGy hr-1 when exposed to fluorescent room lighting at standard room temperature and humidity levels; a negligible dose rate and fractionation effect when operated within the optimal dose ranges; and a light wavelength dependence with dose for film readout.</p> <p>The flat bed scanner was chosen as the primary film digitizer due to its availability, cost, OD range, functionality (transmission and reflection scanning), and digitization speed. As a cost verses functionality comparison, the intrinsic and operational limitations were determined for two flat bed scanners. The EPSON V700 and 10000XL exhibited equal spatial and OD accuracy. The combined precision of both the scanner light sources and CCD sensors measured < 2% and < 7% deviation in pixel light intensities for 50 consecutive scans, respectively. Both scanner light sources were shown to be uniform in transmission and reflection scan modes along the center axis of light source translation. Additionally, RCFs demonstrated a larger dynamic range in pixel light intensities, and to be less sensitive to off axis light inhomogeneity, when scanned in landscape mode (long axis of film parallel with axis of light source translation). The EPSON 10000XL demonstrated slightly better light source/CCD temporal stability and provided a capacity to scan larger film formats at the center of the scanner in landscape mode. However, the EPSON V700 only measured an overall difference in accuracy and precision by 2%, and though smaller in size, at the time of this work, was one sixth the cost of the 10000XL. A scan protocol was developed to maximize RCF digitization accuracy and precision, and a calibration fitting function was developed for RCF absolute dosimetry. The fitting function demonstrated a superior goodness of fit for both RCF types over a large range of absorbed dose levels as compared to the currently accepted function found in literature.</p> <p>The RCF dosimetry system was applied to three novel areas from which a benefit could be derived for 2D or 3D dosimetric information. The first area was for a 3D dosimetry of a pendant breast in 3D-CT mammography. The novel method of developing a volumetric image of the breast from a CT acquisition technique was empirically measured for its dosimetry and compared to standard dual field digital mammography. The second area was dose reduction in CT for pediatric and adult scan protocols. In this application, novel methodologies were developed to measure 3D organ dosimetry and characterize a dose reduction scan protocol for pediatric and adult body habitus. The third area was in the field of small animal irradiation for radiobiology purposes and cancer patient treatment verification. Two methods for small animal irradiation were analyzed for their dosimetry. The first technique was within a gamma irradiator environment using a <super>137</super>Cs source (663 keV), and the second, a novel approach to mouse irradiation, was developed for fast neutron (10 MeV) irradiated by a Tandem Van de Graff accelerator in a <super>2</super>H(d,n)<super>3</super>He reaction. For the patient cancer treatment, RCF was used to verify a 3D radiochromic plastic, PRESAGETM, using multi-leaf collimation (MLC) on a medical linear accelerator (LINAC) with 6 MV x-rays. The RCF and PRESAGE<super>TM</super> dosimeters were employed to verify a simple respiratory-gated lung treatment for a small nodule; the film was considered the gold standard. In every case, the RCF dosimetry system was verified for accuracy using a traditional PDD as the golden standard. When considering all areas of radiation energy applications, the RCF dosimetry system agreed to better than 7% of the golden standard, and in some cases within better than 1%. In many instances, this work provided vital dosimetric information that otherwise was not captured using the PDD in similar geometry. This work demonstrates the need for RCF to more accurately measure volumetric dose.</p> / Dissertation

Une mutation du gène SYN1 a récemment été découverte chez plusieurs membres d'une grande famille canadienne-française ségréguant troubles du langage, épilepsie focale, et troubles du spectre autistique (TSA). Bien qu'aucune anomalie macroscopique apparente n'ait pu être identifiée dans les données d’imagerie par résonance magnétique (IRM) cérébrales, nous avons émis l'hypothèse que des modalités d'IRM quantitatives sensibles à la microstructure et à la composition des tissus permettraient l’identification d’anomalies subtiles. Nous avons fait l’acquisition de données IRM multimodale chez 13 sujets porteurs de la mutation SYN1_Q555x et 13 sujets contrôles appareillés pour l’âge et le sexe. Une analyse statistique de groupe a été effectuée sur les cartes paramétriques corticales surfaciques afin de caractériser l’effet de la mutation sur plusieurs paramètres physiques quantitatifs. En résumé, des altérations ont été observées dans le réseau langagier, de même qu’une latéralisation anormale de celui-ci sur l’hémisphère droit. Les changements les plus significatifs dans ces régions sont une diminution de la diffusivité moyenne et une augmentation de l’anisotropie fractionnelle. Un modèle biophysique est proposé pour expliquer ces résultats, qui suggèrent une augmentation de la densité ou de la fraction volumique du neuropile. Cette étude est, à notre connaissance, la première à utiliser avec succès l'imagerie de diffusion et multiparamétrique conjointement à une méthodologie de cartographie surfacique pour détecter des anomalies corticales chez un groupe de sujets avec un génotype bien défini lié aux troubles du langage, à l'épilepsie et aux TSA. Cette étude démontre également que l'IRM de diffusion, bien que traditionnellement considérée comme une modalité spécifique à la matière blanche, peut effectivement être utilisée conjointement à une cartographie de surface pour caractériser une pathologie corticale subtile non détectable autrement, même si seul un groupe relativement restreint de sujets est disponible. / A mutation of the SYN1 gene has recently been discovered in several members of a large French-Canadian family segregating language disorders, focal epilepsy, and autism spectrum disorders (ASD). Although no apparent macroscopic abnormality could be identified in brain magnetic resonance imaging (MRI) data, we hypothesized that quantitative MRI modalities sensitive to tissue microstructure and composition could allow the identification of subtle anomalies. We acquired multimodal MRI data from 13 SYN1_Q555x mutation carriers and 13 healthy controls matched for age and sex. A surface-based group statistical analysis was performed on the cortical parametric maps to characterize the effect of the mutation on several quantitative physical parameters. In summary, alterations were found in the language network, as well as abnormal lateralization of the latter over the right hemisphere. The most significant changes in these regions are a decrease in mean diffusivity and an increase in fractional anisotropy. A biophysical model is proposed to explain these results, which suggest an increase in neuropil density or volume fraction. This study is, to our knowledge, the first to successfully use diffusion imaging and multiparametric mapping in a surface-based approach to detect cortical anomalies in a group of subjects with a well-defined genotype linked to language impairments, epilepsy and ASD. Importantly, this study also shows that diffusion MRI, although traditionally seen as a white matter modality, can effectively be used in a surface-based approach to characterize subtle cortical pathology not detectable otherwise, even when only a relatively small group of subjects is available.

A ballistic pendulum impulse generator was used to impact networks in primary culture growing on microelectrode arrays. This approach has the advantage of imparting pure tangential acceleration insults (50 to 300 g) with simultaneous morphological and electrophysiological multichannel monitoring for days before and after the impact. Action potential (AP) production, network activity patterns, and cell electrode coupling of individual units using AP waveshape templates were quantified. Network adhesion was maintained after tangential impacts up to 300g with minimal loss of pre-selected active units. Time lapse phase contrast microscopy revealed stable nuclei pre-impact, but post impact nuclear rotation in 95% of observations (n= 30). All recording experiments (n=31) showed a repeatable two-phase spike production response profile: recovery to near reference in 1-2 hrs, followed by a slow activity decay to a stable, level plateau approximately 30-40% below reference. Phase 1 consisted of a complex two-step recovery: rapid activity increase to an average 23.6% (range: 11-34%) below reference, forming a level plateau lasting from 5 to 20 min, followed by a climb to within 20% of reference where a second plateau was established for 1 to 2 hrs. Cross correlation profiles showed changes in firing hierarchy after impact, and in spontaneous network oscillatory activity. Native oscillations were found in the Delta band (2 to 3 Hz), and decreased by approximately 20% after impact. Under network disinhibition with bicuculline, oscillations were slower (0.8-1Hz) and decreased 40% after impact. These data link network performance deficits with microscopically observable subcellular changes.